CH595365A5 - Anthelmintic piperazinyl-benzal-azinium methanesulphonate derivs. - Google Patents

Abstract

In a process for preparing new benzalazinium-methane-sulphonates of formula (I): (where R1 is H, Cl, Br, I, F, NO2, CN, CF3, COOH, OH, amino, lower alkoxy, lower carbalkoxy or lower prim. or sec. amino; and R2 is H, lower alkyl, lower alkenyl, cycloalkyl or (lower alkoxy)-(lower alkyl)), an azine of formula (II) is reacted with a cpd. of the formula HO-CH2-SO3M (III) (where M is an alkali metal).(I) have low toxicity coupled with anthelmintic activity, partic. against trematodes, esp. schistosomes and liver flukes. A specific cpd. (Ie is that in which R1 is Cl and R2 is H. In an example, this is prepd. by reacting (II); R1=Cl, R2=H) in water with (III); M=Na) at 85 degrees C.

Description

  

  
 



  The invention relates to a process for the preparation of piperazinobenzalazinium methanesulfonates of the formula I.
EMI1.1
 wherein R1 represents hydrogen, chlorine, bromine, iodine, fluorine, the nitro, cyano, trifluoromethyl, carboxyl, hydroxy, amino, a lower alkoxy, a lower carbalkoxy or a lower primary or secondary amino group, R2 represents hydrogen, a lower alkyl, a lower alkenyl, a cycloalkyl or a lower (lower alkoxy) alkyl group, both R1 and R2 each having the same meaning.



   According to the invention, the compounds of the formula I are obtained by adding a compound of the formula II,
EMI1.2
 in which R1 and R2 have the above meaning with a compound of the formula III, HOCH2O3-Me III in which Me is an alkali metal, is reacted.



   The inventive method can, for. B. in an inert solvent under the reaction conditions, e.g. B. in dimethylformamide, at room temperature or at elevated temperature, e.g. B. at 80 C, carried out. The end product can be obtained from the reaction mixture by known methods.



   The compounds of the formula I can be converted into their acid addition salts and vice versa.



   The lower alkyl groups appearing as substituents preferably have 1 to 4, in particular 1 to 2, carbon atoms. The lower alkenyl groups symbolized by R2 preferably have 3 to 6 carbon atoms and are in particular the allyl group. The cycloalkyl groups represented by R2 preferably have 5 to 7 ring members.



   The compounds of the formula I and their pharmacologically acceptable acid addition salts have interesting chemotherapeutic properties with low toxicity and can therefore be used as medicaments. They develop an inhibitory effect against helminths, preferably against trematodes, in particular against schistosomes and liver shelves.



   The action against schistosomes can be demonstrated by in vivo tests on mice and hamsters and was achieved in a dose range between 5 and 150 mg / kg body weight once a day for 5 consecutive days with oral and / or parenteral administration. The experimental methods used corresponded to those of J. Pellegrino and Naftale Katz (Advances in Parasitology Vol. 6, 223-290, 1968) and R.H. Duvall and W.B. De Witt (Am. J. Trop. Med. Hyg. 16, 483-486, 1967). The experimental animals used were albino mice and hamsters which had been infected subcutaneously with 100 + 10 and 60 + 10 cercariae of Schistosoma mansoni (Liberia strain).



   The effectiveness against liver fluke was demonstrated by the method of G. Lämmler (Z. Tropenmed. Parasit. 10, 379, 1959) in Fasciola hepatica in the rat model by oral treatment of the animals with a dose of about 100 mg / kg body weight.



   The compounds of the formula I and, if appropriate, their water-soluble, physiologically tolerable salts, alone or in suitable pharmaceutical forms together with inorganic or organic, pharmacologically indifferent auxiliaries for curing various forms of schistosomiasis and fascioliasis in humans and animals can be administered chemotherapeutically as medicaments. For example, they are used as a component of capsules, tablets or an injection solution, the capsules or tablets z. B. may contain 10 to 500 mg of active ingredient per capsule or tablet.



   The compounds of the formula II required as starting materials can be obtained by adding a compound of the formula IV,
EMI1.3
 wherein R1 and R2 have the above meaning, reacts with hydrazine.



   This reaction can advantageously be carried out in a solvent which is inert under the reaction conditions, e.g. B. in water or organic solvents containing hydroxyl groups, such as lower alcohols, at room temperature or elevated temperature, e.g. B. between 40 and 1200 C, preferably between 80 and 1200 C.



   If the production of the starting products is not described, these are known or can be produced by processes known per se or analogously to those described here or analogously to processes known per se.

 

   In the following example, which explains the invention in more detail but is not intended to limit its scope in any way, all temperatures are given in degrees Celsius.



   Example (2-Chloro-4 (1) -piperazinobenzalazinium) -methanesulfonate
5.58 g of 2-chloro-4 (1) -piperazinobenzalazine were suspended in 75 ml of water and 12.5 ml of 3N sodium hydroxymethanesulfonate were added with vigorous stirring. The batch is kept at 85 ° C. for 90 minutes, cooled, filtered and stirred with 40 ml of 1N acetic acid. It is filtered again, washed with a little water, ethanol and ether and dried. Melting point: 2400 ° C. (decomp.).

 

Claims (1)

PATENT CLAIM Process for the preparation of piperazinobenzalazinium methanesulfonates of the formula I, EMI2.1 where R1 represents hydrogen, chlorine, bromine, iodine, fluorine, the nitro, cyano, trifluoromethyl, carboxyl, hydroxy, amino, a lower alkoxy, a lower carbalkoxy or a lower primary or secondary amino group, R2 represents hydrogen, a lower alkyl, a lower alkenyl, a cycloalkyl or a lower (lower alkoxy) alkyl group, where both R and both R2 each have the same meaning, characterized in that a compound of the formula II, EMI2.2 in which Rl and R2 have the above meaning with a compound of the formula III, HO-CH2-SO3-Me III in which Me is an alkali metal, is reacted.