Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-12-22
1997-10-14
Owens, Amelia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514 28, 549264, 536 71, A61K 31335, C07D31500
Patent
active
056773323
DESCRIPTION:
BRIEF SUMMARY
This invention relates to antiparasitic agents and in particular to compounds related to the avermectins and milbemycins but having a cyano substituent at the 3-position.
The avermectins am a group of broad-spectrum antiparasitic agents referred to previously as the C-076 compounds. They are produced by fermenting a certain strain of microorganism Streptomyces avermitilis in an aqueous nutrient medium. The preparation and structure of these compounds obtained by fermentation are described in British Patent Specification 1573955. The milbemycins are structurally related macrolide antibiotics lacking the sugar residues at the 13-position. They may be produced by fermentation, for example as described in British Patent Specification No. 1390336 and European Patent Specification No. 0170006.
In addition to these fermentation-derived products, a large number of publications describe compounds derived semisynthetically from these products, many of which possess useful antiparasitic properties. Some of this chemistry is reviewed in Macrolide Antibiotics, Omura S., Ed., Academic Press, New York (1984) and by Davies, H. G. and Green, R. H. in Natural Product Reports (1986), 3, 87-121 and in Chem. Soc. Rev. (1991), 20, 211-269 and 271-239.
Compounds related to the original C-076 avermectins have also been prepared by fermentation of avermectin-producing micro-organisms. For example European Patent Specifications 0214731 and 0317148 describe production of compounds related to the C-076 avermectins but having a different substituent at the 25-position by fermentation in the presence, in the fermentation medium, of certain acids.
Other publications mentioning different combinations of substituents at various positions on the avermectin or milbemycin nucleus are EP-A-317148, 340932, 355541, 350187, 410165, 259779 and 254583; DE-A-2329486 and GB-A-2166436.
The avermectins and milbemycins and their derivatives have the structure: ##STR1## wherein the broken line represents an optional bond, R.sup.1 and R.sup.4 being absent when this bond is present, R.sup.1, R.sup.3, R.sup.4 and R.sup.12 are independently H, OH, halo, oxo, oximino or an organic radical, R.sup.2 and R.sup.7 are organic radicals, and R.sup.6 is H or an organic radical.
These compounds include the avermectins themselves and their substituted derivatives in which R.sup.3 is a 4'-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrosyloxy group, optionally substituted at the 4" position; the avermectin monosaccharides and their derivatives in which R.sup.3 is .alpha.-L-oleandrosyloxy, optionally substituted at the 4' position; the avermectin aglycones and their derivatives in which R.sup.3 is OH or a substituent other than oleandrosyl replacing this group; and the milbemycins and their derivatives in which R.sup.3 is H.
All the avermectins and structurally related milbemycins and their derivatives hitherto reported do not have a substituent at the 3-position when the double bond is in the C3-C4 position, neither has any process capable of producing such compounds been reported.
It has now been discovered that avermectin and milbemycin derivatives having a cyano substituent at the 3-position may be prepared and that some of these compounds have outstanding antiparasitic properties.
Compounds of the invention are of formula (I): ##STR2## wherein the broken line represents an optional bond, R.sup.1 and R.sup.4 being absent when this bond is present, R.sup.1, R.sup.3, R.sup.4 are independently H, OH, halo, oxo, oximino, or an organic radical, R.sup.2 and R.sup.7 are organic radicals, R.sup.6 is H or an organic radical and R.sup.12 is OH, halo, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.9 alkanoyloxy, or oximino optionally O-substituted by a C.sub.1 -C.sub.8 alkyl, alkenyl, alkynyl, aryl, trialkylsilyl, aralkyl or C.sub.1 -C.sub.9 alkanoyl group.
Compounds according to the invention include those in which the 22-23 optional bond is present and those in which this optional bond is absent (i.e. a single bond between the 22 and 23 positions); R.sup.1 is H, OH, C.sub.1 -C.sub.8 alko
REFERENCES:
Chabala, J. C., J. Med. Chem., 23, 1134-1136, 1980.
Yanai, T., et al., Chemical Abstracts, 113, 13, No. 114954w, 1990.
Benson Gregg C.
Owens Amelia
Pfizer Inc.
Richardson Peter C.
Ronau Robert T.
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