Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-01-14
1996-07-23
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5483087, A61K 31415, C07D23526
Patent
active
055389902
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP92/01578 filed Jul. 13, 1992.
The present invention related to certain benzimidazole anthelmintic agents which, quite unexpectedly, are topically and parenterally active and are thus suitable for transdermal and parenteral (especially intramuscular) administration.
These benzimidazole derivatives are represented by the following formula: ##STR2## and their non-toxic salts, wherein R.sup.1, which is in the 5- or 6- position, is either (i) benzoyl, phenyloxy, phenylthio, phenylsulfinyl, phenylsulfonyl, phenylsulfonyloxy, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, C.sub.1 -C.sub.6 alkylsulfinyl, C.sub.1 -C.sub.6 alkylsulfonyl or (C.sub.3 -C.sub.7 cycloalkyl) carbonyl, said phenyl groups, and the phenyl portion of said benzoyl group, optionally having 1 to 3 substituents each independently selected from halo, C.sub.1 -C.sub.4 alkyl, halo-(C.sub.1 -C.sub.4 alkyl), C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.2 -C.sub.4 alkanoyl, nitro, isothiocyanato, and cyano; or (ii) a group of the formula: ##STR3## where X is O,S,SO,SO.sub.2 or NR.sup.4 in which R.sup.4 is hydrogen, C.sub.1-C.sub.4 alkyl, phenyl or phenyl-(C.sub.1 -C.sub.4 alkyl), said phenyl groups being optionally substituted by 1 or 2 substituents each selected from C.sub.1 -C.sub.4 alkyl, halo, hydroxy and C.sub.1 -C.sub.4 alkoxy; and R.sup.5 is H, C.sub.1 -C.sub.4 alkyl, halo, hydroxy or C.sub.1 -C.sub.4 alkoxy; ##STR4##
R.sup.2 is C.sub.1 -C.sub.4 alkyl; and R.sup.3 is C.sub.1 -C.sub.4 alkyl.
It will be appreciated that since in the compounds (I) the position of the hydrogen atom in the imidazole ring cannot be determined (tautomerism), then the compounds are correctly named as 5(6)-substituted benzimidazoles.
R.sup.1 is preferably C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulphinyl, phenylthio, phenylsulfinyl, benzoyl optionally substituted by halo, phenylsulfonyloxy optionally substituted by halo, or 1,2-benzisoxazol-3-yl.
More preferably, R.sup.1 is benzoyl, 4-fluorobenzoyl, 4-fluorophenylsulfonyloxy, n-propylthio, n-propylsulfinyl, phenylthio, phenylsulfinyl, n-butyl, n-propyloxy, or 1,2-benzisoxazol-3-yl.
Most preferably, R.sup.1 is n-propylthio or n-propylsulfinyl.
R.sup.2 is preferably methyl or ethyl, most preferably methyl.
R.sup.3 is preferably methyl or ethyl, most preferably methyl.
Alkyl and alkoxy groups of 3 or more carbon atoms may be straight or branched chain. "Halo" means F, Cl, Br or I.
Suitable non-toxic acid addition salts, suitable for veterinary use, are for example the hydrochloride, hydrobromide, and sulphate salts. These can all be prepared conventionally.
The benzimidazoles of the formula (I) and their salts are in particular anthelmintics suitable for the control of parasitic diseases in both human and non-human animals such as sheep and cattle and domestic pets. The compounds exhibit activity against mature and immature parasitic forms of, for example, nematodes, trematodes and cestodes such as are represented by Trichostrongylus, Dictyocaulus, Ostertagia, Nematodirus, Stronglyoides, Trichuris, Haemonchus, Cooperia, Dirofilaria, Toxocara, Trichuris, Fasciola and Monezia species.
Efficient control of these species is achieved by introducing into said animals circulatory system an anthelmintically-effective amount of a compound (I) or salt thereof. In the case of these compounds, it has been unexpectedly found that this control can be achieved by percutaneous absorption and/or penetration from a liquid or cream formulation applied directly to the animals' skin. Such liquid formulations are known as "pour-on formulations". Such pour-on formulations are characterised in that the active ingredient, i.e. the compound (I) or salt thereof, is dissolved, emulsified or suspended in a suitable solvent or solvent mixture which is tolerable by the skin and non-toxic to the animal, optionally with certain auxiliary ingredients.
To prep
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Banks Bernard J.
Dutton Christopher J.
Goudie Alexander C.
Benson Gregg C.
Pfizer Inc.
Richardson Peter C.
Richter Johann
Ronau Robert T.
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