DK142617B - Analogous process for the preparation of 4-amino-1,3-benzenedisulfonamides. - Google Patents

Description

(11) PUBLICATION 142617 DENMARK (ai) mt.c, .3 c 07 c U3 / 80 § (21) Application No, 2275/7 ^ (22) Filed on 25 · aPr · 197 ^ (24) Running day 25 · 3pF . 197 ^ (44) The application presented and the 1 q80 petition published on the '· · -7 DIRECTORATE FOR, _. u _ PATENT & TRADEMARKET (30) Wor.tet requested from May 11, 1973 * 359595s Us (71) MERCK & CO. INC., Rahway, New Jersey, US.

(72) Inventor: Helmut Hugo Mrozik, 159 Idlebrook Lane, Matawan, New Jersey, US.

(74) Plenipotentiary under the blessing:

Hofman-Bang & Boutard Engineering Company. ___ (54) Analogous Process for Preparation of 4-Amino-1, J-Benzenedisulfon53 Amides.

The present invention relates to an analogous process for the preparation of novel 4-amino-1,3-benzenedisulfonamides of the formula set forth in the preamble of claim. These compounds have been shown to be suitable for the treatment of hepatitis infections at various stages of development.

Many sulfonamides, in particular benzenesulfonamides, are known to act as antibacterial and diuretic agents, and numerous reports on the bacteriostatic and diuretic activity of sulfonamide compounds have been published. In addition, certain benzene sulfonamides are prepared as intermediates in the preparation of diuretic agents. However, benzene disulfonamides have not been used as anthelmintic agents, and it has not hitherto been known to have any value in controlling liver disease or other helminthic parasites.

The compounds of the process according to the invention can be illustrated by the following general formula: Rr <N from penta-fluoroethyl. The alkyl chain can be either straight or branched. The halogen atoms in a particular perhaloalkyl group need not be the same. Included in the above definition for R are such groups which have several different halogen atoms. The following list gives examples of groups that fall within the definition of Ri α-fluoroethyl β, β, β-trifluoroethyl pentachlorethyl α, α, β-trifluoroethyl α, α-difluoroethyl α, β, β-trifluoro-α, β -difluoroethyl heptafluoroisopropyl heptafluoropropyl perchloropentyl perfluorobutyl

The group R preferably contains fluorine. Particularly preferred are those alkyl groups which are totally fluorinated. Examples of this are heptafluoropropyl.

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The process according to the invention, which is characterized by the characterizing part of the claim, is illustrated in the following reaction scheme: RR NO "R ^ NH2 Μ * ® ^ 3 iT ^ H2 'i' | X chloro-2 -2 | -> | --- y sulfonic acid

II III IV

- * x x —x cio2s **, '' '' ^^ / '', '' ^^ so2ci H2N02 £ r -, ^^ x ^ Avs> .so2m2 'v in which R has the meaning set forth in the claim. The haloalkylbenzene starting material (II) is nitrated to the m-nitro derivative (III) which is reduced by catalytic hydrogenation to form the m-aniline derivative (IV) which is chlorosulfonated with chlorosulfonic acid and sodium chloride to formation of (V). By treating the compound V with ammonia, the product (I) is obtained. A more detailed description of the reaction can be found in an article by Cragoe et al. in the Journal of Medicinal and Pharmaceutical Chemistry, page 898 (1962), from which it is known to prepare 4-amino-6-pentafluoroethyl-1,3-benzenedisulfonamide.

The halogenoalkylbenzene compounds (II) used as starting materials in the above process are well known, and methods for preparing these compounds are described in the chemical literature.

If the halogen atoms in the compound are fluorine, such compounds are prepared from m-iodaniline by treatment with a fluorinated iodo-alkyl compound in the presence of copper powder which has been activated by treatment with iodine and hydrochloric acid. The reaction proceeds in a polar solvent, such as dimethyl sulfoxide, at a temperature of 100 - 150 ° C for 1 - 10 hours. It is preferred to carry out the reaction in a sealed container such as an autoclave under an inert gas atmosphere such as nitrogen. The product is isolated in a manner known per se.

As mentioned, the compounds of the invention are effective anthelminthic agents which are particularly effective against liver lice at various stages of development, such as Fasciola gigantica and Fasciola heptica, the common liver lice in sheep and cattle. The preferred dose sizes depend on the nature of the compound, the nature of the animal, the particular helminth to be controlled, and the strength of the helminthic infection.

Effective control of liver lice is achieved when the compounds are administered in a single oral dose in an amount of 1 - 300 mg / kg of animal weight, preferably 10 - 100 mg / kg of animal weight. The activity of the compounds is shown in the following table.

TABLE

4-Amino-6-heptafluoropropyl-1,3-benzenedisulfonamide Sexually mature Fasciola rats Weak activity 100 mg / kg Sexually mature Fasciola rats Good activity 100 mg / kg Sexually mature Fasciola rats Good activity 50 mg / kg Sexually mature Fasciola rats Weak activity 25 mg / kg

Immature Fasciola sheep Good activity 75 mg / kg

Immature Fasciola gets Good Activity 35 mg / kg 4-amino-6- (2,2,2-trichloro-1,1-difluoroethyl) -1,3-benzenedisulfonamide Sexually mature Fasciola rats Good activity 50 mg / kg Sexually mature Fasciola rats Good activity 25 mg / kg Sexually mature Fasciola rats Moderate activity 12.5 mg / kg

For the preparation of the compositions, the active compounds can be mixed with any known carrier medium which is non-toxic or of nutritional value such as starch, lactose, talc, magnesium stearate or vegetable gums. The compositions may take the form of pills, tablets or capsules which may also contain the usual additives. Instead, liquid preparations can be used or the active compounds can be mixed into the animal's feed or drinking water.

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If the preparation is to be used in conjunction with feedingstuffs, feed supplements or compound mixtures, they are suitably mixed with the foodstuffs for the animal, such as dried cereals, cornmeal, citrus flour, fermentation residues, ground oyster shells, attapulgite, wheat bran, soluble molasses, maize flour, substances, roasted shelled soybean meal, soybean meal, antibiotic mycelium, soybean, crushed limestone and the like. The active compounds are intimately dispersed or mixed with the feed ingredients in a manner known per se.

The process according to the invention is explained in more detail by the following examples.

Example 1 4-Amino-6-heptafluoropropyl-1,3-benzenedisulfonamide A. m-Heptafluoropropylaniline

Technical copper powder is activated by treating 100 g with a liter of a 2% solution of iodine in acetone for 5-10 minutes at room temperature. The solid is filtered and stirred with 500 ml of a 50 $ solution of concentrated hydrochloric acid in acetone. The activated copper powder is filtered off, washed with acetone and dried in vacuo at room temperature.

35.2 g (17.5 ml, 0.118 mol) of heptafluoropropyl iodide, 28.8 g of activated copper powder and 25.0 g (0.114 mol) of 3-iodaniline are combined with 142 ml of dimethylsulfoxide in a glass-coated container for introduction into a steel autoclave. The autoclave is closed under a nitrogen pressure of 4.2 kg / cm and heated to 120 ° C for 3.5 hours with shaking. The autoclave is set at room temperature and the reaction mixture is filtered, washed with 10 ml of dimethyl sulfoxide and 50 ml of ether. The combined filtrate and washings are added to 250 ml of water and extracted with 500 ml of ether. The ether extract is washed with 100 ml of water. The aqueous layer is extracted back with 250 ml of ether and the combined ether layers are dried over mag nesium sulfate. The ether is evaporated at atmospheric pressure and the residue is distilled at 7 mm Hg and 78 ° C to give 20.5 g of m-hepta-fluoropropylaniline.

B. 4-Amino-6-heptafluoropronyl-1,5-benzenedisulfonamide 3.0 g m-heptafluoropropylaniline is added over 20 minutes. under anhydrous conditions to 40 ml of chlorosulfonic acid. 40 ml of sodium chloride are added portionwise over 90 minutes. The temperature is slowly raised to 150 ° C and kept at this value for 2 hours. The reaction mixture is cooled, 500 ml of ice water is added and the aqueous mixture is extracted with ether. The ether extract is washed with water, dried over sodium sulfate, evaporated to a volume of 100 ml and added to 50 ml of liquid ammonia. The liquid ammonia is evaporated and the solid is evaporated with boiling benzene and recrystallized from water to give 4-amino-6-heptafluoropropyl-1,3-benzene disulfonamide, mp: 259-262 ° C.