DE1809225C - 1 (quinazohnyl) -4- (3 ", 4" methylenedioxy benzyiypiperazines and their acid addition salts - Google Patents

Description

The invention relates to 1- (quinazolinyl) -4- (3 ", 4" -me-Ihylenedioxybcnzyl-piperazines of the general formula I.

C)

CH ₁ - N

N-

(D

in which R is either a hydrogen atom or a ! Means methyl group, and their acid addition salts.

The new compounds of the invention are prepared by adding a compound of the general formula II

N-

(H)

in which R has the above meaning and Z is either a chlorine or bromine atom, with 1- (3'.4'-methylenedioxybenzyl) -piperazine in a high boiling point alcohol or aromatic amide or aromatic hydrocarbon solvent at temperatures of 80 to 140 C in the presence of an alkali or alkaline earth carbonate, a tertiary one organic base or an excess of the piperazine compound as an acceptor for the in the course of the Reaction formed acid converts.

Examples of suitable solvents are butanol or alcohols with a high boiling point Pentanol. for the amides dimethylformamide and for the aromatic hydrocarbons benzene and toluene or xylene. Suitable acid acceptors are, for example, sodium or potassium carbonate and calcium carbonate and dimethylaniline as the tertiary organic base. Pyridine or triethylamine.

The new compounds according to the invention are weak bases and can therefore be mixed with acids convert their addition salts. The addition salts can by the action of the invention Compounds on the acids in a suitable solvent, e.g. B. water or miscible with water Alcohols.

The acids which are suitable for the formation of the addition salts are from the series of mineral acids called: hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, from the Range of organic acids: acetic, propionic, maleic. Fumaric, wine, lemon, oxalic, benzoin or methanesulfonic acid, etc.

The new compounds can, if necessary, by physical methods such as distillation, crystallization, Chromatography or by chemical methods such as decomposition of the addition salts by alkaline agents.

The new compounds of the invention have pharmacological and therapeutic interest Properties and can be special * as peripheral vasodiiatator and bronchodiiatatorisclie agents be used.

The acute toxicity was determined in mice, with a DL ₅₀ of 50 to> 500 mg / kg for intraperitoneal administration and of 1200 to 3000 mg / kg for oral administration.

When administering 5 mg / kg of the new compounds intravenous perfusion in the rabbit produced a significant increase in blood volume at the Pfcte. which varies between 1/5 to 225% for the various connections; this shows a remarkable vasodiative effect.

The bronchodilator effectiveness was determined according to the method of K ο η ζ e 11 and R ο s s 1 e r [Arch. exp. Path. and Pharm., 195, 71 (1940)]. It has been found that the new compounds are able to by histamine, serotonin or Acetylcholine to counteract bronchospasm caused in guinea pigs. These spasms are inhibited by 66 to 100% by intravenous doses of 1 to 15 mg / kg.

Test report

The compounds of the invention are in terms of their vasodilator and bronchodilataloristhen Effectiveness of the known commercially available compounds with the same effectiveness or the chemically closest V-bonds the same Effectiveness superior to those given below Show comparative values.

t'ntcrsuchlc connection

Compound of Example I.

Connection of example la

Connection of example Ib

Raubasin (Ajmalicinc)

Choline theophyllinate

2- [r- (3 ", 4" -methylenedioxybenzyl) piperazinyl- (4 ')] pyrimidine

Toxi / itat

at the mouse

m »kg ι ρ > 5 (X)

~ 50

-75

210

190

690

V, Isodll, ιΙ, ιΙιοη Perfusion of the Rabbit paw

Ί mg kg ι ν *)

225%
175%

75%

125%

Bronchial dilatation histamine, Serotonin, * ■ rtyliholin

Si

Λ (

100%
66%

20%
55%

Hist Ser ιυυ% 90% 100% 100% 25% 30% 80% 65%

*) Percentage enlargement of the femoral volume.

**) According to the method of K ο η /. e 11 and R o s s I e r, percentage inhibition by histamine, serotonin and acetylcholine induced bronchospasm.

These properties allow the therapeutic use of these compounds, especially in the Treatment of peripheral circulatory disorders, e.g. B.

Inflammation of the veins or arteries as well as acute or chronic respiratory failure, especially bronchial asthma.

i 809 225

The following example serves to clarify the Process for the preparation of the invention Links.

The melting points were determined on the heating bench according to K o f I e r.

example

6 g of 2-chloroquinazoline of m.p. 102 "C and 8.01 g I-piperonylpiperazine, dissolved in 200 ml of dimethylform-umid, are heated to 130 ° C. for 8 hours in the presence of 10.06 g of dry potassium carbonate. Thereafter the solvent is removed under reduced pressure and the solid, brown, 16 g residue Dissolved 100 ml of 2N hydrochloric acid. The neutral substances are extracted with benzene and the acidic The solution was made alkaline with potassium carbonate. This gives 5 g of a precipitate with a melting point of 138 ° C.

Recrystallization from ethyl acetate finally gives 7.25 g of 1- (2'-quinazoliny!) - 4- (3 ", 4" -melhylenedioxybenzyl) piperazine obtained in the form of beige crystals, melting point 141'C (Kofier).

As described in the previous example, the following were produced:

a) 1 - (4 '- quinazolinyl) - 4 - (3 ", 4" - methylenedioxy _s benzylj-piperazine, starting from 4-chlorochi:' - azoline. The corresponding dichlorohydrate melts at 230 to 233 ° C.

bj I - (2 '- methyl - 4' - quinazolinyl) - 4 - (3 ".4" - methylenedioxybenzyl) - piperazine, starting from 2 ^ 611 ^ 1-4- ^ 10 ^ 11 ^ 201 ^. The corresponding Dichlorohydrate melts at 210 to 218T '.

Claims (1)

Claim: 1- (ChinazoIinyl) -4- (3 ", 4" -methylenediox> benzyl) -piperazine of the general formula I. CH ₂ -N in which R is either a hydrogen atom or a methyl group, and their acid addition salts.