US3017415A - Certain benzimidazoles carrying thiazolyl, thiadiazolyl and isothiazolyl substituents in the 2 position - Google Patents

Certain benzimidazoles carrying thiazolyl, thiadiazolyl and isothiazolyl substituents in the 2 position Download PDF

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US3017415A
US3017415A US2856A US285660A US3017415A US 3017415 A US3017415 A US 3017415A US 2856 A US2856 A US 2856A US 285660 A US285660 A US 285660A US 3017415 A US3017415 A US 3017415A
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benzimidazole
thiazolyl
acid
thiadiazolyl
solution
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US2856A
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Lewis H Sarett
Horace D Brown
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Merck and Co Inc
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Merck and Co Inc
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Priority to BE599143D priority Critical patent/BE599143A/xx
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Priority to US2856A priority patent/US3017415A/en
Priority to US15518A priority patent/US3055907A/en
Priority to DEM45481A priority patent/DE1235321B/de
Priority to GB20378/60A priority patent/GB948635A/en
Priority to ES0263822A priority patent/ES263822A1/es
Priority to FR849060A priority patent/FR1423609A/fr
Priority to CH1531865A priority patent/CH423793A/de
Priority to CH1531565A priority patent/CH423790A/de
Priority to CH1531665A priority patent/CH423791A/de
Priority to CH1531765A priority patent/CH423792A/de
Priority to SE436/61A priority patent/SE310883B/xx
Priority to DK19761AA priority patent/DK107167C/da
Priority to CH49061A priority patent/CH423789A/de
Application granted granted Critical
Publication of US3017415A publication Critical patent/US3017415A/en
Priority to OA51102A priority patent/OA00999A/xx
Priority to CY30965A priority patent/CY309A/xx
Priority to MY196575A priority patent/MY6500075A/xx
Priority to SE11797/67A priority patent/SE320977B/xx
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to new compounds useful against helminthiasis. It relates generally to new derivatives of benzimidazole. More particularly, it relates to benzimidazoles having at the 2 position a heterocyclic radical containing nitrogen and sulfur. It is concerned also with methods of making such compounds.
  • the infection known as helminthiasis involves infestation of the animal body, and particularly the gastrointestinal tract, with various species of parasitic worms. It is a very widespread and serious disease, and the methods heretofore available for its treatment and prevention have not been entirely satisfactory. It is an object of this invention to provide a group of substituted benzimidazoles which are effective in controlling helminthiasis, and which lack many of the objectionable features of the known anthelmintics.
  • benzimidazoles having at the 2 position of the benzimidazole ring nucleus a heterocyclic radical containing nitrogen and sulfur possess a significant degree of anthelmintic activity and may be effectively employed in the treatment and/or prevention of helm-inthiasis. It is one object of the invention to provide such compounds. It is a more particular object to provide benzimidazoles substituted at the 2 position with a five-membered heterocyclic radical containing nitrogen and sulfur. A further object is provision of methods of synthesizing such compounds. Still other objects will become apparent from the following description of the invention.
  • the new compounds of our invention have the general structural formula wherein R is a five-membered heterocyclic radical containing nitrogen and sulfur and R is hydrogen, a lower alkyl or a lower alkenyl radical.
  • R is a five-membered heterocyclic radical containing nitrogen and sulfur and R is hydrogen, a lower alkyl or a lower alkenyl radical.
  • the invention also includes within its scope acid addition salts of these benzimidazoles.
  • the five-membered heterocyclic radical (R in the above formula), which is attached to the benzimidazole at one of its carbon atoms, may be a thiazolyl, isothiazolyl or thiadiazolyl radical.
  • R is a thiazolylor isothiazolyl moiety
  • the point of attachment to the benzimidazole nucleus may be at any one of the three carbon atoms of the heterocyclic ring, as indicated by the broken lines in the partial structures:
  • R is a thiadiazolyl group containing two nitrogen atoms and one sulfur atom in the ring
  • the radical may be attached to the benzimidazole at either of the two carbon atoms in a 1,2,3-thiadiazle or a 1,2,4-thiadiazole:
  • N la is
  • the heterocyclic radical may, if desired, be further substituted at a carbon atom with a lower hydrocarbon group such as a lower alkyl radical, the only limitation in this regard being that imposed by the availability of the substituted thiazoles, isothiazoles or thiadiazoles to be used as starting materials.
  • 2-(2-thiazolyl)-benzimidazoles having a lower alkyl group at the 4 position of the thiazole ring and the 2-(5-isothiazolyl)-benzimidazoles having a lower alkyl group at the 3 position of the isothiazole ring such as 2-(4-methyl-2'-thiazolyl) benzimidazole and 2-(3-methyl-5'-isothiazolyl)-benzimidazole are illustrative of this aspect of the invention.
  • the N-l position of the benzimidazoles may be substituted with hydrogen, a lower alkyl group such as methyl, ethyl, propyl or isopropyl, or a lower alkenyl radical of the type represented by allyl and methallyl.
  • the alkyl and alkenyl radicals preferably contain less than six carbon atoms.
  • the six-membered ring of the benzimidazole nucleus may also be substituted, as with lower alkyl groups at the 5 and/ or 6 positions.
  • Methyl groups are the preferred substituents although ethyl, propyl and similar lower alkyl radicals may, of course, be employed.
  • the so-called pseudo-alkyl radicals such as a trifluoromethyl substituent, may also be present at the 5 or 6 positions of the benzimidazole.
  • the 2-substituted benzimidazoles described herein are isolated as the free bases by the synthetic processes normally employed. They are readily converted to acid addition salts by treatment with acid. Typical salts which may be formed in this manner are mineral acid salts such as the hydrohalides, e.g.
  • hydrochloride hydrobromide, hydroiodide, sulfates, nitrates, phosphates, and the like, aliphatic acid salts such as the acetate, trimethylacetate, t-butylacetate, or propionate, salts of polycarboxylic acids such as the citrate, oxalate, succinate and the like and salts of other insoluble organic acids such as the embonate and hydroxynaphthoate salts. Certain of these salts are much more water soluble than the free bases. This is true of the hydrohalides.
  • solubility properties of a particular compound may be generally adjusted by judicious selection of a salt.
  • the compounds of this invention are used in salt form as anthelmintics, it is, of course, desirable that the particular acid employed be an edible, non-toxic one.
  • the 2-thiazoly1 benzimidazoles wherein the point of attachment to the benzimidazole moiety is either the 2 or 4 position of the thiazole ring, represent the preferred compounds of the invention.
  • the preparation of these substances and the other Z-substituted benzimidazoles described herein comprises broadly the reaction of thiazolyl, isothiazolyl or thiadiazolyl carboxylic acid or derivative thereof, such as an ester, amide, nitrile acid halide or aldehyde, with a compound of the general formula R NH:
  • Y is -NO NH or -NHR
  • R is lower alkyl or lower alkenyl
  • R and R are hydrogen or lower alkyl (or pseudo-alkyl).
  • the Z-heterocyclic benzimidazoles are prepared by reacting together o-phenylenediamine and a heterocyclic carboxylic acid (or derivative thereof) in polyphosphoric acid.
  • the process is carried out at elevated temperatures, and preferably at temperatures of about 150300 C.
  • the optimum reaction time and temperature will of course, depend to some extent on the particular reactants being employed, but in general good yields of the desired compounds are obtained by conducting the process at temperatures of about 175 to about 275 C. for from 2 to 6 hours.
  • the heterocyclic reactant is one that tends to decompose at elevated temperature, e.g.
  • thiazole-2-carboxamide is preferred over thiazole-Z-carboxylic acid as starting material in the synthesis of 2-(2-thiazoyl)-benzimidazole since the free acid tends to decompose to thiazole itself at reaction temperature.
  • the desired Z-substituted benzimidazoles are recovered by cooling the reaction mixture and diluting it with water. Where the benzimidazoles do not crystallize readily under these conditions, they are precipitated by neutralizing the quenched mixture with a base such as ammonium hydroxide, an alkali metal hydroxide or an alkali metal carbonate.
  • the Z-heterocyclic benzimidazole compounds may be synthesized by reacting together o-phenylene-diamine and an aldehydo heterocyclic compound such as thiazole-4-aldehyde or 1,2,3-thiadiazole-4-aldehyde in a reaction medium comprising nitrobenzene.
  • a 1-alkyl-2- heterocyclic benzimidazole, such as 1-methyl-2[4-(1,2, 3'-thiadiazolyl)]-benzimidazole is produced from N- methyl-o-phenylenediamine. Good results are obtained by heating the reaction mixture slowly to the reflux temperature (ca. 210 C.), and maintaining that temperature for a very short time.
  • a solvent such as a lower alkanol may be used to promote solubility of the reactants at lower temperatures. Such solvents are allowed to distil oil during the heating period.
  • the Z-heterocyclic benzimidazoles are readily recovered. In many cases they crystallize directly on cooling the nitrobenzene solution. Alternatively, they may be crystallized by addition of ether or petroleum ether to the nitrobenzene solution.
  • 2-heterocyclic benzimidazoles are prepared by condensation of a heterocyclic aldehyde with a compound of Formula II above.
  • the reaction is preferably brought about in a suitable solvent such as a lower alkanol, e.g. methanol, ethanol, isopropanol or t-butanol.
  • a suitable solvent such as a lower alkanol, e.g. methanol, ethanol, isopropanol or t-butanol.
  • the first product formed is the Schiff base of the aldehyde and the primary amine. In normal practice this is not isolated but rather converted directly to the benzimidazole.
  • the ring closure of the Schiff base to the 2-heterocyclic benzimidazole is effected with a suitable oxidizing agent such as cupric acetate, lead tetracetate, mercuric acetate, air and the like.
  • an ester or an acid halide derivative of the hetrocycle is employed.
  • An intermediate anilide is formed initially.
  • the nitro group is then reduced and benzimidazole formation effected by treatment of the intermediate anilide with a reducing system such as zinc-hydrochloric acid or zinc-acetic acid.
  • a heavy metal reagent is used to bring about benzimidazole formation from an o-phenylenediamine in the above two processes, an insoluble heavy metal salt of the Z-heterocyclic benzimidazole is formed.
  • This material is readily converted to the free benzimidazole by removal of the heavy metal with reagents suitable for this purpose such as hydrogen sulfide, ammonium polysulfide, ammonium hydroxide and the like.
  • 2-heterocyclic benzimidazoles are prepared by heating a mixture of an o-phenylenediame or an N-alkyl-o-phenylenedi amine and a lower alkyl heterocyclic carboxylate with an aqueous mineral acid such as aqueous sulfuric or phosphoric acid in a closed system, i.e. an autoclave or bomb. The process is conducted at temperatures of from about 180 C. for 3-10 hours, and the 2-hetero cyclic benzimidazole recovered from the acid reaction mixture by application of the isolation and purification techniques described hereinabove.
  • 1-substituted-Z-heterocyclic benzimidazoles where R in Formula. I above is alkyl or alkenyl, may further be synthesized by alkylation or alkenylation of the 2-hetero' cyclic benzimidazole itself.
  • an alkali metal salt of the benzimidazole is reacted with an ester of a strong acid and a lower alkanol or lower alkenol, such as methyl bromide, methyl iodide, allyl bromide and the like, or with an alkyl sulfate such as dimethyl sulfate.
  • the Z-Substituted benzimidazoles described herein have a high degree of anthelmintic activity and are useful in the treatment and/ or prevention of helminthiasis, a parasitic disease which causes widespread and often serious infection in domesticated animals such as swine, ruminants such as cattle and sheep and even in man.
  • the compounds are mixed with a non-toxic edible carrier to form a feed supplement which is then incorporated in the animal feed in the desired concentration, or they may be administered in unit dosage forms which, in the case of large domesticated animals, take the form of boluses, or in the form of a liquid drench.
  • water soluble salts or a dispersable, wettable powder containing the 2-heterocyclic benzimidazole may be added to the drinking water of the animals.
  • EXAMPLE 3 2- [4 (1 ,2 ,3 '-thiadiaz0lyl l-benzimidazole 6.0 g. of 4-carbethoxy-1,2,3-thiadiazole and 8.0 g. of o-phenylenediamine are added to 120 g. of polyphosphoric acid preheated to about 80 C. in a nitrogen atmosphere. After stirring for one hour at 125 C. the temperature is raised to 225 C. for one hour. The brown solution is cooled to about 100 C. and poured (with stirring) in a thin stream into 200 cc. of cold water. A dark green amorphous solid is filtered OE and the filtrate neutralized to pH ca. 7 With sodium hydroxide solution.
  • EXAMPLE 4 2- [3 1 ,2',5 -thiadiazolyl) -benzimidaz0le 12.8 g. (0.081 mole) of 3-carbethoxy-1,2,5-thiadiazole, 11 g. (0.1 mole) of o-phenylenediamine and 50 g. of polyphosphoric acid are mixed and heated with stirring at 175 C. in a nitrogen atmosphere for 3 hours. At this time, the dark solution is cooled to about 100 C. and then slowly poured with stirring into about 500 ml. of cold water. The tacky threads slowly change to a brown solid. The suspension is neutralized to pH ca. 7 to precipitate the remainder of the product.
  • the solid is washed with water, sodium bicarbonate solution to insure neutrality and dried in air.
  • the 2-[3'-(1,2,5'- thiadiazolyl)J-benzimidazole is then recrystallized from ethyl acetate solution with a decolorizing charcoal treatment, M.P. 26870 C. (sublimation 240). Recrystalization from ethyl acetate raises the M.P. to 272 274 C.
  • the hydrobromide salt of this product is prepared by dissolving the product in hot alcoholic hydrogen bromide, treating the hot solution with activated charcoal, removing the charcoal by filtration, and adding about 3 volumes of ether to the alcoholic solution.
  • the hydrobromide salt crystallizes on cooling.
  • EXAMPLE 6 l-methyl-Z-(4-thiaz0lyl)-benzimidaz0le A. To 10 g. of 2-(4-thiazolyl)-benzirnidazole in 100 m1. of dry dimethylformamide is added 2.3 g. of a 52% sodium hydride emulsion in mineral oil. The mixture is stirred at room temperature for about 20 minutes and then warmed carefully to about C. for 10 minutes. It is cooled to room temperature and 7.1 g. of methyl iodide in 10 ml. of dimethylformamide is added slowly to the cooled solution. The reaction mixture is then heated to about 80 C. for 20 minutes, cooled, diluted with 200 ml.
  • the above product is also produced by adding 5 g. of N-methyl-o-phenylenediamine dihydrochloride in 75 ml. of 50% alcohol to a solution of 10 g. of cupric acetate and 6 g. of thiazole-4-aldehyde in 300 ml. of Water. The addition is carried out at about 0 C. and the reaction mixture is then heated in a hot water bath for about 30 minutes.
  • the resulting brown solid is recovered by filtration and washed with cold water and ethanol. It is then suspended in dilute hydrochloric acid and a stream of hydrogen sulfide bubbled slowly through the suspension until it is saturated with hydrogen sulfide. It is filtered and the filtrate obtained after removal of the copper sulfide is concentrated to dryness and the residue dissolved in a small volume of water. The solution is neutralized with potassium carbonate solution and extracted with chloroform. The chloroform extract is concentrated to dryness and the resulting residue extracted with petroleum ether. On concentration of the petroleum ether extracts, to a small volume, 1-methyl-2-(4-thiazolyl) -benzimidazole precipitates.
  • the hydrochloride salt is obtained by treatment of the base with ethanolic hydrogen chloride by the method described in Example 10.
  • EXAMPLE 8 2-(2'-thiaz0lyl) -benzimidazole To 11 g. of o-phenylenediamine in 100 ml. of ethanol is added with stirring 11.3 g. of thiazole-Z-aldehyde in 100 ml. of ethanol. This mixture is stirred for about 1 hour at room temperature after which time 20 g. of cupric acetate monohydrate in 200 ml. of water is added dropwise with rapid stirring. After this addition is completed, the reaction mixture is heated at gentle reflux for about 30 minutes. It is then cooled and the copper salt recovered by filtration and washed with water. It is then suspended in 250 ml. of 95% ethanol and saturated with hydrogen sulfide (with stirring). The insoluble copper sulfide is removed by filtering and the clear filtrate concentrated essentially to dryness. The 2-(2'-thiazolyl)- benzimidazole thus obtained is purified by recrystallization from aqueous ethanol.
  • EXAMPLE 10 A. 5 g. of 2-(2-thiazolyl)-benzimidazole is added with stirring to 100 ml. of ethanol saturated with dry hydrogen chloride. An additional 125 ml. of ethanol is added to give a dark brown solution. The solution is treated with 5 g. of activated charcoal and the charcoal removed by filtration. The clear filtrate is diluted with three times its volume of ethyl ether and the resulting mixture chilled. After a short time, crystals of 2-(2'-thiazolyl)-benzimidazole monohydrochloride appear, M.P. 246 C.
  • EXAMPLE 12 2(4-tlziaz0lyl)-5,6-dimethyl benzimidazole 8 g. of 4-thiazolyl aldehyde in ml. of ethanol is added at room temperature to 10 g. of 4,5-dimethyl-ophenylenediamine in 200 ml. of ethanol. The mixture is stirred for one hour at room'temperature and a solution of 16 g. of cupric acetate in 400 ml. of water is added in small portions.
  • EXAMPLE 15 2-(4-thiaz0lyl) -benzimidaz0le 13 g. of 4-thiazolyl acid chloride and 13 g. of o-nitroaniline are stirred together in 35 ml. of pyridine at room temperature for about 12 hours. At the end of this time, the mixture is quenched in ice water and the solid nitroanilide recovered by filtration and Washed with dilute sodium carbonate solution. The solid is suspended in ml. of glacial acetic acid, and 80 ml. of o-N-hydrochloric acid added to the suspension. 60 g. of zinc dust is added in small portions to the acetic mixture.
  • reaction mixture is filtered and the filtrate neutralized with concentrated ammonium hydroxide to precipitate 2-(4-thiazolyl)-benzimidazole.
  • the product is purified by recrystallization from ethyl acetate.
  • 2-(4-thiazolyl)-5-trifluoromethyl benzimidazole is prepared by the method set forth in the preceding paragraph employing 20.5 g. of 3-nitro-4-aminobenzotrifluoride as starting material in place of o-nitroaniline.
  • EXAMPLE 16 3 g. of 2-(4-thiazolyl)-benzimidazole is dissolved in boiling methanol which contains a few drops of phenolphthalein solution. 15 m1. of 1 N sodium methoxide and 2 ml. of dimethyl sulfate are added. After a rapid reaction the solution is no longer alkaline. The same quantities of sodium methoxide and dimethyl sulfate are added again followed by 25 m1. of sodium methoxide solution. The final solution is concentrated to dryness and the residue extracted with benzene. The extracts are treated with activated charcoal and concentrated to a residue of 1- methyl-Z-(4-thiazolyl)-benzimidazole which crystallizes in petroleum ether.
  • R is selected from the group consisting of hydrogen, lower alkyl and lower alkenyl
  • R and R are selected from the class consisting of hydrogen, lower alkyl and trifiuoromethyl groups and acid non-toxic addition salts thereof.

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US2856A 1960-01-18 1960-01-18 Certain benzimidazoles carrying thiazolyl, thiadiazolyl and isothiazolyl substituents in the 2 position Expired - Lifetime US3017415A (en)

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Application Number Priority Date Filing Date Title
BE599143D BE599143A (en)) 1960-01-18
US2856A US3017415A (en) 1960-01-18 1960-01-18 Certain benzimidazoles carrying thiazolyl, thiadiazolyl and isothiazolyl substituents in the 2 position
US15518A US3055907A (en) 1960-01-18 1960-03-17 Acyl benzimidazoles and method of preparing same
DEM45481A DE1235321B (de) 1960-01-18 1960-06-01 Verfahren zur Herstellung von substituierten Benzimidazolen und ihren Salzen
GB20378/60A GB948635A (en) 1960-01-18 1960-06-09 Benzimidazole
ES0263822A ES263822A1 (es) 1960-01-18 1961-01-04 Procedimiento para la obtenciën de productos derivados de bencimidazole
FR849060A FR1423609A (fr) 1960-01-18 1961-01-06 Dérivés de la benzimidazole et leur procédé de fabrication
CH1531665A CH423791A (de) 1960-01-18 1961-01-17 Verfahren zur Herstellung eines Benzimidazols
CH1531865A CH423793A (de) 1960-01-18 1961-01-17 Verfahren zur Herstellung von 1-Alkyl- und 1-Alkenylbenzimidazolen
CH1531765A CH423792A (de) 1960-01-18 1961-01-17 Verfahren zur Herstellung von 1-Acyl-2-substituierten Benzimidazolen
SE436/61A SE310883B (en)) 1960-01-18 1961-01-17
DK19761AA DK107167C (da) 1960-01-18 1961-01-17 Fremgangsmåde til fremstilling af benzimidazolforbindelser eller syreadditionssalte deraf.
CH49061A CH423789A (de) 1960-01-18 1961-01-17 Verfahren zur Herstellung eines Benzimidazols
CH1531565A CH423790A (de) 1960-01-18 1961-01-17 Verfahren zur Herstellung eines Benzimidazols
OA51102A OA00999A (fr) 1960-01-18 1964-12-29 Dérivés de la benzimidazole et leur procédé de fabrication.
CY30965A CY309A (en) 1960-01-18 1965-02-18 Benzinide
MY196575A MY6500075A (en) 1960-01-18 1965-12-31 Benzimidazoles
SE11797/67A SE320977B (en)) 1960-01-18 1967-08-23

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US2856A US3017415A (en) 1960-01-18 1960-01-18 Certain benzimidazoles carrying thiazolyl, thiadiazolyl and isothiazolyl substituents in the 2 position
US15518A US3055907A (en) 1960-01-18 1960-03-17 Acyl benzimidazoles and method of preparing same

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US15518A Expired - Lifetime US3055907A (en) 1960-01-18 1960-03-17 Acyl benzimidazoles and method of preparing same

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BE (1) BE599143A (en))
CH (5) CH423792A (en))
CY (1) CY309A (en))
DE (1) DE1235321B (en))
DK (1) DK107167C (en))
ES (1) ES263822A1 (en))
FR (1) FR1423609A (en))
GB (1) GB948635A (en))
MY (1) MY6500075A (en))
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Cited By (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3183239A (en) * 1961-02-23 1965-05-11 Merck & Co Inc 5-ether and 5-thioether-2-heterocyclic benzimidazoles
US3239532A (en) * 1960-04-07 1966-03-08 Geigy Ag J R Certain diazolylmethyl esters of thiophosphoric and dithiophosphoric acids
US3299080A (en) * 1962-07-05 1967-01-17 Merck & Co Inc Processes and intermediates for preparing certain 2-thiazolylbenzimidazoles
DE1237731B (de) * 1963-05-23 1967-03-30 Merck & Co Inc Mittel zur Bekaempfung von Fungus-Wachstum
US3324102A (en) * 1963-01-31 1967-06-06 Merck & Co Inc Water-soluble benzimidazole-containing coordination compounds and methods relating thereto
US3347908A (en) * 1963-06-24 1967-10-17 Merck & Co Inc Nu-lactoyl and nu-halopyruvoyl-2-nitroanilides
US3350211A (en) * 1964-12-31 1967-10-31 Merck & Co Inc Compositions useful in controlling marine fouling and methods for their use
US3361756A (en) * 1963-11-29 1968-01-02 Merck & Co Inc 2-(alpha-haloalkanoyl) benzimidazoles
US3398157A (en) * 1964-12-31 1968-08-20 Merck & Co Inc Process for preparing benzimidazole nu-oxides
US3429890A (en) * 1964-12-31 1969-02-25 Merck & Co Inc Certain 2-thiazolylbenzimidazole-1-oxy derivatives
US3471508A (en) * 1963-11-06 1969-10-07 Merck & Co Inc 5-aryl (or heteroaromatic) benzazoles
US3475444A (en) * 1966-02-18 1969-10-28 Merck & Co Inc Complexes of 2-substituted benzimidazoles and bis-halogenated phenols
US3478046A (en) * 1963-11-19 1969-11-11 Merck & Co Inc 5-(or 6)-halo(or amino)benzazoles and methods for preparing same
US3484519A (en) * 1965-12-02 1969-12-16 Merck & Co Inc Anthelmintic 2-substituted benzimidazole-metal arsenate compositions and method
US3506678A (en) * 1967-02-21 1970-04-14 Merck & Co Inc Certain 2-substituted thieno(2,3-d) imidazoles
US3535331A (en) * 1967-07-26 1970-10-20 Merck & Co Inc Water-soluble 2-substituted benzimidazole hypophosphite salts
US3538108A (en) * 1967-08-17 1970-11-03 Merck & Co Inc Water - soluble 2 - substituted benzimidazole methanesulfonic acid salts
US3546341A (en) * 1966-02-18 1970-12-08 Merck & Co Inc Complexes of 2-substituted benzimidazoles and bis-halogenated phenols in anthelmintic compositions and methods
US3711608A (en) * 1971-04-13 1973-01-16 Merck & Co Inc The treatment of pain, fever and inflammation with benzimidazoles
US3899503A (en) * 1974-01-25 1975-08-12 Morton Norwich Products Inc Process for preparing 2-(2{40 )-furyl-, 2-(2{40 )-thienyl- 2-(4{40 )-thiazolyl- or 2-(2{40 )-pyrryl-5 (or 6) nitrobenzimidazole
US3928372A (en) * 1967-12-06 1975-12-23 Merck & Co Inc 2-(3-Oxythiazolyl)benzimidazoles
US3998785A (en) * 1974-06-13 1976-12-21 International Business Machines Corporation Anti-fungal and/or anti-bacterial hardware for ink printing apparatus
US4006259A (en) * 1975-04-01 1977-02-01 Fmc Corporation Preservative coating for fruits and vegetables
US4247442A (en) * 1978-03-29 1981-01-27 Toray Silicone Company, Ltd. Mold and mildew resistant organopolysiloxane compositions
JPS6351305A (ja) * 1985-06-05 1988-03-04 ユニロイヤル　リミテツド 相乗作用性の殺菌剤組成物
AU596635B2 (en) * 1986-01-27 1990-05-10 Shell Internationale Research Maatschappij B.V. Fungicidal compositions
US5013746A (en) * 1988-04-08 1991-05-07 Janssen Pharmaceutica N.V. Imazalil containing synergistic compositions
WO2004047769A3 (en) * 2002-11-26 2004-09-10 Isis Pharmaceuticals Inc Benzimidazoles and analogs thereof as antibacterials
US20050148639A1 (en) * 2002-03-21 2005-07-07 Basf Aktiengesellschaft Fungicidal mixtures
WO2009040397A1 (en) 2007-09-26 2009-04-02 Basf Se Ternary fungicidal compositions comprising boscalid and chlorothalonil
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Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3625954A (en) * 1968-03-20 1971-12-07 Pfizer 1-aroylbenzimidazoles
US3864351A (en) * 1971-10-04 1975-02-04 Pfizer 1-({60 -Carboxymethoxybenzoyl-2-(2{40 -pyridyl)benzimidazoles
US4017504A (en) * 1975-06-12 1977-04-12 Merck & Co., Inc. Antifungal 1-substituted benzimidazoles
US4017503A (en) * 1975-06-12 1977-04-12 Merck & Co., Inc. Antifungal 1-substituted benzimidazoles
WO1990010630A1 (en) * 1989-03-15 1990-09-20 Janssen Pharmaceutica N.V. [5(6)-(benzisoxa-, benzisothia- or indazol-3-yl)-1h-benzimidazol-2-yl] carbamates
NZ232785A (en) * 1989-03-15 1991-03-26 Janssen Pharmaceutica Nv 5-(1,2 benzisoxazol-, benzimidazol and benzisothiazol-3- yl)-1h-benzimadazol-2-yl carbamic acid ester derivatives preparatory processes, intermediates and anthelmintic compositions
US5310924A (en) * 1993-04-30 1994-05-10 E. I. Du Pont De Nemours And Company Process for preparing thiabendazole

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2985661A (en) * 1956-02-06 1961-05-23 American Cyanamid Co Preparation of 2(omicron-aminophenyl)-benzimidazole

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2483392A (en) * 1949-10-04 Substituted ethylenes and process

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2985661A (en) * 1956-02-06 1961-05-23 American Cyanamid Co Preparation of 2(omicron-aminophenyl)-benzimidazole

Cited By (69)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3239532A (en) * 1960-04-07 1966-03-08 Geigy Ag J R Certain diazolylmethyl esters of thiophosphoric and dithiophosphoric acids
US3183239A (en) * 1961-02-23 1965-05-11 Merck & Co Inc 5-ether and 5-thioether-2-heterocyclic benzimidazoles
US3299080A (en) * 1962-07-05 1967-01-17 Merck & Co Inc Processes and intermediates for preparing certain 2-thiazolylbenzimidazoles
US3324102A (en) * 1963-01-31 1967-06-06 Merck & Co Inc Water-soluble benzimidazole-containing coordination compounds and methods relating thereto
DE1237731B (de) * 1963-05-23 1967-03-30 Merck & Co Inc Mittel zur Bekaempfung von Fungus-Wachstum
US3370957A (en) * 1963-05-23 1968-02-27 Merck & Co Inc Antifungal compositions and methods for their use
US3347908A (en) * 1963-06-24 1967-10-17 Merck & Co Inc Nu-lactoyl and nu-halopyruvoyl-2-nitroanilides
US3471508A (en) * 1963-11-06 1969-10-07 Merck & Co Inc 5-aryl (or heteroaromatic) benzazoles
US3478046A (en) * 1963-11-19 1969-11-11 Merck & Co Inc 5-(or 6)-halo(or amino)benzazoles and methods for preparing same
US3361756A (en) * 1963-11-29 1968-01-02 Merck & Co Inc 2-(alpha-haloalkanoyl) benzimidazoles
US3350211A (en) * 1964-12-31 1967-10-31 Merck & Co Inc Compositions useful in controlling marine fouling and methods for their use
US3429890A (en) * 1964-12-31 1969-02-25 Merck & Co Inc Certain 2-thiazolylbenzimidazole-1-oxy derivatives
US3398157A (en) * 1964-12-31 1968-08-20 Merck & Co Inc Process for preparing benzimidazole nu-oxides
US3484519A (en) * 1965-12-02 1969-12-16 Merck & Co Inc Anthelmintic 2-substituted benzimidazole-metal arsenate compositions and method
US3546341A (en) * 1966-02-18 1970-12-08 Merck & Co Inc Complexes of 2-substituted benzimidazoles and bis-halogenated phenols in anthelmintic compositions and methods
US3475444A (en) * 1966-02-18 1969-10-28 Merck & Co Inc Complexes of 2-substituted benzimidazoles and bis-halogenated phenols
US3506678A (en) * 1967-02-21 1970-04-14 Merck & Co Inc Certain 2-substituted thieno(2,3-d) imidazoles
US3535331A (en) * 1967-07-26 1970-10-20 Merck & Co Inc Water-soluble 2-substituted benzimidazole hypophosphite salts
US3538108A (en) * 1967-08-17 1970-11-03 Merck & Co Inc Water - soluble 2 - substituted benzimidazole methanesulfonic acid salts
US3928372A (en) * 1967-12-06 1975-12-23 Merck & Co Inc 2-(3-Oxythiazolyl)benzimidazoles
US3711608A (en) * 1971-04-13 1973-01-16 Merck & Co Inc The treatment of pain, fever and inflammation with benzimidazoles
US3899503A (en) * 1974-01-25 1975-08-12 Morton Norwich Products Inc Process for preparing 2-(2{40 )-furyl-, 2-(2{40 )-thienyl- 2-(4{40 )-thiazolyl- or 2-(2{40 )-pyrryl-5 (or 6) nitrobenzimidazole
US3998785A (en) * 1974-06-13 1976-12-21 International Business Machines Corporation Anti-fungal and/or anti-bacterial hardware for ink printing apparatus
US4006259A (en) * 1975-04-01 1977-02-01 Fmc Corporation Preservative coating for fruits and vegetables
US4247442A (en) * 1978-03-29 1981-01-27 Toray Silicone Company, Ltd. Mold and mildew resistant organopolysiloxane compositions
JPS6351305A (ja) * 1985-06-05 1988-03-04 ユニロイヤル　リミテツド 相乗作用性の殺菌剤組成物
AU596635B2 (en) * 1986-01-27 1990-05-10 Shell Internationale Research Maatschappij B.V. Fungicidal compositions
US5013746A (en) * 1988-04-08 1991-05-07 Janssen Pharmaceutica N.V. Imazalil containing synergistic compositions
US20100160399A1 (en) * 2002-03-21 2010-06-24 Basf Aktiengessellschaft Fungicidal mixtures
US8188001B2 (en) 2002-03-21 2012-05-29 Basf Aktiengesellschaft Fungicidal mixtures
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US20050148639A1 (en) * 2002-03-21 2005-07-07 Basf Aktiengesellschaft Fungicidal mixtures
US7683086B2 (en) 2002-03-21 2010-03-23 Basf Aktiengesellschaft Fungicidal mixtures
WO2004047769A3 (en) * 2002-11-26 2004-09-10 Isis Pharmaceuticals Inc Benzimidazoles and analogs thereof as antibacterials
US20100130513A1 (en) * 2002-12-03 2010-05-27 Isis Pharmaceuticals, Inc. Benzimidazoles and analogs thereof as antivirals
US8207173B2 (en) 2002-12-03 2012-06-26 Isis Pharmaceuticals, Inc. Benzimidazoles and analogs thereof as antivirals
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US3055907A (en) 1962-09-25
SE320977B (en)) 1970-02-23
GB948635A (en) 1964-02-05
CH423790A (de) 1966-11-15
ES263822A1 (es) 1961-05-16
CY309A (en) 1965-02-18
CH423792A (de) 1966-11-15
DK107167C (da) 1967-05-01
CH423789A (de) 1966-11-15
DE1235321B (de) 1967-03-02
SE310883B (en)) 1969-05-19
FR1423609A (fr) 1966-01-07
CH423791A (de) 1966-11-15
CH423793A (de) 1966-11-15
OA00999A (fr) 1968-08-07
MY6500075A (en) 1965-12-31
BE599143A (en))

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