DE2336526A1 - Anthelmintic 2,6-diacyloxy-benzanilides - prepd. by acylation of 2,6-dihydroxy-3,5-dichloro-benzanilides - Google Patents

Abstract

Cpds. of formula (I) are new: (where R1 is H, 1-4C alkyl (opt. subst. by halogen, 1-4C alkoxy or phenyl), 1-4C alkoxy, phenoxy, halophenoxy, trifluoromethylphenoxy, bis-trifluoromethylphenoxy, COOH, (1-4C alkoxy)-carbonyl, carbamoyl, amidino, OH, SH, 1-4C alkylthio, NO2, CN, 3-6C cycloalkyl or 3-6C alkenyl, and R2 is H, 1-4C alkyl (opt. subst. by 1-4C alkoxy, halogen or phenyl), 3-6C alkenyl, 3-6C cycloalkyl, an unsaturated 5-6 membered heterocyclic ring, 1-4C alkylamino, di(1-4C alkyl)amino, pyrrolidino, piperidino, morpholino or N-methylpiperazino).

Description

FARBWERKE HOECHST AG formerly master Lucius St Brüning

Ref .: HOE 73 / F2o4

Date: July 17, 1973 Dr.KM/Hei

Diacyloxybenzoic acid anilides and processes for their preparation

The invention relates to diacyloxybenzoic acid anilides of the general formula I

(D

i η the

_{R is hydrogen, C 1} to C alkyl, which may optionally be _{substituted by halogen, C 1 to C 4} alkoxy or phenyl, C to C alkoxy, phenoxy, halogen-substituted phenoxy, trifluoromethylphenoxy, bis-trifluoromethylphenoxy, carboxy , C ₁ to C ^ -alkyl-oxycarbonyl, carbamoyl, amidino, hydroxy, mercapto, C ₁ to C ^ -alkylthio, nitro, cyano,

409886/1471

C ₃ to Cg-cycloalkyl or C ₃ to Cg-alkenyl, and in which

R _{2 is} hydrogen, C ₁ to C ₄ alkyl, which can optionally be substituted by halogen, C to C alkoxy or phenyl, C ₃ to Cg alkenyl, C ₃ to Cg cycloalkyl, an unsaturated heterocyclic 5- or 6-ring, C ₁ to C ₄ -alkylamino or C ^ to C ^ -dialkylamino ^ or a pyrrolidine, piperidine, morpholine or N-meth / lpiperazine ring.

These compounds are prepared by adding a 3,5-dichloro-2,6-dihydroxybenzoic acid anilide of the general formula Cl OH _R l

CONII - //

(II),

OH

It Il Il • 'ι ι If Il π It

in which R has the meaning given above, acylated.

For example, the following dihydroxybenzoic acid aniiides are suitable as starting materials for the reaction:

3,5-dichloro-2,6-dihydroxybenzoic acid anilide

^lf -4'-bromanilide

¹¹ -4 ^f -chloranilide

"-4 ^f -iodanilide

¹¹ -3 ^l, 4'-dichloroanilide

^11-2 ', 6'-dichloroanilide

"" -2 ', 5'-dichloroanilide

" ^ff -2 ', 4 ^f 6'-trichloroanilide

"" -2 '^' G'-tribromanilide

"" -3'-trifluoromethylanilide

"" -3 ¹ , 5 ^f -bis-trifluoromethyl-

anilide

"" -3 ^f -chlor-4 '- (p-chlorophenoxy) -

anilide

"" -3'-chlort '- (m, m-bistrif luor-

methyl-phenoxy) -anilide "" -4 '- (m, m-bis-trifluoromethyl-

phenoxy) anilide

"" -4 ^f -phenoxyanilide

"" -4'-methoxyanilide

"" -4 • -methoxycarbonylanilide

409886 / U71

—Ο- ™

3,5-dichloro-2,6-dihydroxybenzoic acid-4'-carbamoylanilide

"·" "-4'-acetylanilide

".""-4 ^f ~ acetylaminoanilide

"" "-4'-carboxyanilide

¹¹ ""-4'-cyananilide

¹¹ ""-4'-nitroanilide

"" "~ 2'-chloro-4'-nitroanilide

¹¹ "" - ^ '- mercaptobutyl-S'-tri-

fluoromethylanilide

¹¹ ""-4'-n-butylanilide

"" "-4'-t-butylanilide

¹¹ ""-4'-cyclohexylanilide

¹¹ ""-4'-isopropylanilide

The two phenolic hydroxyl groups are acylated by the action of acylating agents. Carboxylic acids or their reactive derivatives such as acid anhydrides, acid halides, in particular acid chlorides, and reactive carbamic acid derivatives, isocyanates, dialkylphosphinyl halides and dialkyl thiophosphinyl halides are suitable for this purpose. For example, the named derivatives of the following carboxylic acids come into consideration: acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, caproic acid, ß-chloropropionic acid, ß, γ-ol chlorobutyric acid, ß-methoxypropionic acid, phenylacetic acid, phenylpropionic acid, <t- phenylisobutyric acid, acrylic acid, 2-hexenoic acid, cyclopentane, cyclohexanecarboxylic acid, benzoic acid, 2-thiophenecarboxylic acid, pyrrole-2-carboxylic acid, pyrocucic acid, picolinic acid, nicotinic acid, thiazole-4-carboxylic acid.

The reaction components can be used to implement the starting materials let act directly on each other. To facilitate acylation, it is often advantageous to use a basic or acidic Add condensation agent. Suitable basic compounds are, for example, tertiary amines, such as pyridine or Triethylamine. Acidic condensing agents include, for example, sulfuric acid, sulfonic acid, polyphosphoric acid and anhydrous zinc chloride or acid halides into consideration. It is also beneficial to

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Settlement of the dihydroxy-benzoic acid anilides in the presence of a Make solvents or thinners. Inert polar or non-polar solvents such as benzene, toluene, Chlorobenzene, methylene chloride, chloroform, acetone, dibutyl ether, Tetrahydrofuran, dioxane, dimethylformamide or tetramethyl sulfone in question. If the acylating agent used is a liquid, it can be used in excess and thus serve as a diluent. The same applies to condensing agents such as pyridine.

The acylation reaction takes place at room temperature or at moderately elevated temperatures. Generally one exceeds the The boiling point of the solvent used is not. The implementation is usually completed in a few hours. The process products can, for example, by distilling off the diluent or isolated by adding water and subsequent crystallization from a suitable solvent.

The new diacyloxybenzoic acid anilides are generally crystalline, colorless compounds that do not dissolve in water or solve very little. They have interesting chemotherapeutic properties, especially as anthelmintics. Their effectiveness against liver fluke is particularly pronounced, preferably against the large liver fluke Fasciola hepatica, the as Parasite of farm animals such as sheep and cattle is of great importance. The application can be carried out orally or subcutaneously, depending on the location of the one or the other type of application, preference is to be given. The following table shows for some products of the process indicated the doses which were administered once to experimentally heavily infected sheep The egg excretion ceased and the liver fluke cured the animals.

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TABEL

Chemotherapeutic examinations

Host animal: Sheep .... Parasite: Fasciola hepatica

substance

Application type Therapeutic dose (mg / kg body weight)

3,5-dichloro-2,6-diacetoxybenzoic acid-4'-chloroanilide

p.o,

7.5

3,5-dichloro-2,6-diacetoxybenzoic acid-4'-bromanilide

p.o,

3,5-dichloro-2,6-diacetoxybenzoe-

acid 3'-chloro-4 '- (p-chlorophenoxy) anilide

-BjG ^ iS-: (methylcarbamoyloxy) benzoic acid 3'-chloro-4 '- (p-chlorophenoxy) anilide

p.o

, p.o.

3.5

Io

3,5-dichloro-2,6-bis (diethy1-carbomoyloxy) -benzoic acid-3 ', 5'-bistrifluoromethylanilide

p.o.

3,5-dichloro-2,6-dipropionyloxybenzoic acid-3'-chloro-4 '- (m, in-bistrifluoromethylphenoxy) anilide p.o,

15th

409886/1471

substance

Application type

Therapeutic dose (mg / kg body weight)

3,5-dichloro-2,6-bis (methyl-carbamoyloxy) -benzoic acid-4 '- (m, m-bis-trifluoromethylphenoxy) -anilide

p.o.

Io

3,5-dichloro-2,6-bis- (methylcarbamoyloxy) -benzoic acid-3'-chloro-4 ^l - (m, m-bis-trifluoromethylphenoxy) -anilide

p.o,

15th

A multiple of the therapeutic dose is well tolerated by sheep.

The new compounds are therefore valuable remedies for combating liver fluke infestation in veterinary medicine.

409886/1

Example 1 a

3,5-dichloro-2, β-diacetoxybenzoic acid-4'-chloroanilide

19.6 g of 3,5-dichloro-2,6-dihydroxybenzoic acid-4 ^f -chloranilide, 98 ml of acetic anhydride and

5 drops of acetyl chloride are kept at 9o C together for 3 hours heated. The solution is evaporated under reduced pressure and the solid residue is recrystallized from benzene. You get 17 g of 3,5-dichloro-2,6-diacetoxybenzoic acid-4 '- chloranilide vom Melting point 187-188 ° C.

Example 1b 3,5-Dichloro-2,6-diacetoxybenzoic acid ^4-t -bromanilid

In an analogous manner, 4'-bromanilide is obtained from 20 g of 3,5-dichloro-2,6-dihydroxybenzoic acid Lo.4 g of 3,5 dichloro-2,6-diacetoxybenzoic acid-4'-bromanilide with a melting point of 181-183 ° C.

Example 1 c

3,5-dichloro-2,6-diacetoxybenzoic acid-3 · -chlor-4 · - (p-chlorophen oxy) -anilide

In an analogous manner, 11 g of 3,5-dichloro-2,6-dihydroxybenzoic acid ^3-t-chloro-4 '- (p-chlorophenoxy) -anilide 8 g of 3,5-dichloro-2,6-diacetoxybenzoic acid-3 '-chlor-4' - (p-chlorophenoxy) -anilide, melting point 192 - 195 ° C.

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Example 2

3,5-dichloro-2,6-dipropionyloxybenzoic acid-S'-chloro-4 '- (m, m bis-trifluoromethy! Phenoxy) anilide

lo, 5 g of 3,5-dichloro-2,6-dihydroxybenzoic acid-3'-chloro-4 '- (m, mbis-trifluoromethylphenoxy) anilide,

5 ml propionic anhydride and
1 drop of conc. H ₂ SO ₄

are heated to 90 ° C for 4 hours together. After cooling, the reaction product is triturated with water, the precipitate is infiltrated and recrystallized from benzene / petroleum ether. 6.9 g of 3,5-dichloro-2,6-dipropionyloxybenzoic acid-3 ^f chloro-4 ^f - (m, m-bis-trifluoromethylphenoxy) anilide with a melting point of 158-159 ° C. are obtained.

Example 3

3,5-dichloro-2,6-bis (methy1-carbamoyloxy) -benzoic acid-4-chloro anilide

Io g of 3,5-dichloro-2,6-dihydroxybenzoic acid-4'-chloroanilide become in 15o ml abs. Tetrahydrofuran dissolved with 2o ml of methyl isocyanate cyanate and 0.5 ml of pyridine added. After 16 hours of standing the precipitate is filtered off at room temperature and recrystallized from ethylene glycol monomethyl ether. You get 8.7 g of 3,5-dichloro-2,6-bis (methyl-carbamoyloxy) -benzoic acid-4'-chloroanilide of melting point 234-236 ° C (dec.).

Example 4 a

3,5-dichloro-2,6-bis (methylcarbamoyloxy) benzoic acid 3'-chloro- 4 '- (p-chlorophenoxy) anilide

4.6 g of 3,5-dichloro-2,6-dihydroxybenzoic acid-3 ^f -chlor-4 '- (pchlorphenoxy) anilide are dissolved in 35 ml of acetone, and 11.5 g of methyl isocyanate and 0.5 ml of pyridine are added. To

A09886 / U71

After standing for 16 hours at room temperature, the deposited precipitate is filtered off and washed with acetone. 5.5 g of 3,5-dichloro-2,6-bis (methylcarbainoyloxy) -benzoic acid-3 ^{liters of} chloro-4 '- (p-chlorophenoxy) anilide with a melting point of 22o - 221 C (dec.) Are obtained. .

Example 4 b

3,5 dichloro-2,6-bis (methylcarbamoyloxy) benzoic acid ~ 4 * - (m _i m bis-trifluoromethylphenoxy) anilide

In an analogous manner, from 5.2 g of 3,5-dichloro-2,6-dihydroxybenzoic acid 4 '- (m, m-bis-trifluoromethylphenoxy) -anilide 5.86 g 3,5-dichloro-2,6-bis- (methylcarbamoyloxy) -benzoic acid-4 '- (m, m-bis-trifluoromethylphenoxy) anilide with a melting point of 235-237 ° C. (decomp.).

Example 4 c

3,5-dichloro-2,6-bis (methylcarbamoyloxy) -benzoic acid -3.5'-bis-trifluoromethylanilide

i
In an analogous manner, from 6.5 g of 3,5-dichloro-2,6-dihydroxybenzoic acid-3 *, ö'-bis-trifluoromethyl-anilide, 8.2 g of 3,5-dichloro-2,6-bis- ( methylcarbamoyloxy) benzoic acid 3 ', 5 * -bis-trifluoromethylanilide with a melting point of 23o - 231 C.

Example 5 a

3,5-dichloro-2,6-bis- (diethylcarbamoyloxy) -benzoic acid-3 * -5- bis-trifluoromethyl-anilide

6.5 g of 3,5-dichloro-2,6-dihydroxybenzoic acid-3 '^ 5' -bis-trifluoromethylanilide are dissolved in 2o ml of pyridine and 4.2 g of N, N-diethylcarbamoyl chloride are added dropwise with stirring over the course of 20 minutes, then heated to 7o C for 3 hours. The reaction solution is then poured into water, the precipitated product is filtered off and recrystallized from petroleum ether. 9 g are obtained

409886 / U 7.1

-lo-

3,5-dichloro-2,6-bis- (diethylcarbamoyloxy) -benzoic acid-3 ^f , 5'-bistrifluoromethylanilide, melting point 129-130 ° C

Example 5 b

3,5-dichloro-2,6-bis- (dimethylcarbamoyloxy) -benzoic acid-4'-chloro anilide

In an analogous manner, from 8.3 g of 3,5-dichloro-2,6-dihydroxybenzoic acid-4 ^f -chloranilide and 5.35 g of N, N-dimethylcarbamoy1-chloride, 5.38 g of 3,5-dichloro-2, 6-bis- (dimethylcarbamoyloxy) -benzoic acid-4'-chloroanilide. The substance is recrystallized from methanol. Melting point 2o4 - 2o6 C.

Jl

Example 6

3,5-dichloro-2,6-bis (methoxymethylcarbamoyloxy) -benzoic acid-4'- chloroanilide __

13.2 g of 3,5-dichloro-2,6-dihydroxybenzoic acid-4'-chloroanilide are dissolved in 2oo ml of acetone, and 8.7 ml of methoxymethyl isocyanate and 2 ml of pyridine are added. After 5 hours of standing it will the precipitated product is filtered off and recrystallized from dimethylformamide. 15.3 g of 3,5-dichloro-2,6-bis (methoxymethylcarbamoyloxy) -benzoic acid-4'-chloroanilide are obtained melting point 222-223 ° C (decomp.).

Example 7

3,5-dichloro-2,6-bis (phenylcarbamoyloxy) -benzoic acid-4'-chloro anilide

16.75 g of 3,5-dichloro-2,6-dihydroxybenzoic acid-4 ^f -chloranilide are dissolved in 250 ml of acetone, and 23.8 g of phenyl isocyanate and 0.5 ml of pyridine are added. After standing for 16 hours, the precipitated product is filtered and recrystallized from ethylene glycol monomethyl ether. 18.1 g of 3,5-dichloro-2,6-bis-

409886 / U71

(phenylcarbamoyloxy) benzoic acid 4'-chloroanilide, melting point 226 ° C (decomp.)

Example 8

3,5-dichloro-2,6-bis (dimethylthiophosphinyloxy) benzoic acid 4'-chloroanilide

In a solution of 33.2 g 3,5-Dichloro ~ 2,6-dihydroxybenzoic acid ^4-t -chloranilid in 3oo ml of dioxane and 21 g of triethylamine with stirring at 25 - 3o ° C 25.6 g Dimethylthiophosphinylchlorid added dropwise. After standing for 1 hour at room temperature, the precipitated castallic mass is filtered, washed with water and recrystallized from ethylene glycol monomethyl ether. 3.2 g of 3,5-dichloro-2,6-bis- (dimethylthiophosphinyloxy) -benzoic acid-4'-chloroanilide with a melting point of 238-242 ° C. (decomp.) Are obtained,

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Claims (4)

PATENT CLAIMS Diacyloxybenzoic acid anilides of the general formula I (I) in the R is hydrogen, C- to C-alkyl, which can optionally be _{substituted by halogen, C- to C 4} -AlkOXy or phenyl, C- to C ₄ -alkoxy, phenoxy, halogen-substituted phenoxy, trifluoromethylphenoxy, bis-trifluoroniethylphenoxy, carboxy, C- to C-alkyl-oxycarbonyl, carbamoyl, amidino, hydroxy, mercapto, C- to C-alkylthio, nitro, cyano, Co to Cg-cycloalkyl or C ₃ to Cg-alkenyl, and in which R is hydrogen, C- to C ₄ -alkyl, which may optionally be _{substituted by halogen, C- to C 4} -alkoxy or phenyl, C ₃ to C -alkenyl, C ₃ to Cg-cycloalkyl, an unsaturated heterocyclic 5- or 6 -Ring, C- to C ₄ -alkylamino or C- to C-dialkylamino, or a pyrrolidine, piperdine, morpholine or N-methylpiperazine ring. 2) Process for the preparation of the diacyloxybenzoic acid anilides of the formula I in claim 1, characterized in that one is a 3,5-dichloro-2,6-dihydroxybenzoic acid anilide of the formula II Cl OH CONH Cl OH 409886 / U71 in which ¹ R has the meaning given in claim 1, acylated. 3) means against worms, characterized by a content of one Diacyloxybenzoic acid anilide of the formula I in claim 1. 4) Use of a diacyloxybenzoic acid anilide of the formula I. in claim 1 for combating worms. 409886/1471