DE2039466C3 - Dioxocyclohexancaibonic acid anilides and thioanilides and processes for their preparation - Google Patents

Description

NCX

R,

or with appropriate isocyanate formers or sothiocyanate formers in the presence of a base and expediently reacted using solvents at preferably 20 to 150 ° C.

Hydrogen, chlorine, bromine or iodine, trifluoromethyl, ^ itro or lower alkyl, lower alkoxy or lower haloalkoxy and X for oxygen or sulfur

The invention also relates to a process for the preparation of the compounds mentioned, the is characterized in that in a known manner cyclohexane-l, 3-dione with corresponding substituted phenyl isocyanates or phenyl isothiocyanates of the general formula II

NCX

or with appropriate isocyanate formers or iso-

thiocyanate formers in the presence of a base and expediently using solvents at preferably 20 to 150 "C.

Among isocyanate and isothiocyanate formers are For the purposes of the invention, those starting materials are to be understood which, under the reaction conditions, are converted into isocyanates or isothiocyanates pass over (cf.Houb e η - W e y 1, Methods of Organic Chemistry, Vol. 8, 4th ed., 1952, p. 119 and Vol. 9, 4th ed., 1955, p. 867). In particular, they then belong accordingly substituted phenylcarbamic acid halides and anhydrides or their sulfur analogues.

The reaction obviously goes on in such a way that only the corresponding urethane becomes the general Formula Hl forms, which is formed by basic catalysts to the desired anilides of the common Formula I can be rearranged (cf. Ber. Dtsch. Chem. Ges., Vol. 37.h627 [1904]).

It is known that by reacting substituted and unsubstituted cyclohexanediones with phenyl isocyanate 2,6-dioxocyclohexanecarboxylic acid anilides can be obtained (Ber. dtsch. chem. Ges Vol. 37, 4627 [1904], J. chem. Soc. 1955, 346 uno Zhur. Obshchei Khim., 30, 542 [1960], reported in C.A. 54, 24 575 [1960]). It has now been found that the reaction also applies to substituted phenyl isocyanates and isothiocyanates can be expanded and that compounds with valuable pharmacological Properties.

The invention therefore relates to dioxocyclohexanecarboxylic anilides and thioanilides of the general formula I

-NH-

(D

wherein R, and R _{2 are} identical or different and + II

base

OH

OCX-NH

(HD

The reaction is expediently carried out in solvents such as benzene, toluene, chloroform, tetrahydrofuran, dimethylformamide, dioxane or sulfolane. The base necessary for the rearrangement, e.g. B. triethylamine, potassium carbonate, sodium acetate, pyridine, tri-n-propylamine and the like can be added immediately or after a certain dwell time. The reaction takes place within a wide temperature range, preferably between 20 and 150 ^° C. After neutralization of the base with acid, the solvent is distilled off and the residue is purified by recrystallization.

The reaction products obtained have interesting chemotherapeutic properties. They show z. B. an effectiveness as an anthelmintica, which is particularly is pronounced against liver fluke and here again against the large liver fluke Fasciola hepatica, the parasite of livestock, such as sheep and cattle, is of great importance. The application can

20 39 4615

be done orally or subcutaneously, on a case-by-case basis one or the other type of application is to be given preference.

Due to their excellent antifungal properties, the process products can also use both in human and in veterinary medicine for combating fungal infections Find.

The advantageous properties of the compounds according to the invention are derived from the following process Search report shows:

Examination of the process products against the large liver fluke compared to two known active substances

The products of the process according to the invention were tested on experimentally infected sheep. Lambs received 200 metacercarias from Fasciola hepatica orally; at the end of the prepatency period , the existence of an infection was confirmed coprologically.

The success of the treatment was confirmed by repeated control of the faeces or by dissecting treated sheep detected.

The table below shows the dose effectiva, after the application of which at least 80% of the worms present were removed. It is true that the effective dose of the process products is higher than that of the known active ingredients. In contrast, the significantly greater toxicity of the known substances is expressed in the chemotherapeutic index, which is given in a further column as the quotient of LD ₅₀ and dose effectiva. The higher index number therefore means that the active ingredient in question is superior to those with a lower index number.

The active ingredients used for comparison are, among others, from Boch and Supperer, "Veterinärmedizinische Parasitologie", Berlin and Hamburg 1971, pp. 80 to 81, known (Niclofolan = Menichlopholan).

Supplement to the table

table

Active ingredient

2,6-Dioxocyclohexanthiocarboxylic acid-2 ', 5'-dimethylanilide

2,6-Dioxocyclohexanthiocarboxylic acid-2'-methyl-4'-chloroanilide

2,6-dioxocyclohexanthiocarbon

acid 3'-bromanilide

2,6-dioxocyclohexanthiocarbon

acid 4'-iodanilide

2,6-dioxocyclohexanecarboxylic acid

2'-chloroanilide

2,6-Dioxocyclohexanthiocarbon-

acid-4'-chlorainilide

Known comparison substances:

"Niclofolan" == 5,5'-DiChIOrO-2,2'-dihydroxy-3,3'-dinitrobiphenyl

"Oxyclozanide" = 3.3 ', 5.5',

6-pentachloro-2,2'-dihydroxybenzoic acid anilide

dose
eflectiva Chem.
index 50 > 16 40 > 10 100 > 32 100 > 16 80 > 10 50 > 30 4th 2.8 15th -5

35

40

45

connection Thera- peu- tisdier index 2,6-dioxocyclohexanecarboxylic acid 7th 3 ', 5'-bis-trifluoromethylanilide 2,6-dioxocyclohexanecarboxylic acid 8th 4'-iodanilide 2,6-DioxocycIohexanecarboxylic acid 8th 3 '- (1 ", 1", 2 ", 2" -tetrafluoroethoxy) -anilide !, o-Dioxocvclohexanecarboxylic acid 10

3- (1 ", i", 2 "-trifluoro-2" -chloroethoxy) -anide

2,6-Dioxocyclohexanecarboxylic acid- 8

3 '- (I ", 1", 2 ", 3", 3 ", 3" -hexa-fluoropropoxyj-anilide

2,6-dioxocyclohexanecarboxylic acid- 10

2'-brumanilide

2,6-Dioxocyclohexanecarboxylic acid-> 10

2'-methoxyanilide

2,6-dioxocyclohexanecarboxylic acid- 20

3'-trifluoromethyl anilide

2,6-Dioxocyclohexanecarboxylic acid-> 32

3'-chloro-2'-methylanide

2,6-Dioxocyclohexanecarboxylic acid-> 32

3'-chloro-4'-methylanide

2,6-Dioxocyclohexanecarboxylic acid-> 16

4'-chloro-2'-methylanilide

2,6-Dioxocyclohexanecarboxylic acid-> 60

2 ', 5'-dimethylanilide

2,6-Dioxocyclohexanthiocarboxylic acid- 8

4'-bromanilide

2,6-Dioxocyclohexanthiocarboxylic acid-> 40

4'-nitroanilide

2,6-Dioxocyclohexanthiocarboxylic acid- 8

4'-n-butoxyanilide

2,6-Dioxocyclohexanthiocarboxylic acid-> 10

4'-isobutoxyanilide

2,6-Dioxocyclohexanthiocarboxylic acid-> 16

3'-methylanilide

2,6-Dioxocyclohexanthiocarboxylic acid- 10

2 ', 5'-dimethyl amide

2,6-Dioxocyclohexanthiocarboxylic acid-> 32

3'-chloroanilide

2,6-Dioxocyclohexanthiocarboxylic acid-> 32

3'-bromanilide

2,6-Dioxocyclohexanthiocarboxylic acid- 20

2'-iodanilide

2,6-Dioxocyclohexanthiocarboxylic acid- 25

3 ', 4'-dichloroanilide

2,6-Dioxocyciohexanthiocarboxylic acid 6

3 ', 5'-bis-trifluoromethylanilide

2,6-Dioxocyclohexanthiocarboxylic acid-> 32

4'-methoxyanilide

2,6-Dioxocyclohexanthiocarboxylic acid- 20

3'-ethoxyanilide

example 1
2,6-Dioxocyclohexanecarboxylic acid-4'-chio-dnilide

To a mixture of 336 g of cyclohexane-M-dione, 450 ml of toluene and 18 ml of triethylamine, 459 g of 4-chlorophenyl isocyanate in 250 ml of toluene are added dropwise with stirring over the course of one hour so that the temperature does not exceed ^{60 ° C.} The mixture is stirred for a further 2 hours at 60 ^° C., 15 ml of glacial acetic acid is added, the toluene is distilled off in vacuo and the solid residue is recrystallized from ethanol. This gives 670 a (84%) 2,6-dioxocyclohexanecarboxylic acid-4'-chioraniHd, F .: 113 to 115 C.

Example 2

a) 2,6-Dioxocyclohexanecarboxylic acid 3 ', 5'-bistrifluoromethylanilide

To a solution of 24 g of cyclohexane-l ^ -dione in 240 ml of chloroform, 55 g of 3,5-bis-trifluoromethylphenyl isocyanate (b.p. ₂₄ = 78 to 80 ° C.) are added dropwise so that the temperature does not exceed 45 "C. 1.3 ml of triethylamine are then added, the mixture is heated under reflux for 2 hours, the solvent is distilled off and the residue is crystallized
Addition of 2 ml of glacial acetic acid from ethanol.
receives 52 g (66%) 2,6-dioxocyclohexanecarboxylic acid-3 ', 5'-bis-trifluoromethylanilide, F .: 123 "C.

In an analogous way one obtains:

Example 3
a) Zo-dioxocyclohexanecarboxylic acid thioanilide

65 g of potassium carbonate and 45 g of cyclohexane-1,3-dione are introduced successively into 120 ml of dimethylformamide with stirring. Then allowed to 54 g of phenyl isothiocyanate are added dropwise so that the internal temperature holds between 3.0 and 40 ⁰ C. The mixture is stirred for a further 2.5 hours, the contents of the flask are diluted with 1 liter of water and left to stand for 2 hours. The solution is filtered, with conc. Acidified hydrochloric acid; the resulting precipitate is filtered off with suction, washed with 120 ml of water and recrystallized from ethanol. 63 g of 2,6-dioxocyclohexanecarboxylic acid thioanilide are obtained. F .: 82 to 83 ° C.
In an analogous way one obtains:

No.

Surname

Fp.

yield

Surname

Fp.

<C)

after 2 B) 2,6-dioxocyclohexane 123-124 . Man 2 c) carboxylic acid 113-115 isic acid ⁱ⁰ 2d) -2'-methyl-thioanilide 105-106 2 c) ^ '- chloro-thioanilide 83-84 20th -4 ^r -bromo-thioanilide 82-83 -4'-n-butoxythioanilide Out-
bcutc -4'-isobutoxythioanilide

2,6-dioxocyclohexane 96-97 72 carboxylic acid 132-135 71 2 B) -3'-chloroanilide 109-111 81 2c) -3 \ 4'-dichloroanilide 128-129 76 2d) -4'-bromanilide 235-236 74 2e) -4'-iodanilide 116-117 60 20th -4'-nitroanilide 102-103 77 2 g) -4'-methylanilide 97-98 78 2h) -4'-methoxyanilide 2i) -3'-l ", l", 2 ", 2" -tetra- 84-85 82 fluorine ethoxyanilide 2k) -3 ^r -l ", l", 2 "-trifluoro- 93-94 83 2 "chloroethoxy anilide 21) -3 '- (l'M "-difluor- 2 ", 2" -dichloroethoxy) - 92-94 75 anilide 2m) -3'-methyl-4'- d ", l" -difluoro-2 ", 2 "-dichloroethoxy) - 87 88 71 anilide 2n) -3 '- (1 ", 1", 2 ", 3",. V, 3 "-hcxafluor- propoxy) anilide

Example 4
2,6-Dioxocyclohexanecarboxylic acid c-4'-chloroanilide

10 g of 4-chlorophenylcarbamic acid acetic anhydride are added, 5.5 g of cyclohexane-l, 3-dione and 60 ml of benzene together, add 3 ml of triethylamine and the mixture is heated to 80 ° C. for 20 minutes. The cloudy solution is filtered and evaporated in vacuo; the residue is recrystallized twice from ethanol after adding 3 ml of glacial acetic acid. You get 6.2 g (49%) 2,6-dioxocyclohexanecarboxylic acid-4'-chloroanilide. F .: 114 C.

50

Example 5

2,6-Dioxocyclohexanecarboxylic acid 4'-chloroanilide

12.4 g of 4-chlorophenyl carbamic acid chloride, 7.5 g Cyclohexane-l ^ -dione and 50 ml of benzene are combined touched. 10 ml of triethylamine are added over the course of 5 minutes and the mixture is heated for 30 minutes to 80 "C. The solvent is distilled off in vacuo, 5 ml of glacial acetic acid are added to the residue recrystallizes from ethanol. Yield 7.1g (41%) 2,6 - Dioxocyclohexanecarboxylic acid - 4 '- chloranilide: F .: 114 to 115 C.

Claims (2)

Patent claims: L Dioxocyclohexanecarboxylic acid anilides of the general formula NH where R, and R _{2 are} glv-cti or different and are hydrogen, chlorine, B.-om or iodine or trifluoromethyl, nitro, lower alkyl, lower alkoxy or lower halo-alkoxy and X is oxygen or sulfur. 2. Process for the preparation of the compounds according to claim 1, characterized in that one in a conventional manner cyclohexane-1,3-dione with appropriately substituted phenyl isocyanates or phenyl isothiocyanates of the general formula II