CS242021B1 - Substituted anilides of 3-benzyl-5-bromosalicylic acid and of its salts - Google Patents

Description

The present invention relates to substituted 3-benzyl-5-bromosalicylic acid anilides and their salts of formula I

wherein R ^{* 1} is hydrogen or chlorine, R ² is nitro, n is 1-2, Y is piperazine, m is 0 or 1.

These novel, yet undescribed substances exhibit useful anthelmintic activity, particularly against the model helminth of Hymenolepis nana.

The compounds of the formula I according to the invention can be prepared by reacting the known 3-benzyl-5-bromosalicylic acid (No. AO No. 177 663 J) with 4-nitroaniline or 2-chloro-4-nitroaniline in the presence of phosphoricrichloride in an inert solvent. elevated temperatures, preferably with 0.3 to 0.4 molar amount of fesfortrichloride in xylene at a temperature of 130 to 140 ° C.

Salts (for example piperazine of formula I) are prepared by reacting compounds of formula I with 1/2 or 1 equivalent of piperazine, preferably in a boiling ethanolic mixture.

Evaluation of anthelmintic efficacy against model helminth Hymenolepis nana

Male H strains weighing 10-13 g in groups of 6 were used in the experiments. Two of the three control groups were invaded, untreated, the third was invaded, treated with a standard formulation - niclosamide piperazine salt - against which the efficacy of the drugs was compared.

The compounds of formula I and their salts were administered orally by gavage at 150 mg / kg on days 13 and 14 after invasion. of. hm.

The standard was also applied on days 13 and 14 after invasion at 150 mg / kg bw. %, which, calculated as niclosamide, represents a dose of 4.58. 10 ⁴ mol / kg bw hm.

The anthelmintic potencies of the compounds of formula I expressed as a percentage by the Steward indirect activity method are shown in Table 1 below.

Table 1

Substituents in formula IR ¹ R ² dose mol / kg bw hm. efficiency in% Example of indirect activity method

H, NO2 3.51. . ⁴ “ ⁴ Cl, H, NO2 NO2 3,25, . 10 ~ ⁴ piperazine salt Cl, NO2 2.92. 10 ~ ⁴ piperazine salt 1.48. . ΙΟ ⁴

91.4 1

92.4 2

of. hm. = live weight

As can be seen from the above evaluation results, the compounds of formula I and their salts are active against the model helminth of Hymenolepis nana. The process for preparing the substances is simple and provides the desired products in satisfactory yields. Further details are given in the following examples. The examples given are merely illustrative and not limiting.

Example 1

4-Nitroanilide acid

3-benzyl-5-bromosalicyl

A mixture of 8.3 g of 3-benzyl-5-bromosalicylic acid (27 mmol) and 3.73 g of 4-nitroaniline (27 mmol) and 140 ml of xylene was heated to boiling and boiling solution dropwise, 1.48 g of phosphoric acid chloride (10, The reaction mixture was heated at 130-140 degrees Celsius for 7 h under reflux and then poured out of the undissolved inorganic residue while hot, and after cooling the crystallized material was washed with xylene, 5% aqueous sodium bicarbonate solution and water after suction. Recrystallization from acetone gave 10.6 g (92 percent) of mp 195 ° C.

Example 2

2-Chloro-4-nitroanilide acid

3-benzyl-5-bromosalicyl

A mixture of 20.26 g of 3-benzyl-5-bromosalicylic acid (66 mmol) and 12.4 g of 2-chloro-4-nitroaniline (66 mmol) and 140 ml of xylene was heated to boiling and 3.15 g of fosfortrichloride added dropwise to the boiling solution. (23 mmol). The reaction mixture was heated at 130

97.8 4 to 140 ° C for 6 h under reflux and then, after cooling, was shaken out with 5% aqueous sodium bicarbonate solution and water. The organic layer was freed from the organic solvent by distillation at 50 mbar and the residue was recrystallized from benzene / acetone. Crystallization gave 29.16 g (95.7%) of m.p. 148-149 ° C.

Example 3

Piperazine salt of 4-nitroanilide acid

3-benzyl-5-bromosalicyl

To a boiling mixture of 12 g of 3-benzyl-5-bromosalicylic acid 4-nitroanilide (28 mmol) and 90 ml of ethanol was added dropwise a solution of 5.66 g of piperazine hexahydrate (28 mmol) in 30 ml of ethanol and boiled for 15 min. under reflux. Cooling and suction to give ¹ 13.1 g (91.2%) of piperazine salt, mp 196-197 ° C, composition (CaoHisBrlNteOd). . C4H10N2.

Example 4

Piperazine salt

Of 2-chloro-4-nitroanilide acid

3-benzyl-5-bromosalicyl

To a boiling mixture of 34.6 g of 3-benzyl-5-bromosalicylic acid 2-chloro-4-nitroanilide (75 mmol) and 500 ml of ethanol was added dropwise 7.3 g of piperazine hexahydrate (37.5 mmol) in 60 ml of ethanol and the mixture. was refluxed for 15 minutes. After cooling and aspiration, 32.0 g (84.5%) of the piperazine salt of (C20H14BrClN2O4) 2 were obtained. C4H10N2. The substance melts at 188 ° C.

Substituted Formula I

Claims (1)

OBJECT OF THE INVENTION 3-Benzyl-5-chlorosalicylic acid anilides of the general formula I (X) (I) wherein R ¹ is hydrogen or chlorine, R ² is nitro, n is 1 to 2, Y is piperazine, m is 0 or 1.