FI60202B - FOERFARANDE FOER FRAMSTAELLNING AV NYA MASKMEDEL VERKSAMMA 5-PHENYLSULPHINYL-2-BENZIMIDAZOLECARBAMINSYRAALKYLESTRAR - Google Patents

Description

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Patent and regulatory framework AmMcm utbfd och utlikiiitM puMictrtd 31.0o, 8l (32) (33) (31) ^ ir> 4 # ey • cuoikaus — B «fird priority 07.73

Federal Republic of Germany-Cörbundsrepubliken 'Cysk-1and (DE) P 2334631.8 (71) Syntex (USA) Inc., 3401 Hillview Avenue, Palo Alto, California 94304, USA (72) Heinz Loewe, Kelkheim / Taunus, Josef Urbanietz, Schvalbach / Taunus,

Reinhard Kirsch, Hofheim / Taunus, Dieter Diivel, Hofheim / Taunus, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (7¾) Oy Kolster Ab (5¾) Method for the preparation of new anthelmintic 5-phenylsulfinyl-5-2-benzimidazolecarbamyrosylalkyl ester

Alkyl esters of benzimidazolecarbamic acid having an alkyl or acyl group in the 5 (6) position are known as anthelmintics (Actor, P. et al.,

Nat. 215 (1967) 321: DOS 2 029 637).

The present invention relates to a process for the preparation of novel anthelmintic alkyl esters of 5-phenylsulfinyl-2-benzimidazolylcarbamic acid having the formula

B

wherein R 1 represents an alkyl group having 1 to 4 carbon atoms, R 4 represents hydrogen, alkyl having 1 to 4 carbon atoms, chlorine, bromine or methoxy, and R 4 represents hydrogen, chlorine, bromine or methyl, the process having the characteristic 2 60202 treated with an oxidant of the formula R1 ^ 2yV_ / | ^ JJ ^^ ^ C-NH-COCR (II)

B

1.2 ·. ...

wherein R, R and R are as defined above, a phenylthio derivative.

Suitable oxidants are preferably equivalent amounts of hydrogen peroxide in an organic acid, preferably glacial acetic acid, peracids such as peracetic acid, pertrifluoroacetic acid and metachloroperbenzoic acid, and nitric acid or chromic acid in glacial acetic acid, salts of these acids, perchlorates, further permanganates, hypochlorites, hypochlorites

It is expedient to carry out the reaction by adding 30% hydrogen peroxide to a suspension of phenylthio compound (II) in glacial acetic acid and stirring the mixture at room temperature until a clear solution is obtained. Elevated temperatures up to about 70 ° C can also be used. The sulfoxide formed is separated by adding water to the reaction solution. The precipitated precipitate is isolated by filtration.

The corresponding phenylthio derivative to be used as a starting material is obtained according to German patent application P 21 61+ 690.2 (HOE 71 / F 3 ^ + 3) by reacting 5-phenylthio-o-phenylenediamine with its S-methylthiourea and an alkyl ester of chloroformic acid.

The alkyl esters of 5-phenylsulfinyl-2-benzimidazole-carbamic acid prepared according to the invention are valuable chemotherapeutic agents and are suitable for controlling diseases caused by parasites in humans and animals. They are particularly effective against numerous intestinal worms, e.g., Haemonchus, Trichostrongylus, Ostertagia, Strongyloides, Cooperia, Chabertia, Oesophagostomum, Hyostrongylus, Ankylostoma, Askaris, and Heterakis. Particularly characteristic is its efficacy against gastrointestinal strongylides, which afflict ruminants in particular. Disease of animals due to these parasites causes great economic damage, which is why the compounds according to the invention have use, especially in veterinary medicine.

The active compounds of the formula I are administered, as the case may be, in doses of 0.5 to 50 mg per kilogram of body weight for 1 to 10 days.

Results of pharmacological tests

The following table compares the compound of the invention, 5-phenylsulfinyl-2-carbomethoxyaminobenzimidazole (oxfendazole). . & '' and the 5-phenylthio-2-carbomethoxy-3 6020 mentioned in Finnish patent publication 51 »299? the therapeutic efficacy of aminobenzimidazole (fenbendazole) and commercially available benzimidazole-type anthelmintics (J.E.D. Kelling and C.H. Burren, Wellcome). Commercial compounds have been studied for 2- (1 + -thiazolyl) -1H-benzimidazole (thiabendazole), 5-butyl-2-carbomethoxyaminobenzimidazole (parbendazole), 5-n-propoxy-2-carbomethoxyaminobenzimidazole (oxybendazole) and 5-ber.t :: yyli -? -Carborne toxiamaminobenzimidazole (mebend at solia). Therapeutic experiments have investigated the destructive effect of the compounds on five intestinal worms in rodents. Mice were infected with Hymenolepsis nana (H. Nana), Nematospiroides dubiuk (N. dub.) And Aspiculuris tetrapter. (A. tetrap.), And rats with Nippostron-gylus brasiliensis (N. Brasil.) And Trichostrongylus colubriformis (T. colub. ). The results are reported as the minimum dose required to remove 95% of the internal worms (N. dubius, N. brasiliensis, T. colubriformis) or to cure the infection from all animals studied (H. Nana, A. tetraptera). The dose is expressed in mg / kg multiplied by the number of doses over 2U hours.

Table Medicine H. Nana A. tetrap. N. dub. N. Brasil. T. colub.

Thiabendazole> 1 + 00x3> 1 + 00x3> 1 + 00x3 50x3 20x1

Parbendazole 100x3 100x3 1 + 00x3 100x3 10x1

Oxybendazole 1 + 00x3> 1 + 00x3 1 + 00x3 1 + 00x3 20x1

Mebendazole> 1 + 00x3 25x3> 1 + 00x3> 1 + 00x3 20x1

Fenbendazole> 1 + 00x3> 1 + 00x3> 1 + 00x3> 1 + 00x3 100x3

Oxfendazole 25x3 5x3> 1 + 00x3 10x3 2x1

Therapeutic experimental results show that the new compound, oxfendazole, is significantly more effective against most of the intestinal worms studied than the reference compounds.

Example 1 Methyl ester of 5-phenylsulfinyl-2-benzimidazolylcarbamic acid

A mixture of 75 g of 5-phenylthio-2-benzimidazolylcarbamic acid methyl ester, 750 ml of glacial acetic acid and 250 ml of 30% hydrogen peroxide is stirred at room temperature until a clear solution is formed which takes about 2 hours. 1.5 l of water are then added, the mixture is heated briefly to 80 [deg.] C. and, after cooling, the precipitate is filtered off. After washing and drying, 65 g of 5-phenylsulfinyl-2-benzimidazolylcarbamic acid methyl ester with a melting point of 21 DEG-8 DEG C. (decomposition) are obtained.

In an analogous manner, the following is prepared: 2) From 5-phenylthio-2-benzimidazolylcarbamic acid ethyl ester 5-Phenylsulfinyl-2-benzimidazolylcarbamic acid ethyl ester with a melting point of 230 ° (decomposes). 3, 3) 5-Phenylthio-2-benzimidazolylcarbamic acid isopropyl ester 5-Phenylsulfinyl-2-benzimidazolylcarbamic acid isopropyl ester, m.p. 237 DEG C. (decomp.).

U) Butyl ester of 5-phenylthio-2-benzimidazolylcarbamic acid 5-phenylsulfinyl-2-benzimidazolylcarbamic acid butyl ester with a melting point of 225 ° C (decomposes).

5) From 5- (3-methylphenylthio) -2-benzimidazolylcarbamic acid methyl ester, 5- (3-methylphenylsulfinyl) -2-benzimidazolylcarbamic acid methyl ester with a melting point of 2 ° C decomposes.

6) From 5- (4-methylphenylthio) -2-benzimidazolylcarbamic acid methyl ester 5 '(k-methylphenylsulfinyl) -2-benzimidazolylcarbamic acid methyl ester with a melting point of 285 ° C decomposes.

7) From 5- (N-chlorophenylthio) -2-benzimidazolylcarbamic acid methyl ester 5- (U-chlorophenylsulfinyl) -2-benzimidazolylcarbamic acid methyl ester with a melting point of 287 ° C decomposes.

8) 5- (U-Chlorophenylthio) -2-benzimidazolecarbamic acid isopropyl ester 5 - (* + - chlorophenylsulfinyl) -2-benzimidazolylcarbamic acid isopropyl ester decomposes at 301 ° C.

9) 5- (U-Methoxyphenylthio) -2-benzimidates from solylcarbamic acid methyl ester 5- (k-Methoxyphenylsulfinyl) -2-benzimidazolylcarbamic acid methyl ester with a melting point of 275 ° C decomposes.

10) Isopropyl ester of 5- (N-methoxyphenylthio) -2-benzimidazolylcarbamic acid 5- (4-methoxyphenylsulfinyl) -2-benzimidazolylcarbamic acid isopropyl ester, m.p. 227 ° C, decomposes.

11) From 5- (2,5-dichlorophenylthio) -2-benzimidazolylcarbamic acid methyl ester 5- (2,5-Dichlorophenylsulfinyl) -2-benzimidazolylcarbamic acid methyl ester decomposes at 285 ° C.

12) Isopropyl esters of 5- (2,5-dichlorophenylthio) -2-benzimidazolylcarbamic acid 5- (2,5-dichlorophenylsulfinyl) -2-benzimidazolylcarbamic acid isopropyl ester with a melting point of 265 ° C decomposes.

13) 5- (2-methyl-5-tert-butylphenylthio) -2-benzimidazolylcarbamic acid methyl ester 5- (2-O-ethyl-5-tert-butylphenylsulfinyl) -2-benzimidazolylcarbamic acid methyl ester having a melting point of 23 ° C, decomposes.

1U) 5- (2-Methyl-5-tert-butylphenylthio) -2-benzimidate from isylcarbamic acid isopropyl ester 5- (2-methyl-5-tert-butylphenylsulfinyl) -2-benzimidazolylcarbamic acid the isopropyl ester with a melting point of 2 [deg.] C. decomposes.

15) From 5- (U-tert-butylphenylthio) -2-benzimidazolylcarbamic acid methyl ester 5- (U-tert-butylphenylsulfinyl) -2-benzimidazolylcarbamic acid methyl ester with a melting point of 20 DEG C. decomposes.

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Claims (1)

A process for the preparation of novel anthelmintic 5-phenylsulfinyl-2-benzimidazolylcarbamic acid alkyl esters of the formula gA / (-) C-NH-COOR (I) H in which R represents an alkyl group having 1 to 1 + C atoms, R 1 represents hydrogen, alkyl containing 1-1 + C atoms, chlorine, bromine or methoxy, and R 2 represents hydrogen, chlorine, bromine or methyl, characterized in that it is treated with an oxidant of the formula R 1 s <π) H 1 · 2 where R , R and R have the same phenylthio derivative as defined above.