US3183239A - 5-ether and 5-thioether-2-heterocyclic benzimidazoles - Google Patents

5-ether and 5-thioether-2-heterocyclic benzimidazoles Download PDF

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US3183239A
US3183239A US90966A US9096661A US3183239A US 3183239 A US3183239 A US 3183239A US 90966 A US90966 A US 90966A US 9096661 A US9096661 A US 9096661A US 3183239 A US3183239 A US 3183239A
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benzimidazole
thiazolyl
solution
benzimidazoles
methoxy
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US90966A
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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 NL275175D priority Critical patent/NL275175A/xx
Priority to NL133760D priority patent/NL133760C/xx
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Priority to US90966A priority patent/US3183239A/en
Priority to FI0311/62A priority patent/FI40464B/fi
Priority to BE613916A priority patent/BE613916A/fr
Priority to GB5868/62A priority patent/GB987069A/en
Priority to FR888352A priority patent/FR1444662A/fr
Priority to BR136552/62A priority patent/BR6236552D0/pt
Priority to DK82962AA priority patent/DK105067C/da
Priority to CH221362A priority patent/CH410965A/de
Priority to FR896713A priority patent/FR1875M/fr
Priority to US339336A priority patent/US3326753A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients

Definitions

  • This invention relates to new chemical compounds. 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 and at the 5-position an ether or thioether substituent.
  • R is a iive-membered heterocyclic ring containing carbon, nitrogen and sulfur
  • R is hydrogen, a lower alkyl or a lower :a-lkenyl group, or an acyl radical
  • R is an alkoxy, :alkylthio, .aryloxy or ary-lthiovrad'ical.
  • the invention also includes within its scope acid addition salts of such benzimidazoles.
  • the new compounds of Formula I, and acid addition salts thereof, have a high degree of anthelmintic activity 0 and are thus useful in the treatment or prevention of helminthiasis.
  • Helminthiasis involves in festation of the animal body, and particularly the gastro-intestinal tract, with various species of parasitic worms. It is a widespread and serious disease causing malnutrition, weight loss and anemia, and in severe cases internal hemorrhaging and death.
  • the substances now commercially available -for treating helminthiasis have been of value in controlling the disease but are not entirely satisfactory.
  • One object of the present invention is to provide a new class of highly efiective anthelmintic compounds. Another object is provision of 2-substituted-S-ether-benzimidazoles and 2-substituted-S-thioethenbenzimidazoles of Formula 1 above. Still another object is the provision of chemical syntheses of such compounds. [Further objects will be evident from the ensuing description of the invention.
  • the benzimidazoles of the present invention are all substituted at the 2-position with a five-membered heterocyolic ring containing carbon, nitrogen and sulfur.
  • the ring has at least two hetero atoms and, as will be seen, may have three hetero atoms. 'In the latter case, two of such atoms will be the same.
  • the heterocyclic ring (R in the above formula), which is attached to the benzimidazole through one of its carbon atoms, may be a thiazolyl, isothiazolyl or thiadiazolyl radical.
  • the point of attachment to the benzimidazole nucleus may be at any one of the three carbon atoms of the ring, as indicated by the broken lines in the partial structures: i
  • 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, isothiaZ-o'les or thiadiazoles to be used as starting materials.
  • 2-(2-thiazolyl)-5-alkoxy benzimidazoles having a lower alkyl group at the 4-position of the thiazole ring and the 2-(5'-isothiazolyl)-5-alky1thiobenzimidazoles having a lower alkyl group at the 3-position of the isothiazole ring such as 2-(4-methyl-2'-thiazolyl)-5-methoxy-benzimidazole and 2-(-3methyl-5-isothiazolyl)-S-ethylthiobenzimidazole are illustrative of this aspect of the invention.
  • the N-l position of the benzimidazoles (R in Formula I) may be substituted with hydrogen, alower alkyl group such .as methyl, ethyl, propyl or isopropyl, or a lower alkenyl radical of the type represented by allyl and metha-l'lyl.
  • the alkyl and al'kenyl radicals preferably contain less than six carbon atoms.
  • R may also be an acyl radical, examples of suitable substit-uents being lower alk-anoyl groups such as acetyl, propionyl, butyryl, and valeryl, ar-oyl radicals such as benzoyl or p-halobenzoyl, or aralkanoyl moieties of which the phenylacetyl groups is exemplary.
  • the preferred N-1 acyl groups are those having less than nine carbon atoms.
  • the preferred compounds of this invention have an a'lkoxy or alkylthio radical at the S-pOsition of the benzimidazole ring.
  • substituents are lower alkoxy groups such as methoxy, ethoxy, isopropoxy, t-butoxy and the like, and lower alkylthio groups, instances of which are methylthio, ethylthio and propylthi-o substituents.
  • substituent at the S-position of the benzimidazole ring is an aryloxy or arylthio group.
  • phenoxy and phenylthio radicals are preferred, although groups such as p-m'ethyl phenoxy and p-methyl phenylthio may be used if desired.
  • groups such as p-m'ethyl phenoxy and p-methyl phenylthio may be used if desired.
  • the 5 and 6-positions of the benzimidazole ring are equivalent, due to the symmetry of the ring, when both of the nitrogen atoms are unsubstituted.- In such cases it is customary to describe the compounds as 5(6)alkoxy(or aryloxy) or 51(6) alkylthio(or arylthio) benzimidazoles. When this symmetry is lost by substitution at one of the nitrogen atoms, the compounds are defined as 5-substituted benzimiclazoles.
  • novel benzimidazoles of this invention are 2- 2'-thiazolyl) -5 (6) -meth-oxy-benzimidazole, '2- (4-thiazolyl -5 6 -methoxy-benzimidazole, 2- 4-thiaz olyl -5 6) -methylthio-b enzimid azole, 2-(4-iso thiazolyl -5 6) -ethylthio-benzimidazole,
  • the 2,5-disubstituted benzimidazoles described herein may be recovered as free bases or as salts by the processes normally employed for their synthesis.
  • the base are readily converted to acid addition salt by treatment with acid.
  • Typical salts which may be formed in this manner are mineral acid salt such as the hydrohalides, e.g.
  • hydro chloride, hydrobrornide and 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 citnate, oxalate, suocinate and the like and salts of insoluble organic acids such as the embonate and hydroxynaphthoate salts.
  • Certain of these salts such as the hydrohali-des are more Water soluble than the free bases.
  • solubility properties of a particular compound may be modified 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. It will be appreciated by those skilled in this art that the acid addition salts will form when the N-l position of the benzimidazole is unsubstituted or is substituted with an alkyl or alkenyl group, but not when it is N-acylated.
  • such benzimidazoles are obtained from an appropriately substituted o-nitroaniline, i.e. an o-nitroaniline having an alkoxy, alkylthio, aryloxy or arylthio substituent meta to either the nitro or amino group.
  • Such substituted o-nitroanilines are intimately contacted with a thiazolyl, isothiazolyl or thiadiazolyl carboxylic acid derivative such as an acid halide or ester, whereupon an o-nitroanilide is produced.
  • the nitro group is then reduced either by catalytic hydrogenation using a noble metal catalyst or by reaction with a metal-acid reducing system such as with zinc or iron in the presence of a hydrohalic acid.
  • a metal-acid reducing system such as with zinc or iron in the presence of a hydrohalic acid.
  • the resulting amino anilide is converted to the desired benzimidazole in the presence of an acid, and preferably a mineral acid.
  • an acid and preferably a mineral acid.
  • the intermediate amino anilide is not isolated but rather ring closed to the benzimidazole directly.
  • the o-nitroanilide is preferably reduced by catalytic hydrogenation employing a rhenium catalyst, such as rhenium heptasulfide, and the intermediate o-aminoanilide converted, without isolation, to the desired benzimidazole by the exposure to acid.
  • a rhenium catalyst such as rhenium heptasulfide
  • any desired o-nitroaniline reactant may be synthesized from nitrophenol or nitrothiophenol by alkylating or arylating the sodium salt of the phenol or thiophenol, reducing the nitro group to an amine, and then nitrating to introduce the nitro groups present in the o-nitroaniline.
  • the l-substituted benzimidazoles of Formula 1 above, where the N-l substituent is a lower alkyl, a lower alkenyl or an acyl radical, are normally synthesized from the parent 2-heterocycle-5-substituted benzimidazole.
  • This l-substitution is brought about by first preparing an alkali metal salt of the benzimidazole, such as a sodium, potassium or lithium salt. It is preferred to produce a sodium salt by contacting the benzimidazole with sodium hydride in an anhydrous reaction medium, preferably at a temperature of 40-75 C. Sodamide or a sodium alkoxide may be used instead of sodium hydride, if desired.
  • the alkali metal salt is intimately contacted with an alkylating or alkenylating agent, such agents normally being esters of a strong acid and a lower alkanol or a lower alkenol.
  • alkylating or alkenylating agent such agents normally being esters of a strong acid and a lower alkanol or a lower alkenol.
  • alkylating or alkenylating agent such agents normally being esters of a strong acid and a lower alkanol or a lower alkenol.
  • alkyl halides such as methyl bromide, methyl iodide, ethyl bromide
  • lower alkenol halides such as allyl bromide or methallyl chloride.
  • alkyl sulfates such as dimethyl and diethyl sulfate may be employed.
  • the l-acyl-benzimidazoles are obtained by contacting the benzimidazole alkali metal salt with an acylating agent, and preferably with an acyl halide.
  • an acylating agent such as acetyl chloride, acetyl bromide, propionoyl chloride and butyryl chloride, aroyl halides of the type represented by benzoyl chloride, and aralkanolyl halides such as phenylacetyl chloride. It is preferred to add the acylating agent to a solution or a suspension of the benzimidazole salt in an inert solvent medium and to carry out the reaction at temperatures of 40-100 C.
  • Suitable solvents are aromatic hydrocarbons and/or dimethylformamide.
  • the resulting acyl benzimidazoles may be recovered and purified by known methods, e.g. by removal of the organic solvents under reduced pressure and crystallization of the residual solid product.
  • acid addition salts of the benzimidazoles of Formula I, wherein R is hydrogen, lower alkyl or lower alkenyl are within the purview of this invention.
  • Such salts are conveniently prepared by treating a solution of the benzimidazole with excess acid. Suitable solvents for this purpose are the lower alkanols such as methanol, ethanol and isopropanol.
  • the salts may be formed by contacting a solution of the benzimidazole base with an anion ion exchange resin in the salt form.
  • the ion exchange resins are conveniently utilized for the metathesis of one acid addition salt to a different acid salt.
  • the 2,5-disubstituted benzimidazoles of Formula I above, and non-toxic acid addition salts thereof, 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 infectron in man and in domesticated animals.
  • the compounds are normally ad ministered orally in unit dosage form as boluses or liquid drenches wherein the active ingredient is admixed with or suspended in an inert carrier vehicle, or as a component of the animal feed or drinking water.
  • a daily oral dose in the range of about 50-400 mg. of benzimidazole compound per kg.
  • animal body Weight is satisfactory. For best results it is preferred to use about l300 mg./kg. of body weight. Larger or smaller doses can, of course, be used depending on particular circumstances, such as severity of the infection. For this purpose, a drench or bolus is the usual mode of administration.
  • feedstutf in which case feeds containing in the range of about 0.05% to about 0.25% by weight of benzimidazole compound may be employed successfully.
  • the feed is also the vehicle of choice when giving the benzimidazole to sheep and cattle over an extended period of time for the prevention of helminthiasis.
  • the anthelmintic may be uniformly distributed throughout the animal feedstufr", or it may be incorporated in the protein supplements that are normally used as top dressings for ruminant feeds. As will be understood by those skilled in the art, the dose levels for continued prophylactic use will be lower than in the therapeutic applications.
  • the sulfate salt is prepared by dissolving 0.5 g. of the free base in 10 ml. of ethanol and treating the solution with a 10% excess of alcoholic sulfuric acid.
  • the acid .solution is diluted with ethyl-ether until turbid and then aisaas EXAMPLE 2
  • Z-(Z-thiazolyl)-5( 6)-methoxy-benzimidaz0le 4.2 g. of Z-thiazole carboxylic acid chloride and 5.1 g. of 2-nitro-4-methoxyaniline are mixed in 60 ml. of pyridine.
  • the solution is held at25 C. for 2 hours and then heated at 70 C. for 4 hours. It is then poured into 500 ml.
  • the hydrochloride salt is prepared by dissolving the free base in a minimum amount of ethanol, adding an excess of ethanolic hydrogen chloride and finally adding ethyl ether until the solution becomes turbid. The solution is then chilled in ice-to give crystals of the hydrochloride salt.
  • reaction mixture is then maintained under gentle reflux for about 3 hours. It. is then cooled in ice and extracted rapidly with three 25-ml. portions of ice water. The aqueous extracts are back-extracted with ethylacetate. The organic solutions are combined, dried over magnesium sulfate and concentrated to dryness in vacuo. The residual l-benzoyl-Z-(4'-thiazolyl)- S-methoxy-benzimidazole thus obtained is purified by recrystallization from ethyl-ether.
  • EXAMPLE 5 1-methyl-2-(4'-tlziazolyl)-5-meth0xy-benzimidazole 5 g. of 2-(4'-thiazolyl)-5-methoxy-benzimidazole in 60 ml. of dry dimethylformami-de are added to 1.6 g. of a 52% sodium hydride emulsion in mineral oil. The resulting mixture is stirred at room temperature for about 30 minutes and then warmed carefully to about 50 C. for minutes. It is cooled to room temperature and 3.6 g. of methyl iodide in 5 ml. of dimethylformamide added slowly to the cooled solution of the benzimidazole sodium salt. The reaction mixture is then heated to about 80 C.
  • EXAMPLE 7 2-[3-(1',2,5-thiadiaz0lyl) ]5(6)-meth0xybenzimidazole 1.3 g. of 1,2,5-thiadiazole-4-carboxylic acid chloride and 1.1 g. of 2-nitro-4-methoxyaniline are added to 40 ml. of a-picoline and the resulting solution heated at C. for 5 hours. The solution is then poured into ml. of ice water and the resulting yellow solid isolated by filtration. This solid, 2-nitro-4-methoxy-3- (1',2',5-thiadiazolyl)-aniline, is washed successively with water, dilute hydrochloric acid, dilute sodium carbonate and with fresh Water.
  • the product is then recrystallized from ethanol.
  • a solution of the purified compound in 200 ml. of dry ethanol is hydrogenated at an initial pressure of 40 p.s.i. in the presence of 1 g. of 5% palladium on charcoal catalyst.
  • the catalyst is filtered olf and 50 ml. of 6 N hydrochloric acid added to the solution.
  • the acidified solution is refluxed for 6 hours and then concentrated to a volume of about 25 ml. in vacuo. 2 [3'-(1,2,5-thiadiazolyl)] (6)-methoxy-benzimidazole hydrochloride crystallizes when the solution is chilled in an ice bath.
  • the free base is obtained by neutralizing an aqueous ethanolic solution of the acid solution with ammonium hydroxide.
  • EXAMPLE 8 1-benz0lyl-2-[3'-(1 ,2,5'-thiadiazolyl) ]-5-phenyllhiobenzimidazole
  • 2- [3'-(l,2,5-thiadiazolyl)] 5(6) phenylthio-benzirnidazole as the starting material there is produced l-benzoyl- 2-[3 (1,2',5'-thiadiazolyl)]-5 phenylthio-benzimidazole.
  • compositions in unit dosage form that are suitable for the oral administration of the benzimidazoles of Formula I above to domesticated animals are:
  • compositions are by conventional formulating techniques.

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US90966A 1961-02-23 1961-02-23 5-ether and 5-thioether-2-heterocyclic benzimidazoles Expired - Lifetime US3183239A (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
NL275175D NL275175A (en)) 1961-02-23
NL133760D NL133760C (en)) 1961-02-23
US90966A US3183239A (en) 1961-02-23 1961-02-23 5-ether and 5-thioether-2-heterocyclic benzimidazoles
FI0311/62A FI40464B (en)) 1961-02-23 1962-02-14
BE613916A BE613916A (fr) 1961-02-23 1962-02-14 Composés benzimidazoliques et leur préparation
GB5868/62A GB987069A (en) 1961-02-23 1962-02-15 Substituted benzimidazoles
FR888352A FR1444662A (fr) 1961-02-23 1962-02-16 Benzimidazols substitués
BR136552/62A BR6236552D0 (pt) 1961-02-23 1962-02-20 Processo para preparar novos derivados de benzimidazol
DK82962AA DK105067C (da) 1961-02-23 1962-02-22 Fremgangsmåde til fremstilling af benzimidazolforbindelser eller syreadditionssalte deraf.
CH221362A CH410965A (de) 1961-02-23 1962-02-23 Verfahren zur Herstellung substituierter Benzimidazole
FR896713A FR1875M (fr) 1961-02-23 1962-05-07 Nouveau médicament anthelmintique a base de benzimidazols substitués.
US339336A US3326753A (en) 1961-02-23 1964-01-22 Benzimidazole anthelmintic compositions and method of use

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5958950A (en) * 1995-10-05 1999-09-28 Warner-Lambert Company Benzimidazole compounds useful for the treatment of inflammatory disease, atherosclerosis, restenosis or inhibiting lipoxygenase

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2933504A (en) * 1959-08-10 1960-04-19 Du Pont Derivatives of polyalkoxycarbonyl imine
US2985661A (en) * 1956-02-06 1961-05-23 American Cyanamid Co Preparation of 2(omicron-aminophenyl)-benzimidazole
US3007938A (en) * 1959-04-17 1961-11-07 Sterling Drug Inc 1-(3-indazolecarbonyl)-hydrazines and their preparation
US3017415A (en) * 1960-01-18 1962-01-16 Merck & Co Inc Certain benzimidazoles carrying thiazolyl, thiadiazolyl and isothiazolyl substituents in the 2 position
US3030270A (en) * 1959-10-05 1962-04-17 Lilly Co Eli Antiparasitic compositions and processes
US3030364A (en) * 1960-02-02 1962-04-17 Merck & Co Inc Imidazolium quaternary salts and methods of preparing same

Patent Citations (7)

* 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
US3007938A (en) * 1959-04-17 1961-11-07 Sterling Drug Inc 1-(3-indazolecarbonyl)-hydrazines and their preparation
US2933504A (en) * 1959-08-10 1960-04-19 Du Pont Derivatives of polyalkoxycarbonyl imine
US3030270A (en) * 1959-10-05 1962-04-17 Lilly Co Eli Antiparasitic compositions and processes
US3017415A (en) * 1960-01-18 1962-01-16 Merck & Co Inc Certain benzimidazoles carrying thiazolyl, thiadiazolyl and isothiazolyl substituents in the 2 position
US3055907A (en) * 1960-01-18 1962-09-25 Merck & Co Inc Acyl benzimidazoles and method of preparing same
US3030364A (en) * 1960-02-02 1962-04-17 Merck & Co Inc Imidazolium quaternary salts and methods of preparing same

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5958950A (en) * 1995-10-05 1999-09-28 Warner-Lambert Company Benzimidazole compounds useful for the treatment of inflammatory disease, atherosclerosis, restenosis or inhibiting lipoxygenase

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CH410965A (de) 1966-04-15
NL275175A (en))
DK105067C (da) 1966-08-15
FI40464B (en)) 1968-10-31
NL133760C (en))
FR1875M (fr) 1963-06-24
GB987069A (en) 1965-03-24
BE613916A (fr) 1962-05-29
BR6236552D0 (pt) 1973-06-14

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