DE2029637C3 - Methyl N-5 (6) acyl-2-benzimidazolyl carbamate - Google Patents

Description

The invention relates to methyl N-5 (6) acyl-2-benzimidazolyl carbamates of formula (I)

? / V

RC-Λ A _n
H

wherein R is a Cj_ door ₃ alkyl, Q_ ₅ cycloalkyl, phenyl, mono-fluoro or mono-chloro-phenyl is substituted with a methyl or methoxy phenyl radical or a 2-thienyl radical. The invention also relates to a process for the preparation of the compounds mentioned. These compounds can be used alone or in combination with other therapeutically active agents for combating worms. The compounds according to the invention are prepared by using the compound of the formula in a manner known per se

S-CH ₃
H ₂ NC = N-COOCH ₃

dl wherein R has the meaning given, and a

protonic acid, preferably in the presence of an alkali salt of the protonic acid.

Preparation of the compounds according to the invention, Example 1

7.8 parts of S-methylisothiourea sulfate are in 10 parts of water stirred in an ice bath, whereby

4.5 parts of methyl chloroformate are added. While the temperature is kept below 20 ^° C., 17 parts of 25% sodium hydroxide solution (pH ± 8) are added dropwise over the course of 10 minutes, whereupon

5.6 parts of acetic acid (pH ± 5) are added. This one The mixture is cooled at 20 ° C. without isolation of the methyl S-methylisothiourea carboxylate which is formed a suspension of 7 parts of 3,4-diaminobenzophenone hydrochloride in 100 parts of water was added, whereupon 2.3 parts of sodium acetate are added. The mixture is slowly heated to 85 ° C and 45 min at this temperature. The reaction mixture is cooled and the filled product filtered off. It is washed successively with water and ethanol, dried and made from a mixture crystallized from acetic acid and methanol, methyl N-5 (6) -benzoyl-2-benzimidazo! y! carbamate with a melting point of 288.5 ° C.

Examples 2 to 11

By repeating the experiment described in Example 1, the 3,4-diaminobenzophenone hydrochloride is replaced by an equivalent amount of a corresponding diaminophenyl ketone, the following carbamates are obtained:

2. Methyl-N-5 (6) -propionyl-2-benzimidazolylcarbamate, melting point 279.5 ° C,

3. methyl N-5 (6) -n-butyryl-2-benzimidazolyl carbamate, Melting point 273 ° C,

4. Methyl N-5 (6) - (cyclopropylcarbonyl) -2-benzimidazolyl carbamate, melting point 250.5 ° C,

5. Methyl N-5 (6) - (cyclobutylcarbonyl) -2-benzimidazolyl carbamate, m.p. > 300 ° C

(Decomposition),

6. Methyl N-5 (6) - (cyclopentylcarbonyl) -2-benzimidazolyl carbamate, melting point> 300 ° C
(Decomposition),

7. methyl N-5 (6Hp-fluorobenzoyl) -2-benzimidazolyl carbamate, Melting point> 260 ° C

(Decomposition),

8. Methyl N-5 (6) - (p -chlorobenzoyl) -2-benzimidazolyl carbamate, melting point> 260 ° C
(Decomposition),

9. Methyl N-5 (6) -p-toluoyl-2-benzimidazolyl carbamate, melting point 284.6 ° C,

10. N-methyl-5 (fi) - (p-methoxybenzoyl) -2-benzimidazolylcarbamate, mp 289 ⁰ C,

11. methyl N-5 (6) - (2-thienoyl) -2-benzimidazolyl carbamate, Melting point 288.7 ° C.

The benzimidazolyl carbamates of the general formula (I) have proven to be valuable anthelmintics. As such, these compounds are particularly advantageous

to combat the most varied of worm infections in the gastrointestinal tract of domestic animals _and economically important animals such as dogs. Sheep, cattle, chicks and chickens. The compounds are effective against a wide range of Hciminthcs. z. B. Trichostrongylus. Ostemmia, Conpcria, Hoemoncus. Strong \ Ioides. Neman> diru.s!

BunosiomumJrichuris.Chabertia. Capillaria.Asearis. Heterakis and Syphacia. Depending on the weight of the host animal, doses of dew of about 0.5 to 40 mg kg of body weight are generally sufficient to completely rid the animal of the pests. Anthelmintics which contain an effective menu of an active compound of the general formula U) alone or in combination with another effective therapeutic ingredient in a mixture with suitable carriers can easily be produced by the usual methods of pharmaceutical and veterinary medicine for the usual forms of administration. , ₀

Example 12

This example illustrates the effectiveness of the compounds of general formula (I) as Anthelmintica. The feces of half-adult or 2s-adult sheep, which are of various species infected by nematodes is examined under the microscope to identify the here of intestinal nematodes / u identify. The number of eggs per gram (IPG) is determined using the MacMaster method Kior ο n, H. McL. and W h i 11 ο c k, H. V.J. Coun. scient. ind Res. [Austr.], 12, 50 [1939]). Each animal is examined twice in the same week. the E PCi for each worm species is the mean number of four M a c M a s t e r counts. The middle EPG for each species after two studies is the average of eight counts. The sheep are then treated with the compound to be assessed, with the drug once with the Gastric tube administered (10 mg / kg). The treated animals are kept separately, and each Animal is examined for two weeks. The EPG data is grazed using the same method as before the treatment determined. The percentage reduction in eggs is the ratio of the middle ones Post-treatment EPG divided by the mean pre-treatment EPG multiplied by 100. The effectiveness of the compounds examined is rated according to the following scale:

+ = Effectiveness 1–25%,

+ + = Effectiveness 26-50%,

+ + -H = effectiveness 51-75%.

+ + + + = Effectiveness 76-100%.

-N

NH-COOCH,

(I)

At- R

game No.

Tricho- Ostertagia Cooperia Hoemoiicus Strong-

strongylus vloides

Ncmatoilirus Htinostomum Chabcrtia

Ph
Et
n-Pr

4 -

7th p-F-Ph + + + + + + + + + + + + + + + + C) - + + + + + + + + + + + + 8th p-CI-Ph 4 + + + O O O C) O O 9 p-Me-Ph + + + + + + + + + + + + + + + + C) ++++ ++++ + + t + 10 P-MeO-Ph + + + O + + + + + + + + ₊ __ - 11th 2-thienyl + + + + + + + + + + + f + ■ f + + + + + + + + +

The most preferred compound is methyl N-5 (6) benzoyl-2-benzimidazolyl carbamate proved to be particularly effective against Syphacia muris. This organism shows its kinship with the Oxyuris, Enterobius vermicularis, occurring in humans, through its life cycle, its cyclical Period of activity and egg-laying in the perianal zone. For creating artificial infections a cellulose tape is used to remove the eggs from the perianal skin, and this tape is administered orally to rats. The animals infected in this way are placed in individual cages with food and water ad libitum. The connection under test becomes administered orally with the drinking water. A sterile saline solution or suspension of the compound is made produced with different concentrations corresponding to 40, 10, 2.5, 0.63 and 0.16 mg'kg body weight. The animal receives 1 ml per 100 g of body weight. Comparison animals receive the same amount Saline solution. The animals are sacrificed five days later. The cecum colon and rectum are isolated

and on a "· sieve with a mesh size of 144 ·; washed. Male, female, and immature worms are sorted and counted. The effective wedge will as a percentage, based on the untreated matched animals, expressed. In this method, methyl - N - 5 (6) - benzoyl - 2 - henzimidazolyl carbamate was found as 100% effective against syphasis muris in rallen after administration of a single oral Dose of 0.63 mg'kg of grain weight. A lead with the well-known Anihelminticum Parbepda / ol (Methylölol-butyl-I-benziinidazolcarbamal) (Natuic. 215 [1967]. P. 321. 3221 arises from! He follows

Really sa ink ei ι

\ on Vc: bnulmiL ¹ B

Tabdle j. - sis .game I letln Effectiveness addiiiiv Parb'c \ on Connect kp. M. oral Ims: () "" 0.16 50 ",, 0.31 100 ",, 0.63 100 ",, 2.5 K) O "/ ,, 10.0 K) O ¹ V ₁ , 40.0 ns: Λ Ν 0 l-NölM-bcn /, Verhiiidu- 11.1! B = - crt ~ i : iula / iil. Vcrbiiiiiii orally) 1 .iuse Oral Dc vi connection s
^ after at * in mc ks; 10 > 20th 40 80 10 160 15th 320 IO 640 K) 1280 10 ID ₅₁₁ -W imu'kii 1280

lOO'O

Cold

(I 15
1 10
1.10
3 10

> 1280

carhani.i!

Efficacy against Syphacia muris in Katien ι Varying attempts I

substance
example

1!
Par-

bend-

a / ol

(Iralc cans in nvj ku

0 ".

() "■■

0 ",

100 ".

XO ",
100 ",

50 ",

KH) ",

0 ",

100 ",,
100 "ο
! (Μ) ¹ ! «
lOO'O

in

100 ",, KX)". ,, I (X)% 100% KK) ",,

100 ",, 100" ,, KM) ",, 100" ,, 100 ",, 100" ,,

The acute toxicity of the compound according to Example I was tested in various species. Suspensions this substance and its derivatives with higher concentrations than 128 mg ml can be used Reason for viscosity and thixotropic properties cannot be produced. The acute oral toxicity for the following derivatives was determined for Rats examined and was greater than 12X0 mg kg in the case of the compounds according to Example 4, 7, 11 and 6.

Guinea fowl rabbits 11 wide

0 30 (I 5

0 30

Kill

0 5

O 5

0 5

0 K

0 3
0.3

03

(I 5
0 5
0 5

0.5 0 5 0 5

1280

(40

640

640

In none of the animals was there any effect other than that administered in doses of 570 to 50 mg, kg. All

Behaviors such as tremors or convulsions are noted. During the trial period all were surviving animals clinically normal.

The substance was also tested on 6 adult cats with a body weight of 2.5 to 3.5 kg Animals survived and there was no toxic effect whatsoever.

Acute oral toxicity of the compound according to Example 1 in domestic animals:

Oral dose
in ηιμ ku

Chicken

l'asancn

Schwciiu Sheep

Beef egg

Horses

(I 30 0 ') (V3it
0 24
0 12

O <36 0.22 0 4

to ζy ο:> /

Pheasants Sehweine Sheep Cattle! 'Suffer

0/6

0/2 0/6

0/2

0/16

> 1280> 20> 320> 80> 400

In none of the animals could effects be noticed that this is only due to the high Behavior, such as tremors or convulsions, noted the viscosity and thixotropic properties of susceptibility. All surviving animals were on the claimed benzimidazole carbamates during the pensions Trial period clinically normal. could not be measured exactly in all

The LD ₅₀ value for the compound according to Example 1, however, should be higher. These LD ₅₀ values

was above 1280 mg / kg orally in mice and rats, are so high compared to the effective concentration,

while for Parbendazole in Nature, Vol. 215, p. 322, 25 that the compounds according to the invention as un-

a value of over 4000 mg / kg is given. can be considered toxic.

Regarding the information on the LD ₅₀ value of> 1280

continuation Chicken Oral dose in mi; kg 160 0/12 200 320 400 640 0/12 1000 1280 LD ₅₀ value > 1000 (mg / kg-OR)

Claims (3)

Palent claims: I. Methyl - N - 5 (6) - acyl - 2 - benzimidazole 1-carhamate of the general formula (I): with compounds of the general 1-formula NH, O
Rc NH ! I R-C -N
Υ- NH-COOCH ₁ wherein R is a C, _ ₃ alkyl, C ₃ _ ₅ cycloalkyl, phenyl, mono-fluoro or mono-chloro-phenyl radical, a substituted mii a methyl or methoxy radical or a 2-thienyl radical Phemlresi stands. 2. Process for the preparation of the compounds according to claim 1, characterized in that the compound of the formula is used in a manner known per se S-CH, H ₂ NC = N-COOCH ₃ with compounds of the general formula NH, NH, 30th wherein R has the meanings given, and a protonic acid, optionally in Reacts the presence of an alkali salt of the protonic acid. 3. Anthelminticum containing a compound according to claim 1.