US3657267A - Benzimidazole carbamates - Google Patents

Benzimidazole carbamates Download PDF

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US3657267A
US3657267A US835246A US3657267DA US3657267A US 3657267 A US3657267 A US 3657267A US 835246 A US835246 A US 835246A US 3657267D A US3657267D A US 3657267DA US 3657267 A US3657267 A US 3657267A
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water
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Josephus Ludovicus Hube Gelder
Leopold Frans Corneel Roevens
Alfons Herman Marg Raeymaekers
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Janssen Pharmaceutica NV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
    • C07C49/813—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C07D235/32—Benzimidazole-2-carbamic acids, unsubstituted or substituted; Esters thereof; Thio-analogues thereof

Definitions

  • 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.
  • 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.
  • novel alkyl N [5(6) acyl 2 benzimidazolyl] carbamates of this invention may be structurally represented by the formula:
  • 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.
  • 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.
  • 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 diaminophenyl ketones of Formula V are obtained by reduction of the nitro function in the corresponding aminonitrophenyl ketones of Formula VI.
  • 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.
  • 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).
  • 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.
  • elevated temperatures about 100-130 C.
  • 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.
  • helminths e.g., Trichostrongylus, Ostertagia, Cooperia, Hoemoncus, Strongyloides, Nematodirus, Bunostomum, Trichuris, Chabertia, Capillaria, Ascaris, Heterakis, Syphacia and the like.
  • 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.
  • 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.
  • 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 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.
  • 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 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.
  • 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.
  • 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 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • EXAMPLE XV This example demonstrates the anthelrnintic activity of the compounds of Formula I.
  • 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
  • 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.
  • Patent NO. 3 57, 7 Dated April 18,1972

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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS505518A (xx) * 1972-12-29 1975-01-21
US3969526A (en) * 1973-05-29 1976-07-13 Smithkline Corporation Anthelmintic 5-heterocycliothio and oxy-2-carbalkoxyaminobenzimidazles
US4010272A (en) * 1974-09-10 1977-03-01 Hoechst Aktiengesellschaft Anthelmintically active basically substituted 2-carbalkoxy-amino-benzimidazolyl-5(6)-phenyl ethers and -ketones
US4026936A (en) * 1975-08-07 1977-05-31 Hoffmann-La Roche Inc. Anthelmintic pyridine and thiazole substituted benzimidazole carbamates
US4031234A (en) * 1975-08-18 1977-06-21 Syntex (U.S.A.) Inc. 1,5(6)-Disubstituted benzimidazole-2-carbamate derivatives having anthelmintic activity
US4032536A (en) * 1976-07-22 1977-06-28 Janssen Pharmaceutica N.V. (1h-benzimidazol-2-yl)carbamates
US4258198A (en) * 1973-05-29 1981-03-24 Smithkline Corporation 5-Cycloalkyl thio- and oxy-2-carbalkoxyaminobenzimidazoles
US4435418A (en) 1982-12-13 1984-03-06 Smithkline Beckman Corporation 5-Phenylethenylbenzimidazoles
US4438135A (en) 1983-01-07 1984-03-20 Smithkline Beckman Corporation 1-(3,4-Bis-(3-(lower alkoxycarbonyl)-2-thioureido)-phenyl-1-phenylthylenes
EP0387941A1 (en) * 1989-03-15 1990-09-19 Janssen Pharmaceutica N.V. [5(6)-(benzisoxa-, benzisothia- or indazol-3-yl)-1H-benzimidazol-2-yl] carbamates
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
US5256681A (en) * 1989-03-15 1993-10-26 Janssen Pharmaceutica N.V. [5(6)-(benzisoxa-,benzisothia-or indazol-3-yl)-1H-benzimidazol-2-yl]carbamates
US5278181A (en) * 1992-05-12 1994-01-11 Board Of Regents Acting On Behalf Of The University Of Michigan Soluble alkyl[5-[amino (phenyl)methyl]-1H-benzimidazol-2-yl] carbamate anthelmintics
US20090131369A1 (en) * 2005-07-28 2009-05-21 Intervet International B.V. Novel Benzimidazole(Thio)Carbamates with Antiparasitic Activity and the Synthesis Thereof
US20090220610A1 (en) * 2006-06-12 2009-09-03 Carsten Schmidt Suspension Comprising Benzimidazole Carbamate and a Polysorbate
WO2014049397A1 (es) 2012-09-27 2014-04-03 Siegfried Rhein S.A. De C.V. Composición sinérgica de nitazoxanida y mebendazol, procesos para prepararla y el uso de dicha composición para el tratamiento de la parasitosis humana
US8777134B2 (en) 2006-06-14 2014-07-15 Intervet International B.V. Suspension comprising benzimidazole carbamate and a polysorbate
US9498441B2 (en) 2012-01-27 2016-11-22 Siegfried Rhein S.A. De C.V. Nitazoxadine composition and process to prepare same
WO2018235103A1 (en) 2017-06-22 2018-12-27 Cipla Limited METHOD OF TREATING CANCER
US11028055B2 (en) * 2015-11-30 2021-06-08 Children's Medical Center Corporation Compounds for treating proliferative diseases
CN113979949A (zh) * 2021-12-17 2022-01-28 山东国邦药业有限公司 一种氟苯咪唑的制备方法

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DE2201208A1 (de) * 1972-01-12 1973-08-02 Basf Ag Verfahren zur herstellung von aromatischen ketonen
IT1076022B (it) * 1977-04-20 1985-04-22 Montedison Spa Benzimidazolcarbammati antielmintici
JPS5535611A (en) * 1978-08-31 1980-03-12 Matsushita Electric Works Ltd Instrument with mouth washing instrument
US4299837A (en) 1979-12-05 1981-11-10 Montedison S.P.A. Anthelmintic benzimidazole-carbamates
CN109467512B (zh) * 2018-12-18 2021-06-08 苏州开元民生科技股份有限公司 一种3,4-二氨基-二苯甲酮的合成方法

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Publication number Priority date Publication date Assignee Title
GB1111957A (en) * 1966-05-20 1968-05-01 Smith Kline French Lab Improvements in or relating to anthelmintic compositions

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS505518A (xx) * 1972-12-29 1975-01-21
JPS5939428B2 (ja) * 1972-12-29 1984-09-22 シンテツクス （ ユ− エス エイ ） インコ−ポレ−テツド 駆虫効果を有する５（６）−ベンゼン環置換ベンズイミダゾ−ル−２−カルバメ−ト誘導体の製造方法
US3969526A (en) * 1973-05-29 1976-07-13 Smithkline Corporation Anthelmintic 5-heterocycliothio and oxy-2-carbalkoxyaminobenzimidazles
US4258198A (en) * 1973-05-29 1981-03-24 Smithkline Corporation 5-Cycloalkyl thio- and oxy-2-carbalkoxyaminobenzimidazoles
US4010272A (en) * 1974-09-10 1977-03-01 Hoechst Aktiengesellschaft Anthelmintically active basically substituted 2-carbalkoxy-amino-benzimidazolyl-5(6)-phenyl ethers and -ketones
US4026936A (en) * 1975-08-07 1977-05-31 Hoffmann-La Roche Inc. Anthelmintic pyridine and thiazole substituted benzimidazole carbamates
US4031234A (en) * 1975-08-18 1977-06-21 Syntex (U.S.A.) Inc. 1,5(6)-Disubstituted benzimidazole-2-carbamate derivatives having anthelmintic activity
US4032536A (en) * 1976-07-22 1977-06-28 Janssen Pharmaceutica N.V. (1h-benzimidazol-2-yl)carbamates
US4435418A (en) 1982-12-13 1984-03-06 Smithkline Beckman Corporation 5-Phenylethenylbenzimidazoles
US4438135A (en) 1983-01-07 1984-03-20 Smithkline Beckman Corporation 1-(3,4-Bis-(3-(lower alkoxycarbonyl)-2-thioureido)-phenyl-1-phenylthylenes
US5256681A (en) * 1989-03-15 1993-10-26 Janssen Pharmaceutica N.V. [5(6)-(benzisoxa-,benzisothia-or indazol-3-yl)-1H-benzimidazol-2-yl]carbamates
EP0387941A1 (en) * 1989-03-15 1990-09-19 Janssen Pharmaceutica N.V. [5(6)-(benzisoxa-, benzisothia- or indazol-3-yl)-1H-benzimidazol-2-yl] carbamates
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
US5278181A (en) * 1992-05-12 1994-01-11 Board Of Regents Acting On Behalf Of The University Of Michigan Soluble alkyl[5-[amino (phenyl)methyl]-1H-benzimidazol-2-yl] carbamate anthelmintics
US20090131369A1 (en) * 2005-07-28 2009-05-21 Intervet International B.V. Novel Benzimidazole(Thio)Carbamates with Antiparasitic Activity and the Synthesis Thereof
US7893271B2 (en) 2005-07-28 2011-02-22 Intervet International B.V. Benzimidazole carbamates and (thio) carbamates, and the synthesis and use thereof
US20090220610A1 (en) * 2006-06-12 2009-09-03 Carsten Schmidt Suspension Comprising Benzimidazole Carbamate and a Polysorbate
US8777134B2 (en) 2006-06-14 2014-07-15 Intervet International B.V. Suspension comprising benzimidazole carbamate and a polysorbate
US9498441B2 (en) 2012-01-27 2016-11-22 Siegfried Rhein S.A. De C.V. Nitazoxadine composition and process to prepare same
WO2014049397A1 (es) 2012-09-27 2014-04-03 Siegfried Rhein S.A. De C.V. Composición sinérgica de nitazoxanida y mebendazol, procesos para prepararla y el uso de dicha composición para el tratamiento de la parasitosis humana
US11028055B2 (en) * 2015-11-30 2021-06-08 Children's Medical Center Corporation Compounds for treating proliferative diseases
US11697640B2 (en) 2015-11-30 2023-07-11 Children's Medical Center Corporation Compounds for treating proliferative diseases
WO2018235103A1 (en) 2017-06-22 2018-12-27 Cipla Limited METHOD OF TREATING CANCER
CN113979949A (zh) * 2021-12-17 2022-01-28 山东国邦药业有限公司 一种氟苯咪唑的制备方法

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AT307798B (de) 1973-06-12
FI52719C (fi) 1977-11-10
SE366045B (xx) 1974-04-08
CH520684A (fr) 1972-03-31
PL72724B1 (xx) 1974-08-30
YU34195B (en) 1979-02-28
HK77976A (en) 1976-12-17
JPS501272B1 (xx) 1975-01-16
ES380579A1 (es) 1973-04-01
NL7009024A (xx) 1970-12-22
YU154470A (en) 1978-09-18
FI52719B (xx) 1977-08-01
IL34746A0 (en) 1970-08-19
DE2029637A1 (de) 1971-02-18
ZA704191B (en) 1972-02-23
DE2029637B2 (de) 1976-09-23
DK580275A (da) 1975-12-19
DK134602B (da) 1976-12-06
CS201522B2 (en) 1980-11-28
IL34746A (en) 1973-01-30
AT302358B (de) 1972-10-10
BE752089A (fr) 1970-12-17
IT1035027B (it) 1979-10-20
FR2052988A1 (xx) 1971-04-16
MY7300477A (en) 1973-12-31
NL147139B (nl) 1975-09-15
GB1307306A (en) 1973-02-21
FR2052988B1 (xx) 1973-08-10
DK134602C (xx) 1977-06-27

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