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
1995-10-17
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5483087, 5483091, A61K 31415, C07D23504
Patent
active
054591554
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT EP 92 015 79 filed on 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 formulae: ##STR2## and their non-toxic salts, wherein R, which in the compounds (IA) is in the 5- or 6-position, is either (i) H, 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##
and either (a) R.sup.1 is a 1-(C.sub.2 -C.sub.6 alkanoyloxy)(C.sub.1 -C.sub.4 alkyl) group and
R.sup.2 is H, C.sub.1 -C.sub.4 alkyl or a 1-(C.sub.2 -C.sub.6 alkanoyloxy)(C.sub.1 -C.sub.4 alkyl) group, or (b) R.sup.1 is H and R.sup.2 is a 1-(C.sub.2 -C.sub.6 alkanoyloxy)(C.sub.1 -C.sub.4 alkyl) group; and
R.sup.3 is a C.sub.1 -C.sub.4 alkyl group.
Preferred alkyl and alkoxy groups have 1 to 4 carbon atoms.
R is preferably H, 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 is H, benzoyl, 4-fluorobenzoyl, 4-fluorophenylsulfonyloxy, n-propylthio, n-propylsulfinyl, phenylthio, phenylsulfinyl, n-butyl, n-propyloxy, or 1,2-benzisoxazol-3-yl.
Most preferably, R is n-propylthio.
R.sup.1 is preferably 1-(C.sub.2 -C.sub.6 alkanoyloxy)(C.sub.1 -C.sub.4 alkyl) and R.sup.2 is preferably H or 1-(C.sub.2 -C.sub.6 alkanoyloxy)(C.sub.1 -C.sub.4 alkyl).
In the 1-(C.sub.2 -C.sub.6 alkanoyloxy)(C.sub.1 -C.sub.4 alkyl) groups represented by R.sup.1 and optionally by R.sup.2, a preferred C.sub.1 -C.sub.4 alkyl group is methyl. A preferred alkanoyloxy group is pivaloyloxy. R.sup.1 is preferably pivaloyloxymethyl and R.sup.2 is preferably H or pivaloyloxymethyl.
When R.sup.1 and R.sup.2 are both a 1-(C.sub.2 -C.sub.6 alkanoyloxy)(C.sub.1 -C.sub.4 alkyl) group, then they are preferably the same, e.g. both are pivaloyloxymethyl. The compounds of the formula (IA) are the preferred compounds of the invention.
Alkyl and alkoxy groups of 3 or more carbon atoms may be straight or branched chain. "Halo" means F, Cl, Br or I.
It will be noted that the alkanoyloxyalkyl groups represented by R.sup.1 and optionally by R.sup.2 have the alkanoyloxy group at the 1-position of the alkyl group, i.e., they can also be represented as follows: ##STR5##
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 (IA) and (IB) 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 rep
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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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