US3657267A

US3657267A - Benzimidazole carbamates

Info

Publication number: US3657267A
Application number: US835246A
Authority: US
Inventors: Josephus Ludovicus Hube Gelder; Leopold Frans Corneel Roevens; Alfons Herman Marg Raeymaekers
Original assignee: Janssen Pharmaceutica NV
Current assignee: Janssen Pharmaceutica NV
Priority date: 1969-06-20
Filing date: 1969-06-20
Publication date: 1972-04-18
Anticipated expiration: 1989-04-18
Also published as: DK134602B; DK134602C; JPS501272B1; SE366045B; AT302358B; DE2029637A1; DK580275A; YU34195B; GB1307306A; NL147139B; CS201522B2; IL34746A; FI52719B; FI52719C; YU154470A; IT1035027B; HK77976A; FR2052988A1; FR2052988B1; ZA704191B

Abstract

COMPOUNDS OF THE CLASS OF ALKYL ESTERS OF N-(5(6)ACYL - 2 - BENZIMIDAZOLY)CARBAMIC ACID HAVING ANTHELMINTIC UTILITY.

Description

United States Patent 3,657,267 BENZIMIDAZOLE CARBAMATES Josephus Ludovicus Hnbertus Van Gelder, Beerse, Leopold Frans Corneel Roevens, Rijkevorsel, and Alfons Herman Margaretha Raeymaekers, Beerse, Belgium, assignors to Janssen Pharmaceutica, N.V. No Drawing. Filed June 20, 1969, Ser. No. 835,246

Int. Cl. C07d 49/38 US. Cl. 2603ll9.2 16 Claims ABSTRACT OF THE DISCLOSURE Compounds of the class of alkyl esters of N [5(6)- acyl 2 benzimidazolyflcarbamic acid having anthelmintic utility.

BACKGROUND OF THE INVENTION The invention pertains to the field of benzimidazole carbamates which are useful in the control of helminths. The prior art discloses alkyl esters of benzimidazole-2- carbamic acids but not with acyl substituents in the 5(6)- position.

SUMMARY An object of this invention is to provide a new class of benzimidazole carbamates, in particular, those alkyl esters of benzimidazole-Z-carbamic acid which have an acyl substituent (as hereinafter described) in the 5(6)- position. Said esters may be used alone or in combination with other therapeutically active agents in controlling helminths, and, accordingly, they are valuable adjuncts to the pesticidal field.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The novel alkyl N [5(6) acyl 2 benzimidazolyl] carbamates of this invention may be structurally represented by the formula:

* N glmno 00R, (I)

wherein AI is a member selected from the group consisting of phenyl, halophenyl, (lower alkyl) phenyl, (lower alkoxy)-phenyl and Z-thienyl. R is a member selected from the group consisting of methyl and ethyl; and the 3,657,267 Patented Apr. 18, 1972 substituent is located at the 5(6)-position of the benzimidazole ring system.

As used herein, lower alkyl and lower alkoxy may be straight or branch chained saturated hydrocarbons having from 1 to about 6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like alkyls, and, respectively, the corresponding alkoxys such as methoxy, ethoxy, propoxy, isopropoxy, etc.; cycloalkyl refers to saturated hydrocarbon rings of from 3 to 6 carbon atoms, i.e., cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and halo refers to halogens of atomic weight less than 80, Le, fluoro, bromo and chloro.

The subject compounds (I) are prepared in accordance with the procedure outlined in US. Pat. No. 3,010,968 for making certain other alkyl esters of benzimidazole-2- carbamic acids. In general, the process involves treating S-methylisothiourea sulfate (II) with an appropriate alkyl chloroformate (III) and a base, preferably, about a 25% aqueous solution of an alkali metal or alkaline earth metal hydroxide, to about pH 8. The thus-obtained alkyl S-methylisothiourea carboxylate (IV), which need not be isolated before proceeding with the next step, is then reacted with an appropriate acyl-substituted o-phenylenediamine (V), preferably in the form of an acid addition salt, and a protonic acid to about pH 5-6, for example, formic, acetic, propionic and the like acids, and, preferably, in the presence of a corresponding alkali metal salt, e.g., sodium or potassium formate, acetate, propionate, etc., to yield the desired acylated alkyl benzimidazole carbamates of Formula I. The foregoing reactions may be illustrated by the following reaction scheme, wherein the symbols R and K, have the same meaning assigned to them previously:

The diaminophenyl ketones of Formula V are obtained by reduction of the nitro function in the corresponding aminonitrophenyl ketones of Formula VI. Such reduction is readily accomplished by the catalytic hydrogenation of (V1), for example, by contact with hydrogen and a palladium-on-charcoal catalyst in a suitable solvent such as a lower alkanol which is preferably acidified, for example, with HCl, in order to increase yields. Conventional treatment with a suitable inorganic or organic acid, e.g., hydrochloric, hydrobromic, sulfuric, acetic, oxalic, lactic, fumaric and the like acids, affords the corresponding acid addition salts of (V). The amino-nitrophenyl ketones (VI) are in turn obtained from the corresponding halo-nitrophenyl ketones of Formula VII, wherein X is halo, preferably chloro or fluoro, by conventional ammonolysis of the latter ketones, for example, by heating (VII) with a lower alkanolic solution of ammonia, preferably under pressure in a suitable polar solvent such as sulfolane. Because of the strong electron-attracting nitrogroup at the position ortho to the halogen, the ammonolysis reaction readily converts the halo function to an amino function. Alternatively, the aminonitrophenyl ketones of Formula VI may be obtained by treating (VII) with ethylene glycol and ammonium hydroxide at elevated temperatures (about 100-130 C.) for several hours. The foregoing reactions may be illustrated by the following schematic diagram:

(a) NHrlmethanol OnN 12.5N NHiOH 0 O [I methanol II H1N o- 1191- OR I Hz/Pd-C OzN HxN Several of the diaminophenyl ketones of Formula V and the amino-nitrophenyl ketones of Formula VI are believed to be novel compounds, and, in view of their utility in the syntheses heretofore described, such ketones constitute an additional feature of this invention. These novel intermediates may be structurally represented by the following formula:

OzN (VII) or, alternatively, by way of the direct nitration of a compound of Formula VIII, such as by contact with concentrated or fuming nitric acid at temperatures of about -5 to C., which compound (VIII) may be obtained by a conventional 'Friedel-Crafts reaction as follows:

O II A101: L- Cl-G-R (Friedel- Crafts) 0 Gone. 0 ll HNO; II x --C-R X- C-R 20 0.

(VIII) OQN The benzimidazolyl carbamates of Formula I have been found to possess valuable anthelmintic properties, and, as such, the compounds are particularly useful against various helmintic infections of the intestinal tract of domestic and economically important animals, such as dogs, sheep, cattle, chickens and the like. The compounds (I) are active against a broad spectrum of helminths, e.g., Trichostrongylus, Ostertagia, Cooperia, Hoemoncus, Strongyloides, Nematodirus, Bunostomum, Trichuris, Chabertia, Capillaria, Ascaris, Heterakis, Syphacia and the like. De-

pending upon the weight of the host animal, dosages of about 0.5 to about 40 mg./kg. of body weight daily will generally be sufficient to effectively clear the animal of the infectious organisms. Anthelmintic compositions comprising an effective amount of an active compound ('I), either alone or in combination with other active therapeutic ingredients, in admixture with suitable carriers may be readily prepared according to conventional pharmaceutical and veterinary techniques for the usual routes of administration.

The most preferred compound, methyl N-[5(6)-benzoyl-2-benzimidazolyl]carbamate has been found to be particularly effective against Syphacia muris, which organism manifests its relationship with the human oxyuris, Enterabius vermicularis, by its life cycle, by its cyclical period of activity and by laying its eggs in the peri-anal zone. For artificial infections, adhesive cellophane tape is used to recover the eggs from the peri-anal skin and this tape is administered orally to rats. The thus-infected animals are housed in individual cages with food and Water ad libitum. The compound to be tested is administered orally by gavage. A sterile saline solution or suspension of the compound is made at various concentrations corresponding to 40, 10, 2.5, 0.63 and 0.16 mg./kg. body weight. The animal receives 1 ml. for each 100 g. body weight. Control animals receive the same amount of saline. Five days thereafter the animals are sacrificed. Coecum colon and rectum are isolated and washed on a sieve of mesh 100. Male, female and immature worms are differentiated and counted. Comparative eflicacy is expressed in percent to untreated controls. In accordance with this procedure, methyl N-[5(6)benzoyl-Z-benzimidazolyl]carbamate has been found to have 100% activity against Syphacia muris in rats upon the administration of a single oral dose of 0.63 mg./kg. body weight. A comparison with the known anthelmintic, parbendazole [methyl 5(6)butyl-Z-benzimidazolecarbamate] is illustrated in the following table:

Compd. A, Compd. 13,

percent percent Single oral dose (mg/kg.) effective ctlective Compd. Azmethyl N-[5(G)-benzoyl2-bcnzimitluzole]carbut C mpd. B:parbendazole.

The oral LD/SO value of Compd. A is mg./kg. in sheep and 40 mg./kg. in mice, rats and chickens. In the same animal species, the oral LD/SO of Compd. B is 40 mg./kg.

The following examples are intended to illustrate, but not to limit, the scope of the present invention. Unless otherwise stated, all parts are by Weight.

EXAMPLE I Methyl N- [5 (6) acetyl-2-benzimidazolyl] carbanlate A mixture of 8.35 parts of S-methylisothioureau sulfate and 5.66 parts of methyl chloroformate in 10 parts of water is cooled on ice to about 10 C. While keeping the temperature between 10 and 15 C., there is added an excess of sodium hydroxide solution 25% (pH 8), followed by the addition of 7 parts of acetic acid (pH 5) and 5.6 parts of 3,4-diaminoacetophenone. Finally there is added a solution of 2.5 parts of sodium acetate in 25 parts of water and the whole is stirred while heating on an oil-bath (8085 C.) for 45 minutes. The reaction mixture is cooled and the precipitate is filtered off and washed successively with water, 2-propanol, water, and ether and dried. It is dissolved in 40 parts of hot acetic acid C.) and 48 parts of methanol are added. The product is crystallized at room temperature, filtered off, washed with methanol and dried. The product is recrystallized from a mixture of 25 parts of glacial acetic acid and 40 parts of methanol, yielding methyl N-[ (6)-acetyl- 2-benzimidazolyl] carbamate; M.P. +300" C.

EXAMPLE II Methyl N- 5 (6 -propionyl-2-benzimidazolyl] carbamate A mixture of 16 parts of 4'-chloro-3-nitropropiophenone, 2.8 parts of ammonia, 72 parts of methanol and 13 parts of sulfolane is heated in a sealed tube at 120 C. for 15 hours. The solvent is evaporated in vacuo and to the residue are added 150 parts of water and concentrated hydrochloric acid solution till acid. The precipitated product is filtered olf, washed successively with water, 2-propanol and ether and dried, yielding 4-amino-3-nitro propiophenone; M.P. 150 C.

A mixture of 9.7 parts of 4-amino-3'-nitropropiophenone, 160 parts of methanol, 10 parts of concentrated hydrochloric acid solution and 0.5 part of palladium-oncharcoal catalyst 10% is hydrogenated at normal pressure and normal temperature. After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The solid residue is treated with parts of 2-propano1, filtered off again, Washed successively with 2-propanol and ether and dried, yielding 3,4=diaminopropiophenone hydrochloride.

A mixture of 10 parts of S-methylisothiourea sulfate and 6.8 parts of methyl chloroformate in 12 parts of water is cooled on ice to about 10 C. At a temperature between 1015 0., there is added sodium hydroxide solution till pH 8, while stirring. Then there are added portionwise 8 parts of glacial acetic acid. Upon completion, there are added 7.2 parts of 3,4-diaminopropiophenone hydrochloride, followed by the addition of a solution of 3 parts of sodium acetate in 20 parts of water. The mixture is stirred for 45 minutes at a temperature of 80-85 C. The formed precipitate is filtered off and triturate'd successively in 200 parts of water, 160 parts of l-propanol 200 parts of water, 120 parts of methanol, Washed with ether and dried, yielding methyl N-[S(6)-propionyl-2- benzimidazolyl]carbamate; M.P. 279.5 C.

EXAMPLE III Methyl N- 5 6) -butyryl-2-benzimidazolyl] carbamate A mixture of 22.8 parts of 4-chloro-3-nitrobutyrophenone, 3.6 parts of ammonia in 72 parts of methanol and 12 parts of sulfolane are heated in a sealed tube for 16 hours at 120 C. The solvent is evaporated in vacuo. The residue is washed with diluted hydrochloric acid solution while stirring for 10 minutes at 60 C. The precipitated product is filtered off, washed with 2-propanol and with toluene and dried, yielding 4'-amino-3'-nitrobutyrophenone; M.P. 130 C.

A mixture of 14.5 parts of 4-amino-3-nitrobutyrophenone, 160 parts of methanol, 7 parts of concentrated hydrochloric acid solution and 1 part of palladium-oncharcoal catalyst 10% is hydrogenated at normal pressure and at room temperature. After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filtered otf and the filtrate is evaporated. The residue is washed with 2-propanol and dried, yielding 3',4- diaminobutyrophenone hydrochloride.

To a. stirred and cooled mixture of 4.2 parts of S- methylisothiourea sulfate and 5 parts of water are added 5.35 parts of methyl chloroformate and then sodium hydroxide solution 25 to keep the pH at 8 (the temperature is kept between 5-10 C.). Upon completion, there is added 3.6 parts of glacial acetic acid and 4.92 parts of sodium acetate in 15 parts of Water. The whole is stirred and after the addition of 5.7 parts of 3',4'-diaminobutyrophenone hydrochloride, an oil is separated, which solidifies. The solid product is filtered off, washed successively with 2-propanol and diisopropylether and recrystallized from 70 parts of dimethylformamide, yielding methyl N- [5(6)-butyryl-2-benzimidazolyl]carbamate; M.P. 273 C.

6 EXAMPLE IV Methyl N- [5 (6) -cyclopropylcarbonyl-2- benzimidazolyl] carbamatev 150 parts of fuming nitric acid (d.=1.5) are cooled and while keeping the temperature between 10 and 20 0., there are added 39 parts of (4-chlorophenyl) cyclopropyl ketone. The whole is further stirred for 45 minutes at the same temperature. The reaction mixture is cooled to -30 C. and poured onto crushed ice. The precipitated product is filtered off while cold, Washed with cold water and then with a little 2-propanol and after recrystallization from 40 parts of 2-propanol, (4- chloro-3-nitrophenyl) cyclopropyl ketone is obtained; M.P. C.

A mixture of 5.16 parts of (4-chloro-3-nitrophenyl) cyclopropyl ketone, 1.275 parts of ammonia, 60 parts of methanol and 12.5 parts of sulfolane is heated in a sealed tube at C. for 15 hours. The solvent is evaporated in vacuo. To the residue is added 50 parts of Water and the formed precipitate is filtered off. After crystallization from 2-propanol, the impure product is purified on column-chromatography (silica gel) using a mixture of chloroform and methanol (98:2). The pure fractions are collected and the solvent is evaporated. The residue is crystallized from 20 parts of 2-propanol, yielding (4- amino-3-nitrophenyl) cyclopropyl ketone; M.P. 167 C.

A mixture of 8.25 parts of (4-amino-3-nitrophenyl) cyclopropyl ketone, 200 parts of methanol, 0.5 parts of palladium-on-charcoal catalyst 10% and 6 parts of sulfuric acid solution 20 N is hydrogenated at normal pressure and at a temperature of about 30 C. After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The solid residue is triturated in 2.5 parts of water, filtered off again, washed once more with Water and then with 2-propanol and dried, yielding (3,4-diarninophenyl)cyclopropyl ketone sulfate; M.P. 180l90 C.

(deC.).

A mixture of 4.2 parts of S-Inethylthiourea sulfate and 5 parts of water is cooled on an ice-salt mixture. At a temperature between 5 and 15 C. there are added simultaneously 5.35 parts of chloroformate and sodium hydroxide solution 25% to keep the pH at about 8, then there are added dropwise 3.6 parts of acetic acid, followed by the addition of a solution of 4.92 parts of sodium acetate in 15 parts of water. Upon completion, there are added 8.2 parts of (3,4- diaminophenyl) cyclopropyl ketone sulfate and the Whole is stirred for 30 minutes at 80 C. The reaction mixture is cooled, the precipitated product is filtered off, washed successively with water (three times), 2-propanol and ether, and dried. The crude product is dissolved in 50 parts of boiling glacial acetic acid. To the hot solution is added 100 parts of methanol and the product is crystallized at room temperature. It is filtered off, washed with methanol and ether and dried, yielding methyl N-[5(6)-cyclopropylcarbonyl-2-benzimidazolyl]carbamate; M.P. 250.5 C.

EXAMPLE V Methyl N- [5 (6)-valeryl-2-benzimidazolyl] carbamate A mixture of 29.2 parts of 4'-fluoro-3'-nitrovalerophenone, 4.9 parts of ammonia, 104 parts of methanol and 17 parts of sulfolane is stirred for 15 hours at room temperature. The solvent is evaporated. To the residue is added parts of water and hydrochloric acid solution till just acid. The formed precipitate is filtered off, washed successively with water and 2-propanol and dried, yielding 4-amino-3-nitrovalerophenone; M.P. 118 C.

A mixture of 9 parts of 4-amino-3'-nitrovalerophenone, parts of methanol, 4 parts of hydrochloric acid solution 10 N and 1 part of palladium-on-charcoal catalyst 10% is hydrogenated at normal pressure and room temperature. Upon the calculated amount of hydrogen being taken up, hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. To the residue are added 40 parts of 2-propanol and the latter is evaporated again. The solid residue is triturated in 24 parts of 2-propanol, filtered off again, washed successively with 2-propanol and ether and dried, yielding 3,4-diaminovalerophenone hydrochloride.

A mixture of 5.57 parts of S-methylisothiourea sulfate and 3.8 parts of methyl chloroformate in 7 parts of Water is cooled on ice. At a temperature of l15 C., there is added dropwise a 25%-sodium hydroxide solution, till pH 8. Then there are added 4.7 parts of acetic acid (pH-i5 followed by the addition of 4.6 parts of 3,4-diaminovalerophenone hydrochloride. To this mixture is added a solution of 1.64 parts of sodium acetate in 40 parts of water and the whole is stirred at 80-85 C. for 45 minutes. The reaction mixture is cooled and the precipitated product is filtered off. It is Washed thoroughly with water, 2-propanol, and ether and dried. The product is dissolved in 50 parts of hot acetic acid and 80 parts of boiling methanol are added. The product crystallizes again after cooling to room temperature. It is filtered off, washed successively with methanol and ether and dried, yielding methyl N-[5 (6)-valeryl-2-benzimidazolyl]carbamate; M.P. 265 C.

EXAMPLE VI Methyl N-[5(6)cyclobutylcarbonyl-2-benzimidazolyl] carbarnate A hot solution of 53 parts of cyclobutylcarbonyl chloride in 45 parts of fluorobenzene is added at 60 C., to a mixture of 107 parts of aluminium chloride in 270 parts of fluorobenzene. Upon completion, the Whole is stirred and refluxed for 45 minutes. The reaction mixture is cooled and poured onto ice. The organic layer is separated and the water is extracted twice with 120 parts of methylene chloride. The combined organic phases are dried, filtered and evaporated. The residue is distilled, yielding cyclobutyl p-fluorophenyl ketone; B.P. 100102' C. at 2 mm. pressure.

64 parts of cyclobutyl p-fluorophenyl ketone are added dropwise (one-hour period) to 225 parts of cone. nitric acid (d.=1.5) While keeping the temperature between 5 to 10 C. Upon completion, the while is stirred first for about 1 hour and 30 minutes at 5 to 10 C. and then cooled to 30 C. and poured onto ice. The product is extracted three times With 120 parts of methylene chloride. The combined extracts are dried and evaporated. The residue is distilled, yielding cyclobutyl 4- fluoro-3-nitrophenyl ketone; B.P. 148-150 C., at 0.8 mm. pressure.

A mixture of 33.4 parts of cyclobutyl 4-fluoro-3-nitrophenyl ketone, 5.6 parts of ammonia, 120 parts of meth anol and parts of sulfolane is stirred for 15 hours at room temperature. The solvent is evaporated. To the residue is added 100 parts of water and concentrated hydrochloric acid till acid. The precipitate is filtered 01f, Washed thoroughly with water and 2-propanol and dried. The product is recrystallized from 100 parts of 2-propanol, yielding 4-amino-3-nitrophenyl cyclobutyl ketone; M.P. 156 C.

A mixture of 8.8 parts of 4-amino-3-nitrophenyl cyclobutyl ketone, 128 parts of methanol, 4 parts of hydrochloric acid solution 10 N and 0.5 part of palladium-oncharcoal catalyst 10% is hydrogenated at normal pressure and at room temperature. After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. To the residue is added 32 parts of 2-propanol and then evaporated again. The solid residue is treated with 16 parts of 2-propanol and the precipitated product is fil tered off, washed successively with 2-propanol and ether, and dried, yielding 3,4-diaminophenyl cyclobutyl ketone hydrochloride; M.P. 170 C.

A mixture of 7 parts of S-methylisothiourea sulfate, 4.73 parts of methyl chloroformate and 9 parts of water is cooled on ice. At a temperature between 10 and 15 C. there is added dropwise a 25% sodium hydroxide solution until the pH remains at :8. Then there are added 6 parts of acetic acid, followed by the addition of 5.6 parts of 3,4-diaminophenyl cyclobutyl ketone hydrochloride. To this mixture is further added a solution of 2.25 parts of sodium acetate in 50 parts of water and the whole is stirred at C. for 45 minutes. The reaction mixture is cooled and the precipitated product is filtered off. It is washed successively with water, 2-propanol and ether, dried and recrystallized from a mixture of 50 parts of acetic acid and 80 parts of methanol, yielding methyl N-[5-(6) cyclobutylcarbonyl 2 benzimidazolyl]carbamate; M.P. 300 C.

EXAMPLE VII Methyl N- [5 (6 -cyclopentylcarbonyl-Z-benzimidazolyl] carbamate To a stirred mixture of 58.5 parts of aluminium chloride in 120 parts of fluorobenzene is added dropwise a hot solution of 33.4 parts of cyclopentanecarbonyl chloride in 20 parts of fluorobenzene at 60 C. Upon completion, stirring is continued at reflux temperature for 30 minutes. The reaction mixture is cooled and poured onto ice. The product is extracted three times with methylene chloride. The combined extracts are dried, filtered and evaporated. The oily residue is distilled, yielding cyclopentyl p-fluorophenyl ketone; B.P. 108111 C. at 1.5- 2 mm. pressure.

120 parts of concentrated nitric acid are cooled to 15 C. and while keeping the temperature between 20 and 10 0, there are added 39.6 parts of cyclopentyl p-fluorophenyl ketone. The mixture is stirred for 30 minutes at 15 to 10 C. After cooling to 30 C., it is poured onto crushed ice and the product is extracted three times with 80 parts of methylene chloride. The combined extracts are washed with water, dried and evaporated. The oily residue is distilled, yielding cyclopentyl 4-fiuoro- 3-nitrophenyl ketone; B.P. 120-160 C. at 0.8 mm. pressure.

A mixture of 37 parts of cyclopentyl 4-fluoro-3-nitrophenyl ketone, 5.35 parts of ammonia, 160 parts of methanol and 20 parts of sulfolane is heated in a sealed tube at 120 C. for 3 hours. The solvent is evaporated and to the residue is added parts of water and bydrochloric acid solution. The precipitated product is filtered off, washed thoroughly with water, 2-propanol and ligroin and dried, yielding 4-arnino-3-nitrophenyl cyclopentyl ketone; M.P. 131.8 C.

A mixture of 9.35 parts of 4-amino-3-nitrophenyl cyclopentyl ketone, parts of methanol, 4 parts of hydrochloric acid solution 10 N and 0.5 part of palladiumon-charcoal catalyst 10% is hydrogenated at normal pressure and at room temperature. After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. To the residue are added 40 parts of 2-propanol and the latter is evaporated again. The residue is triturated once more in 2-propanol, filtered off, washed with 2-propanol and dried, yielding 3,4-diaminophenyl cyclopentyl ketone hydrochloride; M.P. 300 C.

To a mixture of 7 parts of S-methylisothiourea sulfate and 4.73 parts of methyl chloroformate in 9 parts of water is added an excess of sodium hydroxide solution 25 till pH remains at 8, at a temperature below 20 C. Then there is added 6 parts of acetic acid, followed by the addition of 6 parts of 3,4-diaminophenyl cyclopentyl ketone hydrochloride. To this mixture is added a solution of 2.25 parts of sodium acetate in 50 parts of water and the whole is heated in a water-bath at 85 C. for 45 minutes. The reaction mixture is cooled and the precipitated product is filtered off. It is washed successively with water, 2-propanol and ether, dried and recrystallized from a mixture of 40 parts of acetic acid and 64 parts of methanol, yielding methyl N-[(6)-cyclopentylcarbonyl-2-benzimidazolyl]carbamate; M.P. 300 C.

EXAMPLE VIII Methyl N- [5 (6 -benzoyl-2-benzimidazolyl] carbamate A mixture of 5.2 parts of 4 chloro 3 nitrobenzophenone, 5 parts of ammonia, 72 parts of methanol and 13 parts of sulfolane is heated overnight at 125 C. in a sealed tube. The reaction mixture is evaporated in vacuo. The semi-solid residue is boiled in 100 parts of a diluted hydrochloric acid solution. After cooling, the precipitated product is filtered off and dissolved in chloroform. The chloroform phase is dried and evaporated. The residue is crystallized from toluene, yielding 4-amino-3-nitr0benzophenone; M.P. 141 C.

A mixture of 9.6 parts of 4-amino-3-nitrobenzophenone, 160 parts of methanol, 8 parts of concentrated hydrochloric acid and 1 part of palladium-on-charcoal catalyst is hydrogenated at normal pressure and at room temperature. After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filtered off and the solvent is evaporated, The solid residue is triturated in 2-propanol. The latter is partly evaporated and the solid product is filtered off, washed with 2-propanol and dried, yielding 3,4-diaminobenzophenone hydrochloride; M.P. 207 C.

7.8 parts of S-methylisothiourea sulfate are stirred in 10 parts of water in an ice-bath and there are added 4.5 parts of methyl chloroformate. While keeping the temperature below C., there are added dropwise, in the course of 10 minutes, 17 parts of sodium hydroxide solution (pHi8), followed by the addition of 5.6 parts of acetic acid (pHiS). To this mixture is added at 20 C. a suspension of 7 parts of 3,4-diaminobenzophenone hydrochloride in 100 parts of water, followed by the addition of 2.3 parts of sodium acetate. The whole is slowly heated to 85 C. and stirred at this temperature for 45 minutes, The reaction mixture is cooled and the precipitated product is filtered off. 'It is washed successively With water and ethanol, dried and crystallized from a mixture of acetic acid and methanol, yielding methyl N- 5 (6) -benzoyl-2-benzimidazolyl] carbarnate; M.P. 288.5 C.

EXAMPLE IX Ethyl N- [5 (6) -benzoyl-2-benzimidazolyl]carbamate 7.8 parts of S-methylisothiourea sulfate in 10 parts of water are cooled in an ice-bath and 5.2 parts of ethyl chloroformate are added. Then there are added dropwise 17 parts of sodium hydroxide solution 25% in the course of about 10 minutes at a temperature of about 20 C. (pHdzS). The pH is brought again to :5 by the addition of acetic acid (5.6 parts). Then there are added 7 parts of 3,4-diaminobenzophenone hydrochloride in 100 parts of water, followed by the addition of 2.3 parts of sodium acetate. The whole is heated slowly to 85 C, and stirred for 45 minutes. The reaction mixture is cooled and the precipitated product is filtered off. It is washed sucessively with water and ethanol and recrystallized twice: first from a mixture of 250 parts of glacial acetic acid and 80 parts of ethanol and further from a mixture of 100 parts of dimethylformamide and 80 parts of ethanol, yielding ethyl N-[5(6)-benzoyl-2- benzimidazolyl1carbamate; M.P. 300 C.

EXAMPLE X Methyl N-[5 (6)-p-fiuorobenzoyl-2-benzimidazolyl] carbamate To a stirred and cooled (ice-bath) suspension of 25 parts of aluminium chloride in 52 parts of fluorobenzene is added dropwise a solution of 27.5 parts of 4-chloro- 3-nitrobenzoyl chloride in 52 parts of fluorobenzene. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is poured onto water and the product is extracted with methylene chloride. The extract is washed successively with sodium hydrogen carbonate solution and water, dried, filtered and evaporated in vacuo. The solid residue is crystallized from 2-propanol, yielding 4-chloro-4' fluoro-3-nitrobenzophenone; M.P. 97.9 C.

A mixture of 24.5 parts of 4-chloro-4'-fluoro-3-nitrobenzophenone, 72 parts of methanol, 13 parts of sulfolane and 3.12 parts of ammonia is heated in a sealed tube for 20 hours at 120 C. To the reaction mixture is added successively 50 parts of water and 25 parts of a diluted hydrochloric acid solution and the whole is stirred and refluxed for 5 minutes. The reaction mixture is cooled and the precipitated product is filtered 01f. It is washed with 2-propanol and recrystallized from 640 parts of toluene, yielding 4-amino-4-fiuoro-3-nitrobenzophenone; M.P. 199 C.

A mixture of 14.5 parts of 4-amino-4-fluoro-3-nitrobenzophenone, 160 parts of methanol, 6 parts of concentrated hydrochloric acid solution and 0.5 part of platinum oxide is hydrogenated at normal pressure and at room temperature. After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The residue is washed with 2-propanol and dried, yielding 3,4-diamino-4'-fluorobenzophenone hydrochloride; M.P. 226-230.5 C.

A mixture of 8.9 parts of S-methylisothiourea sulfate, 6.05 parts of methyl chloroformate in 7 parts of water is cooled, and at a temperature of 510 0, sodium hydroxide solution 25% is added til pH=8. Then there are added successively 6.4 parts of acetic acid, 2.6 parts of sodium acetate and 8.9 parts of 3,4-diamino-4-fiuorobenzophenone hydrochloride and the whole is stirred while heating at C. for 45 minutes (during this reaction time, water and 2-propanol is added). The precipitated product is filtered otf, washed with methanol and recrystallized from a mixture of 200 parts of acetic acid and 80 parts of methanol, yielding methyl N-[5(6)- p-fluorobenzoyl 2 benzimidazolyl]carbamate; M.P. 260 C.

EXAMPLE XI Methyl N- [5 (6) -p-chlorobenzoyl-2-benzimidazolyl] carbamate To a stirred and cooled (ice-bath) suspension of 25 parts of aluminium chloride in 52 parts of chlorobenzene is added dropwise a solution of 27.5 parts of 4-chloro- 3-nitrobenzoyl chloride in 52 parts of chlorobenzene. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is poured onto water and the product is extracted with methylene chloride. The extract is washed successively with a solution of sodium hydrogen carbonate solution and water, dried, filtered and evaporated in vacuo. The solid residue is crystallized from 2-propanol, yielding 4,4'-dichloro-3- nitrobenzophenone; M.P. 83.4 C.

A mixture of 17.8 parts of 4,4'-dichloro-3-nitrobenzophenone, 10 parts of ammonia gas, 145 parts of methanol and 25 parts of sulfolane is heated overnight in a sealed tube at a temperature between -130 C. The methanol is distilled in vacuo and the residue is boiled in a diluted hydrochloric acid solution. The whole is cooled and the precipitated product is filtered off. It is washed with water and recrystallized from ethanol, yielding 4-amino- 4'-chloro-3-nitrobenzophenone; M.P. 200.9 C.

A mixture of 1.38 parts of 4-amino-4'-chloro-3-nitrobenzophenone, 40 parts of methanol, 0.5 part of concentrated hydrochloric acid solution and 0.2 part of platinum oxide is hydrogenated at normal pressure and at room temperature. After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The solid residue is crystallized from a mixture of methanol and ether,

11 yielding 3,4-diamino-4'-chlorobenzophenone hydrochloride; M.P. 190 C. (dec.).

To a cooled mixture of 5.1 parts of S-methylisothiourea sulfate in 10 parts of water are added 2.85 parts of methyl chloroformate. While keeping the temperature below 20 C., there are added dropwise (in about 10 minutes) 12 parts of sodium hydroxide solution 25% (pH=8). Then there are added 3.7 parts of acetic acid (pH=), followed by the successive additions of a suspension of 5.5 parts of 3,4-diamino-4-chlorobenzophenone hydrochloride in 40 parts of methanol and 50 parts of water, and then at once 1.5 parts of sodium acetate. The whole is heated to 85 C. and stirred at this temperature for 45 minutes. The reaction mixture is cooled and the precipitated product is filtered off. It is washed successively with water and ethanol and recrystallized twice from a mixture of acetic acid and methanol, yielding methyl N-[5(6)-p-chlorobenzoyl-2-benzimidazolyl] carbamate; M.P. 260 C.

EXAMPLE XII Methyl N-[S (6) -p-toluoyl-2-benzimidazolyl]carbamate A mixture of 16.6 parts of 4-chloro-4'-methyl-3-nitrobenzophenone, parts of gaseous ammonia, 145 parts of methanol and 25 parts of sulfolane is heated for about hours in a sealed tube at a temperature of about 120- 130 C. The methanol is distilled off in Nacuo. The residue is boiled in diluted hydrochloric acid solution. The precipitated product is filtered off, washed successively with 2-propanol and diisopropylether and crystallized from a mixture of acetic acid and water, yielding 4-a mino-4'- methyl-3-nitrobenzophenone; M.P. 145 C.

A mixture of 6.5 parts of 4-amino-4'-methyl-3-nitrobenzophenone, 200 parts of methanol, 2.5 parts of concentrated hydrochoric acid and 0.5 part of platinum oxide is hydrogenated at normal pressure and at room temperature. After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from a mixture of methanol and diisopropylether, yielding 3,4-diamino-4'-methylbenzophenone hydrochloride.

A mixture of 2.8 parts of S-methylisothiourea sulfate in 5 parts of water is cooled in an ice-bath and 1.55 parts of methyl chloroformate are added. While keeping the temperature below 20 C., there are added 7 parts of sodium hydroxide solution in the course of 10 minutes (pH-i8). Then there are added 2 parts of glacial acetic acid (pHiS), followed by the addition of a suspension of 2.6 parts of 3,4-diamino-4-methylbenzophenone hydrochloride in parts of water and 24 parts of methanol and finally 0.82 part of sodium acetate. The whole is heated on an oil-bath (85 C.) for 45 minutes. The precipitated product is filtered off, washed with water and ethanol and recrystallized from a mixture of glacial acetic acid and methanol, yielding methyl N-[5(6)-p-toluoyl-2- benzimidazolyl]carbamate; M.P. 284.6 C.

EXAMPLE XIII Methyl N- [5 (6 -p-methoxybenzoyl-2-benzimidazolyl] carbamate To a stirred and cooled (ice-bath) suspension of 25 parts of aluminium chloride in 5 2 parts of methoxybenzene is added dropwise a solution of 27.5 parts of 4-chloro-3- nitrobenzoyl chloride in 52 parts of methoxybenzene. Upon completion, stirring is continued overnight at room temperature. The mixture is poured onto crushed ice and the product is extracted with methylene chloride. The extract is washed with sodium hydrogen carbonate solution, dried, filtered and evaporated in vacuo. The residue is crystallized from 2-propanol, yielding 4-chloro-4'-methoxy-3-nitrobenzophenone; M.P. 105.5 C.

A mixture of 16.5 parts of 4-chloro-4'-methoxy-3- niu-obenzophenone, 2.1 parts of ammonia gas, 72 parts of methanol and 12.5 parts of sulfolane is heated for 16 hours in a sealed tube at 120 C. To the solution is added 25 parts of hydrochloric acid and 50 parts of water and the whole is stirred and refluxed for 5 minutes. The reaction mixture is cooled and the precipitated product is filtered off. It is crystallized from 120 parts of toluene, yielding 4-amino 4'-methoxy-3-nitrobenzophenone; M.P. 155.6 C.

A mixture of 5.8 parts of 4-amino-4'-methoxy-3-nitrobenzophenone, 96 parts of methanol, 2.1 parts of concentrated hydrochloric acid solution and 0.5 part of palladium-on-charcoal catalytst 10% is hydrogenated at normal pressure and at room temperature. After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The residue is washed with 2-propanol, yielding 3,4-diamino-4'-methoxybenzophenone hydrochloride.

A mixture of 2.8 parts of S-methylisothiourea sulfate, 5 parts of water and 1.55 parts of methyl chloroformate is cooled and while keeping the temperature between 5 and 15 0., there is added an excess of sodium hydroxide solution 25 till the pH remains at 8. Then there are added successively 2 parts of acetic acid, 0.82 part of sodium acetate and 2.73 parts of 3,4-diamino-4'-methoxybenzophenone hydrochloride and the whole is stirred for 45 minutes at a temperature of C. (during this time, water and methanol are added). The precipitated product is filtered off, washed with methanol, filtered oif again and finally .washed with 200 parts of water, yielding methyl N-[5(6)-p-methoxybenzoyl 2 benzimidazolyl]carbamate; M.P. 289 C.

EXAMPLE XIV Methyl N- [5 6) -2-then0yl) -2-benzimidazolyl] carbamate A suspension of 15 parts of aluminium chloride in 60 parts of methylene chloride is cooled in an ice-bath and there is added dropwise a solution of 25 parts of 4-ch1oro- 3-nitrobenzoyl chloride in 60 parts of methylene chloride, while keeping the temperature below 0 C. Upon completion, stirring is continued at room temperature, till all aluminium chloride enters solution. Then there are added dropwise, at 0 C., 10 parts of thiophene and the whole is stirred for one hour at room temperature. The reaction mixture is poured onto crushed ice. The organic layer is separated, washed with a sodium hydrogen carbonate solution, dried and evaporated. The oily residue solidifies on triturating in 2-propanol. The solid product is filtered olT and recrystallized from 2-propanol. The less pure fraction is dissolved in warm benzene, treated with activated charcoal, filtered and on the addition of petroleumether to the filtrate, the product is crystallized again, yielding 4chloro- 3-nitrophenyl 2-thienyl ketone; M.P. 117.8 C.

A mixture of 9.5 parts of 4-chloro-3-nitrophenyl 2- thienyl ketone, 5 parts of ammonia, 72 parts of methanol and 13 parts of sulfolane is heated in a sealed tube for 20 hours at -130 C. The methanol is evaporated and the residue solidifies on triturating in water. The solid is filtered off, washed once more with water and recrystallized from a mixture of acetic acid and water, yielding 4-amino-3-nitrophenyl Z-thienyl ketone; M.P. 168.4 C.

A suspension of 5.1 parts of 4-amino-3-nitrophenyl 2- thienyl ketone in 120 parts of methanol and 2 parts of concentrated hydrochloric acid solution is hydrogenated at normal pressure and at room temperature, in the presence of 0.5 part of palladium-on-charcoal 10% as catalyst. After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated in vacuo. The solid residue is triturated in a mixture of 2-propanol and diisopropylether and dried, yielding 3,4-diaminophenyl 2-thienyl ketone hydrochloride; M.P. C.

To a stirred and cooled (ice-bath) mixture of 4.7 parts of S-methylisothiourea sulfate in 7 parts of water are added 2.6 parts of methyl chloroformate. While keeping the temperature below 20 C., there are added dropwise about 11 parts of sodium hydroxide solution 25% (pHiB), followed by the addition of 3.4 parts of acetic acid (pHiS). Then there are added successively 1.4 parts of sodium acetate and a solution of 4.3,.p'arts of 3,4-diaminophenyl'Z-thienyl ketone hydrochloride in 75 parts of water. The whole is heated (water-bath) to 85 C. and stirred at this temperature for 45 minutes. The reaction mixture is cooled and the precipitated product is filtered off, washed with water and ethanol and recrystallized from a'fmixture of acetic acid and methanol, yielding methyl N-[S (6 -(2-thenoyl) -2-benzimidazolyl] carbamate; M.P. 288.7 C.

' EXAMPLE XV This example demonstrates the anthelrnintic activity of the compounds of Formula I. The faeces of half-grown or adult sheep, infected with different species of nematodes, are microscopically examined to identify the eggs of intestinal nematodes and the number of eggs per gram (EPG) is determined using the MacMaster technique. Each? animal is examined twice within the same week. The EPG for each worm species is the mean number of 4 MacMa'ster counts. The mean EPG for each species, after two examinations, is the average of 8 counts. The sheep are then treated with the compound to be evaluated, the drug being administered once by oesophagal intubation (10 mg.-"j/kg.). The treated animals are maintained in separate quarters and each animal is examined for two weeks. TheEPG data are recorded using the same technique as betfore treatment. The percent egg reduction is the ratio of the mean EPG after treatment divided by the mean EPG before treatment and multiplied by 100. The eirectivenessof the studied compounds are thus rated according to the following scale: 1

Percent activity It is understood that the compounds in the following table are not listed for purposes of limiting the invention thereto, but only to exemplify the useful properties of all the compounds within the scope of Formula I.

1 Gordon, H. McL. and WlhltlOCk, H. V. .1. Corn, scient. 1nd. Res. (Austn), 12, 50 (19\39) 14 EXAMPLE XVI 4-amino3-nitrobenzophenone O *N at NH-COOR; N

wherein R is a member selected from the group consisting of lower alkyl, cycloalkyl having 3 to 6 carbon atoms, phenyl, halophenyl in which said halo is of atomic weight less than 80, (lower alkyl)-phenyl, (lower alkoxy)-phenyl and Z-thienyl; R isfa member selected from the group consisting of methyl and ethyl; and the RCO substituent is located at the 5(6)-position.

2. An alkyl N-[5(6)-aroyl 2 benzimidazolyl1carbamate of the formula:

wherein Ar is a member selected from the group consisting of phenyl, halophenyl in which said halo is of atomic weight less than 80, (lower alkyl)-phenyl, (lower alkoxy)-phenyl and Z-thienyl; R is a member selected from the group consisting of methyl and ethyl; and the substituent is located at the 5(6)-position 3. Methyl N-[5(6)-acetyl 2 benzimidazolyllcarbamate.

ll R-C N -NHGOOR1 Tricho- Stron- N emato- Bunos- R R strongylus Ostertagla Cooperla Hoemoncus glyoides d1rus tomum Chabertia Me Me 0 0 0 Et Me n-P Me n-Bu M as. h: iiii iiii iiii 5 3F15 %e 0 0 0 I I M26-Ph M (l 2-th1enyl Me l l pH m 0 0 4. Methyl N-[5(6)-propionyl-2-benzimidazolyl]carbamate.

5. Methyl N-[5(6)-butyryl 2 benzimidazoly1]carbamate.

6. Methyl N-[5(6)-cyclopropylcarbonyl-Z-benzimidazolyl] carbamate.

7. Methyl N-[5(6)-valeryl 2 benzimidazolyHcarbamate.

8. Methyl N-[5(6)-cyclobutylcarbonyl-2 benzimidazolyl] carbamate.

9. Methyl N-[5(6)-cyclopentylcarbonyl-2-benzimidazolyl] carbamate.

10. Methyl N-[5(6)-benzoyl-2 benzimidazolyl1carbamate.

'11. Ethyl N-[5(6)-benzoyl 2 benzimidazolyl]carbamate.

12. Methyl N[5 (6)-p-fluorobenzoyl 2 benzimidazolyl]carbamate.

13. Methyl N-[5 (6)-p-chlorobenzoyl 2 benzirnidazolyl]carbamate.

14. Methyl N-[5(6)-p-toluoyl-2 benzimidazolyHcarbamate.

16 15. Methyl N-[5(6)-p-methoxybenzoy1-2 benzimidazoly1]carbamate.

16. Methyl N-[5(6)-(2-thenoy1) 2 benzimidazolyl] carbamate.

References Cited UNITED STATES PATENTS 2,034,274 3/1936 Story 44-9 3,010,968 11/1961 Loux 260-3092 10 3,480,642 11/1969 Stedrnan 260-309.2

FOREIGN PATENTS 1,123,317 8/1968 Great Britain 260-309.2

15 HENRY R. JILES, Primary Examiner G. T. TODD, Assistant Examiner US. Cl. X.R.

po-ww UNITED STATES PATENT OFFICE CERTIFICATE W CORREC T. IQN

Patent NO. 3, 57, 7 Dated April 18,1972

rg) Josephus Ludovicus Hubertus Van Gelder et al It is certified that error appears in the above-identified patentv and that said Letters Patent are hereby corrected as shown below:

1 H zN-C- -N-COOR In Column 2, lines +7 and n8, S-CH should read S-CH Signed and sealed this 3rd day of October 1972;

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK' Attesting Officer Commissioner of Patents