Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1988-11-14
1990-04-10
Bond, Robert T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540459, C07D49808, A61K 31399
Patent
active
049161261
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel diacyl derivatives of rifamycins that carry a substituted 1-piperazinyl radical in the 3-position, namely 8-O,N- and 8-O,21-O-diacyl derivatives of rifamycin S compounds of the formula ##STR2## in which R represents lower alkyl, R.sub.1 represents tri-lower alkylmethylcarbonyl, and one of the radicals R.sub.2 and R.sub.3 represents tri-lower alkylmethylcarbonyl and the other represents hydrogen, to their salts, and to mixtures of isomeric compounds of the formula I or their salts.
The invention relates also to processes for the manufacture of compounds of the formula I and their salts, to pharmaceutical preparations containing them, and to the use of these compounds and preparations.
The numbering used herein corresponds to the numbering used, for example, in U.S. Pat. No. 4,005,077.
Lower alkyl R contains preferably up to and including 4 carbon atoms and is, for example, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert.-butyl, but especially methyl.
Lower alkyl radicals in a tri-lower alkylmethylcarbonyl radical normally contain up to and including 4, preferably up to and including 2, carbon atoms and especially one carbon atom, and are, inter alia, n-propyl, isopropyl, n-butyl or tert.-butyl, especially ethyl and more especially methyl.
In the compounds of the formula I, the radicals R.sub.1 and R.sub.2 or R.sub.3 preferably have identical meanings.
Non-acylated rifamycin S compounds that have, in the 3-position, a piperazino group substituted in the 4-position are known. For example, U.S. Pat. No. 4,005,077, especially Example 77, mentions rifamycin derivatives that contain, in the 4-position, a benzyl radical that may be substituted in the aromatic moiety by one or more alkyl radicals having from 1 to 6 carbon atoms, such as 3-(4-benzyl-1-piperazinyl)-rifamycin SV, 3-[4-(4-methylbenzyl)-1-piperazinyl]-rifamycin SV, 3-[4-(2-methylbenzyl)-1-piperazinyl]-rifamycin SV, 3-[4-(3-methylbenzyl)-1-piperazinyl]-rifamycin SV, 3-[4-(4-isopropylbenzyl)-1-piperazinyl]-rifamycin SV, 3-[4-(2,3-dimethylbenzyl)-1-piperazinyl]-rifamycin SV and 3-[4-(4-tert.-butylbenzyl)-1-piperazinyl]-rifamycin SV. Further compounds of that type that have, especially, a 4-(2,6-dimethyl-4-alkylbenzyl)-piperazine radical are described, for example, in the PCT application having the publication No. WO 87/02361. Those compounds are distinguished by an antibiotic action, especially an antitubercular action, which can be demonstrated in vivo in mice and rats and which, as regards the spectrum of action, corresponds approximately to that of the known antitubercular agent, rifampicin.
In contrast, the diacyl compounds of the present invention have, if at all, only a marginal antibiotic action. Surprisingly, however, they have a lipid-reducing action which can be demonstrated in animal experiments, preferably on mammals, for example rats. For example, it is possible to demonstrate the reduction of "very low density", "low density" and "high density" lipoproteins (VLDL, LDL and HDL) in serum in two test procedures, namely in genetically hypercholesterolaemic male rats (procedure A) and normolipaemic rats of both sexes (procedure B).
Albino rats having a body weight of from 180 to 240 g and having free access to normal rat food and drinking water are used, Sprague Dawley derivatives of the strain Tif:RAI in procedure A and animals of the Wistar strain IVa-WI in procedure B. The test compound is administered orally in a polyethylene glycol solution (average molecular weight 400) to groups of from 8 to 10 rats, in procedure A once daily at 8 a.m. for three consecutive days and twice, at 8 a.m. and 4 p.m., on the fourth day, and in the case of procedure B, daily for 5 consecutive days. In experiment A the animals are sacrificed 16 hours, and in experiment B two hours, after the final administration by bleeding from the neck under anaesthesia with ether. The animals are given no food during the 16 hours before they are sacrificed. A 0.05% aqueous ethylenediaminetetraacetic acid solution and a 0.01% aqueous thio
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Kump Wilhelm
Muller Klaus
Traxler Peter
Bond Robert T.
Ciba-Geigy Corporation
Fishman Irving M.
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