Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1995-11-20
1998-03-31
Owens, Amelia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514450, 536 71, 549450, A61K 3170, A61K 31335
Patent
active
057338876
DESCRIPTION:
BRIEF SUMMARY
This invention relates to new antiparasitic agents, related to the milbemycins and avermectins and to processes for their preparation and compositions thereof.
The avermectins are a group of broad spectrum antiparasitic agents referred to previously as the C-076 compounds. They are produced by fermenting a strain of the micro-organism Streptomyces avermitilis under aerobic conditions in an aqueous nutrient medium containing inorganic salts and assimilable sources of carbon and nitrogen. The isolation and the chemical structure of the eight individual components which make up the C-076 complex is described in detail in British Patent Specification 1573955.
The C-076 complex comprises eight distinct but closely related compounds described as C-076 A1a, A1b, A2a, A2b, B1a, B1b, B2a and B2b. The "a" series of compounds refers to the natural avermectins wherein the 25-substituent is (S)-sec-butyl and the "b" series to those wherein the 25-substituent is isopropyl. The designations "A" and "B" refer to avermectins wherein the 5-substituent is methoxy or hydroxy, respectively, and the numeral "1" refers to avermectins wherein a double bond is present at the 22-23 position, and numeral "2" to avermectins lacking the 22-23 double bond and having a hydrogen at the 22-position and hydroxy at the 23 position.
In our European Patent Applications 0214731, 0284176, 0317148, 0308145, 0340832, 0335541 and 0350187 there are described preparations of compounds related to the avermectins but having a group at the 25-position other than the isopropyl or (S)-sec-butyl groups found in the original avermectin compounds disclosed in British Patent Specification 1573955. Such compounds may be prepared by fermentation of particular strains of Streptomyces avermitilis in the presence of organic acids or derivatives thereof. Production of such avermectins is described in Journal of Antibiotics (1991), 44, No. 3, pp 357-365.
The milbemycins form another group of related macrolides which are distinguished from the avermectins in lacking a sugar residue attached at the C-13 position. Examples of such compounds are described in UK patent 1390336, and European patent publications 170006, 254583, 334484 and 410615. In addition to these fermentation products a large number of publications describe compounds derived semisynthetically from these fermentation products many of which possess useful antiparasitic activities. Some of this chemistry is reviewed in Macrolide Antibiotics, Omura S., Ed., Academic press, New York (1984) and by Davies, H. G., Green, R. H. in Natural product Reports (1986), 3, 87-121 and in Chem. Soc. Rev., 1991, 20, 271-339.
European Patent Application 340 849 discloses fluoroavermectin and fluoromilbemycin compounds with the fluorine residing on at least one of the 4a, 5 or 4" positions, and arising from displacement of hydroxy or hydroxy-derived substituents. With regard to the synthesis of the 5-fluoro compounds, the chemistry disclosed therein results in the exclusive formation of the 5-.alpha.-fluoro compounds, and none of the 5-.beta.-diastereomers.
It has been found that certain compounds synthetically derivable from known avermectins and avermectin derivatives possess unexpected beneficial biological properties.
According to one aspect of the invention there are provided compounds of formula (I): ##STR2## wherein the broken line at the 22-23 position represents an optional bond and either this bond is present and R.sup.1 and R.sup.4 are absent or this bond is absent and R.sup.1 and R.sup.4 are independently H, OR.sup.8 wherein R.sup.8 is H, C.sub.1 -C.sub.8 alkyl, C.sub.1 -C.sub.8 alkenyl, aralkyl, C.sub.2 -C.sub.8 alkanoyl, C.sub.3 -C.sub.8 alkenoyl, aralkanoyl, aroyl, optionally substituted carbamoyl, optionally substituted methylene, oxo or optionally O-substituted oximino;
R.sup.2 is: alkylthioalkyl group; an alpha-branched C.sub.4 -C.sub.8 alkynyl group; a (C.sub.5 -C.sub.8 cycloalkyl)alkyl group wherein the alkyl group is an alpha-branched C.sub.2 -C.sub.5 alkyl group; a C.sub.3 -C.sub.8 cycloalkyl or C.sub
REFERENCES:
Davies et al., Chem. Soc. Rev., 20, pp. 271-339 (1991).
Patent Abstracts of Japan, vol. 12, No. 263 (C-514) (1988).
Ginsburg Paul H.
Holtrust Gezina
Owens Amelia
Pfizer Inc.
Richardson Peter C.
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