Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1996-03-08
1997-09-09
Kight, John
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
536 71, A61K 3170, C07H 1708
Patent
active
056657080
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to novel intermediates in the preparation of the compound of formula (I) below, ##STR2## hereinafter referred to as doramectin, and improved processes for preparing said intermediates. The invention also relates to the utility of said intermediates as antiparasitic compounds in their own right. The invention further relates to an improved process for preparing doramectin from the compound of formula (II) below. ##STR3##
Doramectin is a broad spectrum antiparasitic and anthelmintic agent belonging to a class of secondary metabolites known as avermectins. Doramectin can be prepared by fermenting an avermectin producing strain of the microorganism Streptomyces avermitilis such as ATCC 31267, 31271 or 31272 under aerobic conditions in an aqueous nutrient medium containing inorganic salts and assimilable sources of carbon and nitrogen as described in U.S. Pat. No. 5,089,480, which is incorporated herein by reference. Another strain of avermectin producing microorganism is Streptomyces avermitilis ATCC 53568, which is described in Dutton et al., Journal of Antibiotics, 44, 357-65 (1991). Streptomyces avermitilis ATCC 31267, 31271, 31272 and 53568 are currently on deposit with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Md. 20852, U.S.A., under the terms of the Budapest Treaty.
During the fermentation procedure which produces the compound of formula (I) hereinabove various co-products can be isolated. A major co-product which can be isolated during the fermentation of the above-identified microorganisms has the structure of formula (II) hereinabove. The isolation of the compound of formula (II) from the fermentation broth of Streptomyces avermitilis ATCC 53568 is described in Dutton et al., Id. The compound of formula (II) is an active antiparasitic and anthelmintic compound which has been disclosed and claimed in U.S. Pat. No. 5,089,480. However, doramectin is preferred. The process of the present invention makes use of the co-product of formula (II) by converting it into the more valuable antiparasitic agent doramectin of formula (I).
The overall transformation in this process is the elimination of the C-23 hydroxyl group, leaving an olefin in the C-22 to C-23 positions of the molecule. Low yield processes which effect the same transformation on slightly different avermectins have been reported. For example, where the C-25 cyclohexyl group is instead a sec-butyl group, the transformation has been achieved using a five step sequence in approximately 3.6% overall yield. Mrozik et al., Tetrahedron Letters, 1982, 23, 2377-78. In light of the low yield of this prior art process, it is desirable to devise a process whereby the starting material is more efficiently converted to doramectin.
Therefore, it is an object of this invention to convert the compound of formula (II) to doramectin in high overall yield. It is a further object of this invention to provide useful intermediates for the process.
SUMMARY OF THE INVENTION
The present invention provides novel intermediates of the formula (III) ##STR4## wherein R.sup.1 is (C.sub.2 -C.sub.5)alkanoyl, or aryloxyacetyl and R.sup.2 is hydrogen or aryloxythiocarbonyl.
This invention further provides novel intermediates of the formula (IV): ##STR5## wherein R.sup.1 is (C.sub.2 -C.sub.5)alkanoyl or aryloxyacetyl.
Particularly preferred compounds of this invention are those compounds of formula (III) wherein R.sup.1 is (C.sub.2 -C.sub.5)alkanoyl, phenoxyacetyl or (C.sub.1 -C.sub.4)alkylphenoxyacetyl and R.sup.2 is hydrogen or (C.sub.1 -C.sub.4)alkylphenoxythiocarbonyl. Especially preferred compounds within this group are the compounds of formula (III) wherein R.sup.1 is acetyl or phenoxyacetyl and R.sup.2 is hydrogen or p-tolyloxythiocarbonyl.
Also particularly preferred compounds of this invention are the compounds of formula (IV) wherein R.sup.1 is (C.sub.2 -C.sub.5)alkanoyl, phenoxyacetyl or (C.sub.1 -C.sub.4)alkylphenoxyacetyl. Especially preferred compounds within this group are the compounds
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Mrozik, et al., "Partial Synthesis of Avermectin B.sub.1a from Avermectin B.sub.2a ", Tetrahedron Letters, 1982, 23, 2377-78.
Dutton et al., "Novel Avermectins Produced by Mutational Biosynthesis," Journal of Antibiotics, 1991, 44, 357-65.
Hafner et al., "Branched-chain Fatty Acid Requirement for Avermectin Production by a Mutant of Streptomyces Avermitilis Lacking Branched-chain 2-oxo Acid Dehydrogenase Activity", Journal of Antibiotics 1991, 44, 349-56.
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Crawford Thomas Charles
Demers Neil
Gibson Stephen Paul
Murtiashaw, deceased Charles William
Sklavounos Constantine
Benson Gregg C.
Kight John
Lee Howard C.
Pfizer Inc.
Richardson Peter C.
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