CH577487A5 - Anthelmintic piperazino-benzaldehyde derivs prepn. - by reacting 4-piperazino-benzaldehydes with (thio)carbohydrazide - Google Patents

Abstract

Piperzainobenzaldehyde derivs. of formula (I): (where R1 is H, Cl, Br, I, F, NO2, CN, CF3, COOH, OH, NH2, lower alkoxy, lower carbalkoxy or substd. amino; R2 is H, lower alkyl, lower alkenyl, cycloalkyl or (lower alkoxy)-(lower alkyl); X is O, S, or NH); e.g. 2-chloro-4-(1-piperazinyl)benzalthiocarbohydrazone, are predp. by reacting a cpd. of formula (II) with a cpd. of formula (III). (I) and their pharmacologically tolerable acid addn. salts combine low toxicity with anthelmintic activity. They are particularly active against trematodes, esp. schistosomes and liver flukes.

Description

  

  
 



   The invention relates to a process for the preparation of new piperazinobenzaldehyde derivatives of the formula 1 (see formula.



  sheet), where R1 is hydrogen, chlorine, bromine, iodine, fluorine, nitro, cyano, trifluoromethyl, carboxyl, hydroxy, amino, a lower alkoxy, a lower carbalkoxy or a substituted amino group, R2 represents hydrogen, a lower alkyl, a lower alkenyl, a cycloalkyl or a lower (lower alkoxy) alkyl group and X represents oxygen, sulfur or the imino group, where both R1 and both R each have the same meaning.



   According to the invention, the compounds of the formula I are obtained by reacting a compound of the formula II, in which R1 and R2 are as defined above, with a compound of the formula III, in which X is as defined above.



   The process according to the invention is advantageously carried out in a solvent which is inert under the reaction conditions, e.g. in water or organic solvents containing hydroxyl groups such as lower alcohols at elevated temperature, e.g. performed between 80 and 100 ".



   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 fluke.



   The action against schistosomes can be shown by in vivo experiments on mice and hamsters and was shown in tablets or tablets e.g. Can contain 10 to 500 mg of active ingredient per capsule or tablet.



   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 examples, which explain the invention in greater detail but are not intended to limit its scope in any way, all temperatures are given in degrees Celsius.



   Example I 2-chloro-4- (1) -piperazinobenzaithiocarbohydrazone:
7.85 g of 2-chloro-4- (1) -piperazinobenzaldehyde hydrochloride are dissolved in 60 ml of water while hot, and 2.1 g of solid thiocarbohydrazide are added in portions. 0.5 ml of concentrated hydrochloric acid are then added and the batch is kept at 80 "for 20 minutes. After cooling, the pH is carefully adjusted first to pH 7, then to pH 9, and the amorphous precipitate is made to crystallize by grinding.



  The product is filtered off, washed with water, isopropanol and ether. M.p .: 1330 (decomp.).



   Example 2
2 -Chlor4- (1) - piperazinobenzalcarbokydrazone:
5.22 g of 2-chloro-4- (1) -piperazinobenzaldehyde hydrochloride are dissolved in 40 ml of water while hot, and 1.17 g of carbohydrazide are added in portions. After adding 2.6 ml of concentrated hydrochloric acid, the mixture is kept at 80 "for 30 minutes. The pH is then carefully adjusted to 10 in the cold and the resulting precipitate crystallized by rubbing and gentle heating. It is filtered off with water, isopropanol and ether rewashed.



  M.p .: 169-1710 (from dimethylformamide / water).
EMI1.1




  a dosage range between 5 and 250 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, 233-290, 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
EMI1.2
 

 

Claims (1)

PATENT CLAIM Process for the preparation of piperazinobenzaldehyde derivatives of the formula I, EMI2.1 where R1 is hydrogen, chlorine, bromine, iodine, fluorine, nitro, cyano, trifluoromethyl, carboxyl, hydroxy, amino, a lower alkoxy, a lower carbalkoxy or a substituted amino group, R2 is hydrogen, a lower alkyl, a lower alkenyl, a cycloalkyl or a lower (lower alkoxy) alkyl group and X stands for oxygen, sulfur or the imino group, where both R1 and both R2 each have the same meaning, characterized in that one Compound of formula II, EMI2.2 wherein R1 and R2 have the above meaning, with a compound of the formula III, EMI2.3 wherein X has the above meaning, converts.