NO751872L - - Google Patents

Description

The object of the invention is substituted phenyl-mercaptobenzimidazoles with the general formula

wherein R1 means (C1-C1)-alkyl and R2 means (C1-C1)-alkyl 1, (C2-C1)-alkoc sy alkyl, (C-^-C^)-alkoxy carbonyl- (C-^- C 1 -alkyl resp. (Cj-C^)-alkenyl, in which the alkyl or alkenyl groups are each substituted with one or two halogen atoms, preferably chlorine and/or bromine, further phenyl phenylsulfony1, phenoxysulfonyl, in which the phenyl radical can each be substituted with halogen atoms, preferably fluorine, chlorine , bromo, with .(C-^-C,-,)-alkyl, (C 1-C 2 )-haloalkyl, (C 1-C 2 )-alkyloxy and/or (C 1-C 8 )-haloalkyl one, two or three times and as halogenalkyl-resp. the halogeno alkoxy groups can have one, two, three or four halogen atoms or in which R 2 means a cyclic hydrocarbon radical of formula or a radical of formula

where X means a number between 1 and 12.

Among phenymercapto-benzimidazoles of the general formula I, those in which

R^ means methyl or ethyl and

R2 is methyl, ethyl, propyl or butyl, methoxymethyl or ethoxyethyl, methoxycarbonylmethyl, methoxycarbonyl1-ethyl, methoxycarbonylpropyl, methoxycarbonylbuty1, ethoxycarbonylmethyl, ethoxycarbonylethyl, ethoxycarbonylpropyl, ethoxycarbonylbutyl, propoxycarbonylmethyl, propoxycarbonylethyl, propoxycarbonylpropyl, propoxycarbonylbutvl, butoxycarbonylmethyl, butoxycarbonyl . , difluoromethoxyphenyl, trifluorochloroethoxyphenyl, trifluorobromoethoxyphenyl, difluorodichloroethoxyphenyl, tetrafluoroethoxyphenyl or a residue of formula

in that in the latter residue x means the numbers 4, 5, 6, 7, 8, 9, 10, 11 or 12, particularly preferably the numbers 6, 8, 10 or 12. The object of the invention is further a method for preparing compounds of formula I, the method being characterized in that a benzimidazole of the general form 1■ is suitably reacted in an approximately molar ratio with an isocyanate of the general formula or with a carbamic acid halide, preferably chloride of the general formula or suitably in an approximately molar ratio of 2:1 with a diisocyanate with the formula or with a dicarbamic acid halide, preferably chloride with the general formula

wherein R 1 , R 2 and x have the above-mentioned meanings.

The reactions with a carbamic acid chloride Illa

or IVa is suitably carried out in the presence of bases such as pyridine, triethylamine or alkali carbonates, preferably in approximately stoichiometric conditions.

All transactions are preferably carried out in

an inert organic solvent such as methylene chloride, chloroform, acetone, methyl ethyl ketone, dimethyl ether, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene, petroleum ether, chlorobenzene or the like.

The reaction temperature can be between -20°C and the boiling point of any solvent. Usually work is done between 0°C and 80°C.

The reaction duration is between 10 minutes and

20 hours. When reacting with an isocyanate, the reaction rate can be accelerated by adding catalytically active substances such as triethylamine.

The benzimidazoles of the general formula II used as starting materials can be prepared from 4-phenylmercapto-1,2-diaminobenzene and a cyanaminocarboxylic acid ester NC-NH-COOR-^ by condensation in a pH range of 1 - 6, compare DOS no. 2.164. 690.

The aforementioned isocyanates with the general formula III, the carbamic acid halide IIIa, the diisocyanate IV and the dicarbamic acid chloride IVa are partly known, and partly can be prepared according to known methods. The 3-isocyanato-alkanoic acid esters of formula

in which the residue FU is (C^-C^-alkyl which is independent of each other, can be obtained from the corresponding 3-lactams of formula by ring opening and esterification in R^OH/HCl at 0°C to 50°C during of one to several hours to the B-amino acid esters or their hydrochlorides

by subsequent treatment with phosgene in boiling toluene.

Since in formula II the position of the hydrogen atom to the N atom of the imidazole ring is undeterminable (2 tautomeric forms), the phenyl mercapto groups in the final product with formula I can be in the (5) position as well as in the (6) position, which is indicated by the formula image. The object of the invention is thus (5)- and (6)-phenylmercapto-benzimidazoles of formula I, as well as the isomeric mixtures formed by the process according to the invention.

The new benzimidazoles of the general formula I

are valuable chemotherapeutics and are suitable for combating parasitic diseases in humans and animals. These products have a special effect on nematodes, such as e.g. against different species of trichostrongylids and strongylids of the digestive tract of beneficial animals. Alongside this pronounced effect against intestinal nematodes, there is also a good effect against nematodes whose developmental stages have a transient

or permanent residence.in other body tissues.

The effect of these substances is particularly pronounced on the one hand against gastrointestinal strongylids, of which above all ruminants are attacked, and also against hookworms, which are particularly parasitic on humans and carnivores. Both parasite types lead to considerable health and economic damage, so that the use of these substances as anthelmintics in human and veterinary medicine comes into consideration.

The subject of the invention is therefore also chemotherapeutic agents containing compounds of formula I as active substance as well as the use of compounds of formula I to combat parasitic diseases.

The agents according to the invention usually contain 1-80% by weight, preferably 3-70% by weight, of compounds of formula I in admixture with the usual solvents, carriers and/or additives.

The active substances and the agents containing them are applied orally or parenterally. The individual doses are between 0.1 and 50, preferably between 0.5 and 20 mg/kg body weight...

The application concentration depends on the chosen application form. The dose of the active substance depends on the type of treated animal and the degree and type of parasite attack. For oral treatment of larger animals, e.g. of pigs, sheep and cattle, suspensions 1 to 80%, preferably 3 to 15% or powders suspendable in water 1 to 80%, preferably 40 to 70% are particularly suitable. Boli, pastes and granules with corresponding active substance concentrations are also considered. For parenteral treatment, sterile, liquid preparations of concentrations 0.5 - 50%, preferably 3 - 25% are available for use.

The new benzimidazoles with the general formula I are superior to known compounds in their action against nematodes, especially against gastro-intestinal strongylids and hookworms. They have a low dose curativa minima. This can be derived, from the tables II and III below,

For oral treatment in human medicine, special consideration is given to tablets, dragees, capsules, powders and granules that contain the active substances together with usual excipients and carriers such as starch, cellulose powders, talc, magnesium stearate, sugar, gelatin, calcium carbonate, finely divided silicic acid, carboxymethyl cellulose or similar substances. The concentration of the active substances is for use as a human medicine, preferably between 20 and 80% by weight. Manufacturing examples.

General procedural regulations.

Equivalent amounts of 2-methoxy-carbonylamino-5- . ■-phenylmercapto-benzimidazole with formula I and isocyanate with formula III resp. diisocyanate with formula IV is stirred (possibly with an excess of isocyanate up to 10%) in approximately ten times the volume of a suitable solvent at approx. 20 to 50°C for 2 to 10 hours (depending on the reactivity of the isocyanate). The reaction product is then isolated by filtration. In the case of soluble products, the solvent is distilled off, the residue is mixed with the same volume of petroleum ether and the product is suctioned off.

Corresponding to this procedure, the following substances were produced:

The starting product of No. 4 is known according to J. Amer.

Chem. Soc. 46, 2518 (1924).

The starting products of numbers 14, 16, 33, 34 and 35 are known according to W. Siefken, Liebigs Ann. Chem. 552, 76

(1949).

The output products of numbers 15 and 17 - 21 can

is produced analogously to the working method stated by W. Siefken.

The starting product of No. 28 is known according to H. Ulrich, Chem. Reviews 65, 369 (1965).

The starting products of numbers 29 - 31 are known

according to US Patent No. 3,304,167.

The starting product of No. 32 is known according to

G. Lohaus, Chem. Pray. 105, 2791 (1972).

The starting products of Nos. 22 - 27 can be obtained by addition of corresponding nitrophenols to difluorocarbene (Nos. 22 and 23) or fluoroolefins (Nos. 2r to 27) in a polar solvent in the presence of alkali at elevated

■ temperature (compare G. Horlein et al. Z. Naturforsch. 28 c, 653 (1973)). The starting product of No. 26 can alternatively also be obtained by addition of m-acetaminophenol to trifluorobromethylene in dimethylformamide with a molar amount of potassium carbonate at 60-80°C (compare G. Horlein et al., see above page 655- .

The compounds in Table I can also be prepared by reacting a 2-methoxy-carbonylamino-5-phenylmercapto-benzimidazole of formula II with a carbamic acid halide of formula Illa or a dicarbamic acid halide of formula IVa.

Example 1.

29.9 g (0.1 mol) of 2-methoxycarbonylamino-5-phenylmercapto-benzimidazole and 15.6 g (0.1 mol) of N-phenylcarbamic acid chloride (preparable according to Gatewood, J. Am. Chem. Soc. 47, 410) is stirred in 200 ml of chloroform at 30°C. 10.1 g (0.1 mol) of triethylamine are added drop by drop. After 3 hours of boiling, the chloroform solution is suctioned off from the secreted triethylammonium chloride. Evaporation gives 39 g of 1-phenylaminocarbonyl-2-methoxy-carbonylamino-5-phenylmercaptobenzimidazole (decomposition point 122°C).

Preparation of 3-isocyanato-alkanoic acid ester

under formula II as starting materials for

example 5 to 12.

3-isocyanato-propionic acid butyl ester

(Starting material for example 6).

Mix while stirring and cooling at 0°C

500 ml of anhydrous butanol dropwise with 79 ml (1.1 mol) of thionyl chloride and then introduce under -5°C 89.1 g (1 mol) of 3-alanine. It is then slowly heated, as lively sulfur dioxide and chlorine hydrogen develop and the amino acid gradually dissolves. After stirring for 3 hours at 70°C, the reaction is finished, one evaporates in a vacuum, removes adherent thionyl chloride and butanol by three times over-distillation from anhydrous benzene, dries the residue for approx. 1 hour at 70°C on a circulation evaporator and recrystallizes the 8-alanine butyl ester hydrochloride from acetic ester/petroleum ether.

Yield: 176 g (97% of the theoretical),

melting point 6l - 63°C,

C7Hl6ClN02(MG 181.7)•

Analysis: Calculated C 46.3%, H 8.9%, Cl 19.5%,

. N 7.7%,

found C 46.5%, H 8.8%, Cl 19.7%,

N 7.7%.

175 g (0.96 mol) of the amino acid ester hydrochloride is suspended in 1 liter of anhydrous toluene. In the mixture introduces

one by constant boiling under reflux gaseous phosgene. After 3 hours, trading has ended. The solvent is removed by distillation under reduced pressure and moisture exclusion over a column and the residue is fractionally distilled in vacuum.

Yield: 150 g (91% of theoretical), boiling point (13 torr)

108°C.

CgH^NC^Molecular weight 1.71.2

Analysis: Calculated C 56.1%, H 7.65%, N 8.2%.

Found C 56.2%, H 7.6%, N 8.4%.

Analogously, with methanol instead of n-butanol, an average yield of 60% is obtained.

3_- isocy anato- propionic acid methyl ester.

(Source material for example 5).

.of boiling point (12 torr) 75°C.

C^NC^Molecular weight 129.1-

Analysis: Calculated C 46.5%, H 5.46%, N 10.84%.

Found C 46.2%, H 5.5%, N 10.9%.

The other 3-isocyanato-alkanoic acid esters for examples 7-12 were prepared from azetidin-2-ones.

(D, L)- 3- isocyanato- butyric acid methyl ester

(Output connection according to example 7).

200 ml of anhydrous methanol, which contains 1-2 mol of hydrogen chloride, is introduced and a solution of 85.1 (1 mol) (R,S)-4-methyl-azeti-din-2-one in 200 ml is added dropwise with stirring and ice-cooling methanol slowly. It is then stirred for 30 minutes at room temperature and again for 30 minutes at boiling temperature. After distilling off the solvent on a circulation evaporator and drying the residue in high vacuum, it is possible to recrystallize (D,L)-3-aminobutyric acid methyl ester hydrochloride from

tetrahydrofuran/ether.

Yield: 152.7 g (99% of the theoretical),

melting point 82 - 84°C.

C5H12C1N02 Molecular weight 153.6.

Analysis: Calculated C 39.1%, H 7.9%, Cl 23.1%,

N 9.1%-'

Found C 38.8%, H 7.9%, Cl 23.0%,

N 9.4%.

153.6 g (1 mol) of the amino acid ester hydrochloride is phosgenerated in 1000 ml of anhydrous toluene as described in the preceding example.

Yield: 125 g (87% of the theoretical).

Boiling point (29 torr) 91°C.

CgHgN03 Molecular weight 143.1.

Analysis: Calculated C 50.3%, H 6.3%, N 9.8%.

Found C 50.6%, H 6.3%, N 10.1%.

In an analogous way, (R,S)-4-methyl-azetidin-2-one and isopropanol are obtained instead of methanol

(D ? L)- 3- is ocyanato- butyric acid isopropyl ester

(Starting material for example 8) of boiling point (14 torr) 86-87°C,

of (R,S)-4-methylazetidin-2-one and butanol instead of methanol (D,L)-3-isocyanato-butyric acid butyl ester

(Starting compound of example 9) of boiling point (13 torr) 108°C,

of (R,S)-4-vinylazetidin-2-one and methanol

(D, L)- 3- isocyanato- 3- vinyl I- propionic acid methyl ester (Starting material for example 10) of boiling point (16 torr) 87°C,

of 3,4-dimethylazetidin-2-one and methanol

3~ isocyanato- 2- methyl butyric acid rethyl ester

(for example 11) with boiling point (15 torr) 79-80°C

and of 4,4-dimethylazetidin-2-one and .methanol

3- isocyanateq- isovaleric acid methyl ester

(for example 12)

of boiling point (18 torr) 82°C.

Biological examples.

In order to establish the effect of the compound according to the invention, schema therapeutic investigations were carried out on sheep and dogs. Sheep were experimentally infected with larvae of Haemonchus contortus and additionally with Trichostrongylus colubriformis, dogs with larvae of Ankylostoma canium. The experimental animals were kept in tiled boxes which were thoroughly cleaned daily to avoid superinfections. After the preparation period (the time between infection and sexual maturation of the parasites with the beginning of secretion of reproduction products) the number of eggs per grams of faeces (EpG) (literature: Tierårztliche Umschau 6, 209-210, 1951). After the end of the pre-patent period, the treatment of the animals usually took place 4-8 animals per group, however at least 2 animals, orally or parenterally, as a suspension of 0.5 - 20.0 mg/kg body weight was applied in 10 ml of a tylose suspension (1% aqueous suspension). Each time on the 7th, 14th and 28th day after the treatment, the number of eggs per grams of faeces and their change determined as a percentage to the initial value before treatment.

In the event of a convincing effect, a section of the test animals took place and an examination of the digestive canal and other organs for any nematodes still present, resp. their developmental stages.

In the following tables II and III, the anthelmintic effect of new benzimidazoles with the general formula I is reproduced, which has been determined according to the experimental method mentioned above. Comparatively, the anthelmintic effect of two known compounds is listed.

Biological examples.

Claims (4)

1. Phenyl mercapto-benzimidazole of the general formula in which R1 means (C^-C^ )-alkyl and R2 means (C^-C^ )-alkyl , (C2-C^ )-alkoxyalkyl, (C-^-C^ J-Alkoxycarbonyl- (C-^-C^ )-alkyl or (C-^-C^ )-alkeny 1, in which the alkyl or alkenyl groups can each be substituted on one or two halogen atoms, preferably chlorine and/ or bromine, furthermore, R 2 means phenyl, phenyl-sulfonyl, phenoxysulfonyl, in which the phenyl radical can each be substituted one, two or three times with the halogen atom, or preferably fluorine, chlorine, bromine with (C;]_-C 2 )-alkyl, (C-^ -.. C2 )-halogenalky 1, (C-^-C^ )-alkoxy and/or (C-^-C^)-halogenal-oxy and as the haloalkyl- or halogenalkoxy groups can have one, two , three or four halogen atoms or in which R 2 means a cyclic hydrocarbon residue of formula or a remainder with a formula where x means a number between 1 and 12. 2. Process for the preparation of benzimidazoles with the general formula I in claim 1, characterized in that a benzimidazole with the general formula is reacted with an isocyanate of the general formula ' or with a carbamic acid halide of the general formula or with a diisocyanate of the formula or with a dicarbamic acid halide of the general formula . idet , and x -have the above meanings. 3. Pharmaceutical agent, characterized by a content of a benzimidazole with formula I in claim 1. 4. Use of a benzimidazole of formula I in claim 1 for combating parasitic diseases.