WO1990010630A1 - [5(6)-(benzisoxa-, benzisothia- ou indazol-3-yl)-1h-benzimidazol-2-yl] carbamates - Google Patents

[5(6)-(benzisoxa-, benzisothia- ou indazol-3-yl)-1h-benzimidazol-2-yl] carbamates Download PDF

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WO1990010630A1
WO1990010630A1 PCT/EP1990/000373 EP9000373W WO9010630A1 WO 1990010630 A1 WO1990010630 A1 WO 1990010630A1 EP 9000373 W EP9000373 W EP 9000373W WO 9010630 A1 WO9010630 A1 WO 9010630A1
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formula
4alkyl
hydrogen
aryl
halo
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PCT/EP1990/000373
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English (en)
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Alfons Herman Margaretha Raeymaekers
Eddy Jean Edgard Freyne
Gustaaf Maria Boeckx
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Janssen Pharmaceutica N.V.
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Priority to KR1019910701108A priority Critical patent/KR920701199A/ko
Priority to ZM1090A priority patent/ZM1090A1/xx
Publication of WO1990010630A1 publication Critical patent/WO1990010630A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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

  • the benzimidazole carbamates of the present invention differ therefrom by the fact that they contain a benzimidazole moiety which is invariably substituted in the 5(6) position with a benzisoxa-, benzisothia-, or indazol radical and in particular by their favourable anthelminthic spectrum.
  • the present invention is concerned with novel benzimidazole carbamates of formula
  • R! is hydrogen, C ⁇ _4_lkyl, halo, hydroxy or C ⁇ _4alkyloxy;
  • R ⁇ is Cj_ alkyl
  • X is O, S, SO, SO2 or NR3, said R ⁇ being hydrogen, C ⁇ alkyl, aryl or arylC ⁇ _4alkyl; wherein aryl is phenyl optionally substituted with 1 or 2 substituents each independently selected from C ⁇ alkyl, halo, hydroxy or C ⁇ alkoxy.
  • halo is generic to fluoro, chloro, bromo and iodo and the term "C ⁇ _4alkyl" is me.ant to include straight and branch chained saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, butyl and the like.
  • the compounds of formula (I) may occur in tautomeric forms which tautomeric forms are intended to be within the scope of the present invention.
  • Preferred compounds within the present invention are those compounds of formula (I) wherein R is hydrogen or halo; R ⁇ is C ⁇ _4»alkyl; and X is O,S or NR3, said R3 being hydrogen, C ⁇ _4alkyl or aryl.
  • Particularly preferred compounds within the present invention are those preferred compounds wherein R* is hydrogen or fluoro and/or R ⁇ is methyl or ethyl and/or X is O,S or NR3, wherein R ⁇ is hydrogen, methyl or phenyl.
  • More preferred compounds within the invention are those preferred compounds wherein R is hydrogen, R ⁇ is methyl and X is O or S.
  • the most preferred compounds of the invention are selected from the group consisting of methyl [5-(l ,2-benzisoxazol-3-yl)- lH-benzimidazol-2-yl]carbamate and the pharmaceutically acceptable acid addition or metal substitution salts thereof.
  • the acid addition and metal substitution salts as mentioned hereinabove comprise the therapeutically active, and in particular, pharmaceutically acceptable non-toxic acid addition and metal substitution salt forms which the compounds of formula (I) are able to form.
  • the acid addition salts can conveniently be obtained by treating the base form with appropriate acids such as, for example, inorganic acids, such as hydrohalic acid, e.g.
  • organic acids such as, for example, acetic, hydroxyacetic, propanoic, 2-
  • the metal substitution salts hereinabove are meant to comprise the therapeutically active non-toxic metal substitution salt forms or metal complexes which the compounds of formula (I) are able to form, the term metal also comprising ammonium.
  • the latter can conveniently be obtained by treating the compounds of formula (I) with appropriate inorganic bases or salts, for example, ammonia or bases derived from alkali or earth alkaline metals, e.g. alkali metal or earth alkaline metal oxides or hydroxides such as sodium hydroxide, calcium hydroxide, calcium oxide and the like.
  • the salt form can be converted by treatment with alkali into the free base form or with acid into the free acidic form.
  • the term salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
  • the compounds of formula (I) can generally be prepared by ring closure of .an appropriately substituted benzenediamine of formula (II) or an acid addition salt thereof, with an appropriate isourea or isothiourea derivative of formula (HI).
  • the cyclization of (II) with (IE) can conveniently be carried out by stirring the reactants in a suitable solvent preferably in the presence of an appropriate acid, either organic or inorganic.
  • Organic acids comprise, for example, carboxylic acids, e.g. formic, acetic or propionic acid. Somewhat elevated temperatures may be appropriate to enhance the rate of the reaction and most preferably the reaction is carried out at the reflux temperature of the reaction mixture. In certain instances it may be advantageous to carry out the reaction under pressure.
  • Suitable solvents comprise organic solvents such as, for example, lower alkanols, e.g. methanol, ethanol, 2-propanol and the like alcohols; aromatic hydrocarbons, e.g.
  • benzene methylbenzene and the like; halogenated hydrocarbons, e.g. trichloromethane, dichloromethane, trichloroethane, trichloro- ethylene, chlorobenzene and the like; ethers such as tetrahydrofuran; ketones such as 2-propanone, 3-methyl-2-butanone; esters such as ethyl acetate; nitriles, e.g. acetonitrile and the like; and other common polar aprotic solvents such as, N,N-dimethylformamide, N,N-dimethylacetamide and the like solvents. Mixtures of such solvents with water may also be employed, e.g. mixtures of water with lower alkanols.
  • Benzimidazole carbamates of formula (I) may also be prepared by reacting a benzenediamine of formula (II) or an acid addition salt thereof with a cyanocarbamate of formula (IV).
  • Said reaction may be effected according to art-known procedures as described, for example, in U.S. Pat. Nos. 3,682,952 and 3,969,526, by reacting a benzene- diamine of formula (II) or an acid addition or metal substitution salt thereof with a cyanocarbamate of formula (TV) in a suitable solvent such as, for example, water, a lower alkanol, e.g. methanol, eth.anol; a ketone, e.g. 2-propanone; a polar aprotic solvent, e.g.
  • a suitable solvent such as, for example, water, a lower alkanol, e.g. methanol, eth.anol; a ketone, e.g. 2-propanone; a polar aprotic solvent, e.g.
  • an acid such as, for example, a mineral acid, e.g. hydrochloric acid.
  • Somewhat elevated temperatures may be appropriate to enhance the rate of the reaction, more in particular the reaction may be conducted between 30 and 100°C.
  • the benzimidazole carbamates of formula (I) may be prepared by reacting a benzenediamine of formula (II) with cyanogen bromide (VI) and reacting the thus obtained 2-aminobenzimidazole (VII) with an appropriate haloformate ester (V), e.g. chloroformate ester.
  • V haloformate ester
  • benzimidazole carbamates of formula (I) may alternatively be prepared under similar procedures as are described in the literature for the preparation of related benzimidazole carbamates starting from appropriately substituted benzenediamines. A number of such procedures are described, for example, in "The chemistry of Hetero- cyclic Compounds" Vol. 40, part 1, pages 1-60, J. Wiley & Sons, New York (1981) and the references and Patents cited therein.
  • reaction products may be isolated from the reaction mixture and, if necessary, further purified according to methodologies generally known in the art such as, for example, extractions, distillation, crystallization, trituration and chromatography.
  • the compounds of formula (I) may also be converted into each other following art-known functional group transformation procedures.
  • the compounds of formula (I), wherein X is S may be converted into the corresponding compounds of formula (I), wherein X is SO or SO2 by an appropriate oxidation reaction, e.g. by reacting the former compounds with a suitable oxidating agent such as, for example, sodium chlorate, potassium permanganate, potassium periodate, a peroxide, e.g. 3-chlorobenzenecarboperoxoic acid, hydrogen peroxide and the like in a suitable solvent such as, an ether, e.g. tetrahydrofuran, l,l'-oxybisethane, a hydro ⁇ carbon, e.g. benzene, a halogenated hydrocarbon, e.g.
  • a suitable oxidating agent such as, for example, sodium chlorate, potassium permanganate, potassium periodate, a peroxide, e.g. 3-chlorobenzenecarboperoxoic acid, hydrogen peroxide and the like in a suitable solvent such as
  • said oxidation reaction is preferably conducted at lower temperatures with approximately one equivalent of the oxidating agent, while were a sulfonyl is desired, said oxidation reaction may be conducted at room or at an elevated temperature with an excess of oxidating agent.
  • the intermediates of formula (II) can be prepared from the corresponding nitro- substituted intermediates (VIII) following art-known nitro-to-amine reduction procedures such as for example, catalytic hydrogenation in a suitable solvent e.g. methanol or ethanol, in the presence of hydrogen and an appropriate catalyst e.g. platinum-on- charcoal, palladium-on-charcoal, Raney nickel, and the like. In some cases it may be useful to add an appropriate catalyst poison such as thiophene to the reaction mixture.
  • said nitro group may also be reduced to an amino group by reaction with a reducting agent such as, for example, sodium sulf ⁇ de, sodium dithionate and the like.
  • Said reaction can be carried out by stirring the reactants in a suitable solvent such as for example, water, an alcohol e.g. methanol, ethanol or a mixture of such solvents.
  • the intermediates of formula (VIII), wherein X is S, said compounds being represented by formula (Vlll-a), can be prepared by reacting an appropriately substituted benzoyl of formula (IX) with sulfur and ammonia in a reaction-inert solvent such as, for example, an ether, e.g. l,l'-oxybismethane, 2-methoxyethanol and the like, optionally under pressure.
  • a reaction-inert solvent such as, for example, an ether, e.g. l,l'-oxybismethane, 2-methoxyethanol and the like, optionally under pressure.
  • Z represents an appropriate leaving group, such as, for example, halo, e.g. fluoro or chloro; or a nitro group.
  • the intermediates of formula (VIII), wherein X is NR ⁇ " a , with R ⁇ _a being hydrogen or Cj ⁇ alkyl, said intermediates being represented by formula (Vlll-b), can be obtained by reacting the benzoyl intermediate (IX) with an appropriate hydrazine derivative R ⁇ - a -NH-NH2 (X) or an acid addition salt thereof.
  • Said reaction can be carried out in a suitable reaction-inert solvent optionally in the presence of a suitable base.
  • suitable solvents are, for example, water, alkanols, e.g. methanol, ethanol, 1-butanol and the like.
  • Appropriate bases preferably are amines such as N,N-diethylethanamine, 4-ethylmorpholine, pyridine and the like.
  • the benzoyl intermediates of formula (IX) can also be treated with hydroxyl- amine or an appropriate hydrazine derivative R3-b- H-NH2 (XI) or an acid addition salt thereof to form an intermediate of formula (XII) wherein X is O or NR ⁇ -b, said X being represented by X*, with R ⁇ - being aryl or arylC ⁇ alkyl.
  • Said reaction can be carried out with or without a suitable reaction-inert solvent and optionally in the presence of a base.
  • Suitable solvents are, for example, water, alkanols, e.g. methanol, ethanol, 1-butanol and the like.
  • Appropriate bases preferably are amines, such as N,N-diethyl- ethanamine, 4-ethylmorpholine, pyridine and the like.
  • Said cyclization reaction may conveniently be conducted by treatment with an appropriate base, preferably in a suitable reaction-inert solvent such as, for example, water, hydro ⁇ carbons, e.g., benzene, dichloromethane and the like; lower alkanols, e.g. methanol, ethanol and the like; dipolar aprotic solvents, e.g. N,N-dimethylformamide,
  • a suitable reaction-inert solvent such as, for example, water, hydro ⁇ carbons, e.g., benzene, dichloromethane and the like; lower alkanols, e.g. methanol, ethanol and the like; dipolar aprotic solvents, e.g. N,N-dimethylformamide,
  • Appropriate bases are for example, hydroxides, alkoxides or hydrides, e.g. sodium hydroxide, sodium methoxide, sodium hydride and the like bases.
  • the intermediates of formula (IX) can be obtained by an aromatic nucleophilic substitution reaction of the halo group of intermediate (XIII).
  • halo is generic to fluoro, chloro, bromo and iodo.
  • the nucleophilic substitution reaction can be carried out with ammonia in a reaction-inert solvent such as for example, a hydrocarbon, e.g. pentane, benzene; a halogenated hydrocarbon such as dichloromethane and the like; an alcohol, e.g. methanol, ethanol and the like; a dipolar aprotic solvent, e.g. N,N-dimethylformamide, N,N-dimethyl- acetamide, dimethyl sulfoxide and the like.
  • a reaction-inert solvent such as for example, a hydrocarbon, e.g. pentane, benzene; a halogenated hydrocarbon such as dichloromethane and the like; an alcohol, e.g. methanol, ethanol and the like; a dipolar aprotic solvent, e.g. N,N-dimethylformamide
  • the intermediates of formula (XIII) can in turn be obtained by Friedel-Crafts acylation of a benzene of formula (XIV) with an acyl halide, a carboxylic acid or an anhydride of formula (XV).
  • Said Friedel-Crafts reaction can be carried out by stirring the reaction mixture optionally in the presence of a reaction-inert solvent and in the presence of a catalyst such as, for example, a Lewis acid, e.g. ferric chloride, ferric bromide, aluminum trichloride and the like.
  • Suitable solvents are, for example, hydrocarbons, e.g. pentane, hexane, nitrobenzene, dichloromethane, tetrachloromethane and the like.
  • the intermediates of formula (VIII) wherein X is O, said intermediates being represented by formula (Vlll-d), may also be prepared by cyclizing an activated oxime derivative of formula (XVI), wherein T is an acyl residue and more particularly is (C ⁇ _4alkyl or aryl)carbonyl, e.g. propionyl and the like; (Chalky 1 or aryl)oxycarbonyl, e.g. methoxycarbonyl and the like; (C ⁇ alkyl or aryl)sulfonyl, e.g. methanesulfonyl, benzenesulfonyl and the like; N-acylaminocarbonyl, e.g. trichloromethylcarrx>nylamino- carbonyl and the like.
  • T is an acyl residue and more particularly is (C ⁇ _4alkyl or aryl)carbonyl, e.g. propionyl and the like; (Ch
  • Said cyclization reaction of the activated oxime derivative of formula (XVI) may conveniently be conducted by treatment with an appropriate base, preferably in a suitable reaction-inert solvent. In some instances however, it may be advantageous not to add a base to the reaction mixture and to remove the acid liberated during the reaction by distillation. Alternatively, said cyclization may also be effected by heating the oxime derivative (XVI) in vacuo without a solvent.
  • Appropriate bases are for example, alkali and earth alkaline metal carbonates, hydrogen carbonates and amines, e.g. sodium carbonate, potassium carbonate, sodium hydrogen carbonate, j ,N-diethylethanamine, pyridine and the like bases.
  • Suitable solvents for said cyclization are, for example, aromatic hydrocarbons, e.g. benzene, methylbenzene and the like; ethers, e.g. l,l'-oxybisethane, tetrahydrofuran, 1,4-dioxane and the like; dipolar aprotic solvents, e.g. N,N-dimethylformamide, £ N-dimethylacetamide and the like; halogenated hydrocarbons, e.g. trichloromethane, tetrachloromethane and the like solvents.
  • aromatic hydrocarbons e.g. benzene, methylbenzene and the like
  • ethers e.g. l,l'-oxybisethane, tetrahydrofuran, 1,4-dioxane and the like
  • dipolar aprotic solvents e.g. N,N-dimethylformamide, £ N-dimethylacet
  • intermediates of formula (II), wherein X is NR ⁇ and R ⁇ is hydrogen, Ci _4alkyl, aryl, or arylC ⁇ alkyl, said intermediates being represented by formula (II- a), may also be prepared by a series of conversions starting from an aniline of formula
  • the aniline (XVII) is treated with an alkali metal nitrite, e.g. sodium nitrite, in an aqueous acidic medium thus obtaining the corresponding M-nitroso compound (XVIII-a) or, in case R ⁇ is hydrogen, thus obtaining the diazonium salt (XVIII-b).
  • an alkali metal nitrite e.g. sodium nitrite
  • R 3_c has the same meaning as R 3 with the proviso that hydrogen is excluded and in formula (XVIH-b) A " represents the conjugated base of the acid of the aqueous acidic medium mentioned hereinabove.
  • the N-nitroso compound (XVIII-a) or the diazonium salt (XVIH-b) is treated with an appropriate reducing agent such as, for example, hydrogen in the presence of a hydrogenation metal catalyst, e.g. Raney nickel or Raney cobalt ; or a sulfite, e.g. sodium sulfite; thus yielding the corresponding hydrazine derivative of formula (XIX), which in most instances spontaneously, or if necessary upon increasing the temperature, will cyclize to a compound of formula (Il-a).
  • a hydrogenation metal catalyst e.g. Raney nickel or Raney cobalt
  • a sulfite e.g. sodium sulfite
  • (XVII), (XVIII) and (XIX) P represents a suitable protective group which preferably is readily removable by hydrogenation such as, phenylmethyl and the like.
  • a suitable protective group which preferably is readily removable by hydrogenation such as, phenylmethyl and the like.
  • the unprotected intermediate (XLX) is obtained.
  • K-protected derivatives of formula (XIX) are obtained which may be deprotected, or may be converted as such to the H-protected intermediate (Il-a), which is afterwards deprotected.
  • the isourea or isothiourea derivatives of formula (HI) may be prepared by the reaction of an iso(thio)urea of formula (XX) or an acid addition salt thereof with an appropriate haloformate ester (V), e.g. chloroformate ester, in the presence of a base, as illustrated in the following scheme; with Y and R ⁇ being as defined hereinabove.
  • V haloformate ester
  • Suitable bases for the purpose of this procedure include metal alkoxides, metal hydroxides, alkali or earth alkali metal carbonates, hydrogen carbonates or organic bases, e.g. sodium methoxide, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, M > -diethylethanamine and the like.
  • the compounds of formula (I) and some of the intermediates in this invention may have an asymmetric carbon atom in their structure, e.g. when R ⁇ is a branched alkyl. This chiral center may be present in a R- and a S-configuration, this
  • Diastereoisomers may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. counter current distribution, and enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids, or the like methods.
  • Pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • the compounds of formula (I), the pharmaceutically acceptable acid-addition salts and stereochemically isomeric forms thereof have anthelminthic properties, in particular they posses a broad spectrum activity against parasites of warm blooded animals (human or animal), including both mature and immature parasitic forms, as represented for example by Nematodes, such as, Syngamus trachea in turkeys and pheasants, Ascaridia and Heterakis in chickens, Toxocara cati in cats, Ankylostoma tubaeforme in cats, Toxocara cams in dogs, Toxascaris leonin in dogs, Uncinaria stenocephala in dogs, Ankylostoma caninwn in dogs, Trichu ⁇ s vulpis in dogs, Trichinella spiralis in pigs and rats, Haemonchus contortus in sheep, Dictyocaulus filar ia in sheep and Trichostrongylides in sheep.
  • Nematodes such
  • Some compounds of the present invention are even found to be active against Cestodes, such as, Taenia pisiformis in dogs, Taenia hyda ⁇ gena in dogs, Taenia ovis in dogs, Dipylidium caninum in dogs, Taenia taeniaeformis in cats, Moniezia in sheep, Anitellina sp in sheep, Raillietina, Hydatigera taeniaformis and the like.
  • the compounds of the invention are found to exhibit high activity against various helminths infecting the intestinal tract of man and economically important animals, such as, sheep, cattle, horses, pigs and poultry, coupled with low systemic toxicity to the host.
  • the anthelminthic properties of compounds of formula (I) can be demonstrated for example in the "Taenia pisiformis in artificially infected dogs"-test and the "Heter ⁇ Ms g ⁇ llin ⁇ um in chicken”-test illustrating the useful anthelminthic properties of the compounds of the present invention.
  • the subject compounds may be formulated into various pharmaceutical forms for administration purposes.
  • an effective amount of the particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection.
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • Injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the carrier option comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as a pour-on, as an ointment.
  • Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
  • the compounds of formula (I) may also be added dissolved or suspended in drinking water.
  • the present invention provides anthelminthic compositions comprising an anthelminthically effective amount of an active compound of formula (I), either alone or in admixture with other active therapeutic ingredients such as, closantel, in admixture with suitable carriers.
  • the compounds of this invention constitute useful tools for the destroying or prevention of the growth of helminths and more particularly they can effectively be used in the treatment of subjects suffering from such helminths. Therefore the present invention provides a method of destroying or preventing the growth of helminths in warm blooded animals suffering from such helminths by administration of an anthelminthically effective amount of a compound of formula (I), a pharmaceutically acceptable acid addition salt or a possible stereochemically isomeric form thereof.
  • an effective amount would be from 1 to 100 mg/kg body weight, more particularly between 2.5 and 25 mg/kg body weight, preferably in a single administration.
  • Example 1 Preparation of the intermediates Example 1 a) To a stirred mixture of 465 parts of 1,3-difluorobenzene and 133.3 parts of aluminum trichloride was added dropwise a mixture of 110.1 parts of 4-chloro-3-nitro-benzoyl chloride and 116 parts of aluminum trichloride at 70°C. After stirring for 2 hours at reflux temperature, the reaction mixture was poured into ice-water. There were added 127 parts of hydrochloric acid and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was stirred in 2,2'-oxybis- propane.
  • Example 5 A mixture of 4 parts of intermediate 6, 2 parts of a solution of thiophene in methanol 4%, 119 parts of methanol and 89 parts of tetrahydrofuran was hydrogenated at 50°C and normal pressure with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was co-evaporated with methylbenzene, yielding 3.6 parts (99.9%) of 4-(l -phenyl- lH-indazol-3-yl)- 1,2- benzenediamine (interm. 13). In a similar manner there were also prepared :
  • Example 7 Taenia pisjformis in artificially infected dogs
  • Proglottids of Taenia pisiformis were collected from the faecal material of the infected dogs. After maceration and washing in tapewater the eggs were collected by passing the proglottids suspension through a sieve with aperture of 53 micron. The number of eggs was counted and about 1000 eggs were administered by gavage to young rabbits. After 5 weeks the rabbits had infectious Cvsticercus pisiformis in the peritoneal cavity. After autopsy of the rabbits the cysticerci were collected and administered orally in a gelatine capsule to young Beagle dags. The infective dose was about 15 cysticerci.
  • a hybrid line of 4 weeks old male Hisex chickens were infected orally with 600 Heterakis gallinae eggs.
  • the eggs were admixed in the normal chicken feed and administered for two consecutive days.
  • compound nos. 3 and 4 showed 100% after a single treatment 10 mg/kg.
  • compositions in dosage unit form suitable for systemic or topical administration to warm-blooded animals in accordance with the present invention.
  • Active ingredient as used throughout these examples relates to a compound of formula (I), a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof.
  • Example 9 oral drops
  • Example 10 oral solution
  • Example 11 capsules
  • Example 12 film-coated tablets Preparation of tablet core
  • the wet powder mixture was sieved, dried and sieved again.
  • the whole was mixed well and compressed into tablets, giving 10.000 tablets, each comprising 10 mg of the active ingredient Coating
  • Example 13 iniectable solution 1.8 g methyl 4-hydroxybenzoate and 0.2 g propyl 4-hydroxybenzoate were dissolved in about 0.5 1 of boiling water for injection. After cooling to about 50°C there were added while stirring 4 g lactic acid, 0.05 g propylene glycol and 4 g of the AX. The solution was cooled to room temperature and supplemented with water for injection q.s. ad 1 1 volume, giving a solution of 4 mg A.I. per ml. The solution was sterilized by filtration (U.S.P. XVII p. 811) and filled in sterile containers.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

[5(6)-(benzisoxa-, benzisothia- or indazol-3-yl)-1H-benzimidazol-a-yl] carbamates de formule (I) dans laquelle R1 représente hydrogène, alcoyle C¿1-4?, halo, hydroxy ou alcoyloxy C1-4; R?2¿ représente alcoyle C¿1-4?; et X représente O, S, SO, SO2 ou NR?3¿, ledit R3 représentant hydrogène, alcoyle C¿1-4?, aryle ou arylalcoyle C1-4. Les composés de la formule (I) ont des propriétés anthelmintiques. Compositions contenant lesdits composés comme ingrédient actif, procédé de lutte contre les helminthes, et procédé de préparation desdits composés et desdites compositions.
PCT/EP1990/000373 1989-03-15 1990-03-07 [5(6)-(benzisoxa-, benzisothia- ou indazol-3-yl)-1h-benzimidazol-2-yl] carbamates WO1990010630A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
KR1019910701108A KR920701199A (ko) 1989-03-15 1990-03-07 [5(6)-(벤즈이소옥사-, 벤즈이소티아- 또는 인다졸-3-일)-1h 벤즈이미다졸-2-일]카르바메이트
ZM1090A ZM1090A1 (en) 1989-03-15 1990-03-14 (5(6)(benzisoxa-,benzisothiora-indazol-3-yl)-1h-be(5(6)(benzisoxa-benzisothia-or indazol-3-yl)-1h-benzimidazol 2-yl)carbamates nzimidazol-2-yl)carbamates

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US32427089A 1989-03-15 1989-03-15
US324,270 1989-03-15
US45990990A 1990-01-02 1990-01-02

Publications (1)

Publication Number Publication Date
WO1990010630A1 true WO1990010630A1 (fr) 1990-09-20

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PCT/EP1990/000373 WO1990010630A1 (fr) 1989-03-15 1990-03-07 [5(6)-(benzisoxa-, benzisothia- ou indazol-3-yl)-1h-benzimidazol-2-yl] carbamates

Country Status (1)

Country Link
WO (1) WO1990010630A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5859742A (en) * 1995-11-17 1999-01-12 Fujitsu Limited Disk storage apparatus having head overshoot and undershoot control

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1423609A (fr) * 1960-01-18 1966-01-07 Merck & Co Inc Dérivés de la benzimidazole et leur procédé de fabrication
GB1070702A (en) * 1964-11-03 1967-06-01 Commw Scient Ind Res Org New metal chelates of substituted benzimidazoles having anthelmintic properties and the preparation thereof
US3657267A (en) * 1969-06-20 1972-04-18 Janssen Pharmaceutica Nv Benzimidazole carbamates
US3954791A (en) * 1971-12-27 1976-05-04 Hoechst Aktiengesellschaft Anthelmintically active 2-carbalkoxy-amino-benzimidazole-5(6)-phenyl ethers
US3969526A (en) * 1973-05-29 1976-07-13 Smithkline Corporation Anthelmintic 5-heterocycliothio and oxy-2-carbalkoxyaminobenzimidazles

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1423609A (fr) * 1960-01-18 1966-01-07 Merck & Co Inc Dérivés de la benzimidazole et leur procédé de fabrication
GB1070702A (en) * 1964-11-03 1967-06-01 Commw Scient Ind Res Org New metal chelates of substituted benzimidazoles having anthelmintic properties and the preparation thereof
US3657267A (en) * 1969-06-20 1972-04-18 Janssen Pharmaceutica Nv Benzimidazole carbamates
US3954791A (en) * 1971-12-27 1976-05-04 Hoechst Aktiengesellschaft Anthelmintically active 2-carbalkoxy-amino-benzimidazole-5(6)-phenyl ethers
US3969526A (en) * 1973-05-29 1976-07-13 Smithkline Corporation Anthelmintic 5-heterocycliothio and oxy-2-carbalkoxyaminobenzimidazles

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5859742A (en) * 1995-11-17 1999-01-12 Fujitsu Limited Disk storage apparatus having head overshoot and undershoot control

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