Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1991-08-27
1993-10-26
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514379, 514388, 548212, 548241, 5483051, C07D41304, C07D40304, C07D41704, A61K 31415
Patent
active
052566811
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
A large number of benzimidazole carbamates have been described as anthelminths. As most successful representatives there may be named mebendazole and flubendazole both described in U.S. Pat. No. 3,657,267, albendazole described in U.S. Pat. No. 3,915,986, oxibendazole described in U.S. Pat. No. 3,682,952 and fenbendazole described in U.S. Pat. No. 3,954,791.
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.
DESCRIPTION OF THE INVENTION
The present invention is concerned with novel benzimidazole carbamates of formula ##STR1## the acid addition or metal substitution salts thereof and the stereochemically isomeric forms thereof, wherein alkyl, aryl or arylC.sub.1-4 alkyl; each independently selected from C.sub.1-4 alkyl, halo, hydroxy or C.sub.1-4 alkoxy.
As used in the foregoing definitions the term halo is generic to fluoro, chloro, bromo and iodo and the term "C.sub.1-4 alkyl" is meant 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.sup.1 is hydrogen or halo; R.sup.2 is C.sub.1-4 alkyl; and X is O,S or NR.sup.3, said R.sup.3 being hydrogen, C.sub.1-4 alkyl or aryl.
Particularly preferred compounds within the present invention are those preferred compounds wherein R.sup.1 is hydrogen or fluoro and/or R.sup.2 is methyl or ethyl and/or X is O,S or NR.sup.3, wherein R.sup.3 is hydrogen, methyl or phenyl.
More preferred compounds within the invention are those preferred compounds wherein R.sup.1 is hydrogen, R.sup.2 is methyl and X is O or S.
The most preferred compounds of the invention are selected from the group consisting of methyl [5-(1,2-benzisoxazol-3-yl)-1H-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. hydrochloric, hydrobromic and the like, and sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic, hydroxyacetic, propanoic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. 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. Conversely 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 als
REFERENCES:
patent: 3657267 (1972-04-01), Van Gelder
Boeckx Gustaaf M.
Freyne Eddy J. E.
Raeymaekers Alfons H. M.
Gerstl Robert
Janssen Pharmaceutica N.V.
Metz Charles J.
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