Halogenated unsaturated alkyl benzenedisulfonamides as anthelmintics

#Many sulfonamides, especially benzenedisulfonamide compounds have been known in the art for many years. They have been generally prepared and studied for their activity as antibacterial and diuretic agents and much data is published concerning the bacteriostatic and diuretic activity of sulfonamide compounds. In addition, certain benzenedisulfonamides have been prepared as intermediates in the preparation of diuretic agents having substantial diuretic activity. Said diuretic agents have not been disclosed as having any anthelmintic activity. The instant benzenedisulfonamides, however, are novel compounds not having been disclosed in the prior art.

#The novel anthelmintic compounds of this invention are classified generally as benzenedisulfonamides. Specifically they may be described as 4-amino-6-substituted-1,3-benzenedisulfonamides. Said compounds have significant and unexpected anthelmintic activity and in particular demonstrate high activity against Fasciola or liver fluke in animals. The instant compounds also possess significant parasiticidal activity.

#Thus, it is an object of this invention to provide for novel anthelmintic compounds. A further object of this invention is to provide for novel substituted benzenedisulfonamide compounds which have significant anthelmintic and fasiolicidal activity. A still further object of this invention is to provide for processes for the preparation of said novel substituted benzenedisulfonamides. Another object is to provide for compositions and methods of treatment which contain said novel substituted benzenedisulfonamides, and which are useful in the prevention and treatment of fascioliasis. Further objects will become apparent from the following description.

#32.8 G. of 2-(3-aminophenyl)-1,1,2-trichloro ethylene is added dropwise with stirring to 107 ml. of chlorosulfonic acid maintained at +10.degree. C. When the addition is completed, the reaction mixture is heated to 125.degree.-130.degree. and stirred at this temperature for 2 1/2 hours. Then it is cooled to 20.degree. C. and 40.2 ml. of thionylchloride is added in portions. After this, the reaction mixture is stirred at 80.degree. C. for 1 1/2 hours and then cooled in ice to +10.degree. C. The reaction mixture is poured onto ice and the 4-amino-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonylchloride is extracted into methylene chloride, washed with water, dried over MgSO.sub.4 and concentrated in vacuo to 52 g. of a brown foam. The brown solid is dissolved in 60 ml. of CH.sub.2 Cl.sub.2 and added in portions to 250 ml. of liquid ammonia. The excess ammonia and the methylene chloride are allowed to evaporate overnight. Water is added to the residue, and it is carefully acidified with concentrated HCl, giving an amorphous precipitate. This is extracted into ethyl acetate, washed with water, dried over MgSO.sub.4 and concentrated in vacuo to 45 g. of brown foam. This is extracted twice with hot benzene leaving 38.5 g. of brown solids. The residue is extracted three times by boiling with 1000 ml. portions of ether, and the ether solutions are concentrated in vacuo to 250 ml., and crystalline product is precipitated by careful addition of hexane giving after filtration 20.8 g. of product -- ether complex with melting point of 130.degree.-135.degree.. This is boiled with 175 ml. of water, without dissolving much of the compound for 1/2 hour then allowed to come to room temperature, filtered washed with water, dried in vacuo at 50.degree. C. to give 17.0 g. of 4 -amino-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonamide with m.p. 188.degree.-193.degree. C. A small sample is recrystallized for analysis from aqueous methanol to melt at 205.degree.-207.degree..

#10G. of 4-amino-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonylchloride prepared as in example 1A is added to 150 ml. of liquid methylamine at -78.degree. C. When the addition is completed, the cooling bath is removed and the excess methylamine is allowed to evaporate. The solid residue is taken up in water and acidified with acetic acid. A dark precipitate is collected by filtration and dried to give 7.4 g. of crude product. Purification by chromatography on a silica gel column and crystallization from ethanol gives 2.9 g. of 4-amino-N.sup.1, N.sup.3 -dimethyl-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonamide with a m.p. of 211.degree. to 212.degree. C.

#10 G. of 4-amino-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonylchloride prepared as in example 1A is treated with 125 ml. of dimethylamine. The reaction mixture is worked up in a manner similar to example 1B affording 5.2 g. of pure 4-amino-N.sup.1, N.sup.1, N.sup.3, N.sup.3 -tetramethyl-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonamide with a m.p. of 238.degree. to 239.degree. C.