Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2002-08-13
2004-10-05
Levy, Neil S. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S029000, C424S405000, C424S406000
Reexamination Certificate
active
06800614
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a new group of natural pesticidal products, and to a novel Saccharopolyspora species that produces the compounds.
BACKGROUND OF THE INVENTION
Fermentation product A83543 is a family of compounds, referred to as spinosyns, that are produced by certain strains of
Saccharopolyspora spinosa
. The previously disclosed naturally produced spinosyns have a 5,6,5-tricylic ring system, fused to a 12-membered macrocyclic lactone, a neutral sugar (rhamnose) and an amino sugar (forosamine) (see Kirst et al. (1991). The known spinosyns have been referred to as factors or components, and each has been given an identifying letter designation, i.e. spinosyn A, B, etc. The compounds are useful for the control of arachnids, nematodes and insects, in particular Lepidoptera and Diptera species, and they are quite environmentally friendly and have an appealing toxicological profile.
U.S. Pat. No. 5,362,634 and corresponding European Patent Application No. 375316 A1 disclose spinosyns A, B, C, D, E, F, G, H, and J. WO 93/09126 discloses spinosyns L, M, N, Q, R, S, and T. WO 94/20518 and U.S. Pat. No. 5,6704,486 disclose spinosyns K, O, P, U, V, W, and Y, and derivatives thereof.
A large number of synthetic modifications to spinosyn compounds have been made, as disclosed in WO 97/00265, but modification of spinosyns at the C-21 position has not been feasible. C-21 of the known compounds is substituted with methyl or ethyl. If means could be found to introduce a reactive functional group in place of the methyl or ethyl group without causing unwanted changes in other portions of the molecule, the way would be opened for synthesis of many additional spinosyn compounds. This has been a long sought and previously unrealized goal of those working in the field of spinosyn synthesis.
SUMMARY OF THE INVENTION
The present invention provides an isolated strain of a novel Saccharopolyspora species designated LW107129 (NRRL 30141).
The invention also provides compounds that can be produced by culturing LW107129 in a suitable culture medium and that have the following general formula 1 or 2:
wherein
R1 is a group of formula 2a, 2b, or 2c
R2 is H or OH;
R3 is H or CH
3
;
R4 in formula 1 is 1-butenyl, 1,3-butadienyl, n-butyl, 3-hydroxy-1-butenyl, or 1-propenyl; and R4 is ethyl in formula 2;
and R5 is H or a group having one of the following formulas 4a through 4i
Specific compounds of Formula 1 or 2 that have been prepared and isolated by culturing Saccharopolyspora strain LW107129 are identified in Table I.
TABLE I
Compound
No.
formula
R1
R2
R3
R4
R5
1
1
2a
H
H
1-butenyl
4a
2
1
2a
H
H
1-butenyl
4b
3
1
2a
H
H
1-butenyl
4c
4
1
2a
H
H
1-butenyl
4d
5
1
2b
H
H
1-butenyl
4a
6
1
2c
H
H
1-butenyl
4a
7
1
2a
H
Me
1-butenyl
4a
8
1
2a
OH
H
1-butenyl
4a
9
1
2a
H
H
3-hydroxy-1-butenyl
4a
10
1
2a
H
H
3-hydroxy-1-butenyl
4c
11
1
2a
H
H
1,3-butadienyl
4a
12
1
2a
H
H
1-butenyl
4e
13
1
2a
H
H
1-butenyl
4f
14
1
2a
OH
H
1-butenyl
4e
15
1
2a
OH
H
1-butenyl
4g
16
1
2a
H
H
1-propenyl
4a
17
1
2a
H
H
1-butenyl
H
18
1
2a
H
Me
1-butenyl
H
19
1
2a
OH
H
1-butenyl
H
20
1
2a
H
H
3-hydroxy-1-butenyl
H
21
1
2a
OH
H
3-hydroxy-1-butenyl
H
22
1
2a
H
H
1,3-butadienyl
H
23
1
2a
H
H
n-butyl
H
24
1
2a
H
H
1-butenyl
4h
25
1
2a
H
H
1-butenyl
4i
26
1
2a
OH
H
1,3-butadienyl
4a
27
1
2a
OH
Me
1-butenyl
4a
28
1
2a
OH
H
1-propenyl
4a
29
1
2b
H
H
1-butenyl
H
30
1
2c
H
H
1-butenyl
H
31
2
2a
H
H
ethyl
4a
All of the components listed in Table I are structurally distinct from previously known spinosyns because, with reference to group R4, no previously known spinosyn compounds have had a 1-butenyl, 3-hydroxy-1-butenyl, 1,3-butadienyl, 1-propenyl, or n-butyl group at C-21 of the macrolide. Further, several of the compounds in Table I differ from all previously known spinosyns because, with reference to group R5, these compounds have new groups linked the oxygen at C-17 on the macrolide. R2 is always H in known spinosyns, therefore variation at this position is novel. Additionally, compound 31 has a new 14-carbon macrolide ring system not previously known in the compounds reported from
S. spinosa.
The compounds of the invention can react to form salts. Salts that are physiolocally acceptable are also useful in the formulations and methods of this invention. The salts are prepared using standard procedures for salt preparation. For example compounds of the invention can be neutralized with an appropriate acid to form an acid additional salt. The acid addition salts are particularly useful. Representative suitable acid addition salts include salts formed by reaction with either an organic or inorganic acid such as, for example, sulfuric, hydrochloric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, cholic, pamoic, mucic, glutamic, camphoric, glutaric, glycolic, phthalic, tartaric, formic, lauric, stearic, salicylic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic and like acids.
Another aspect of this invention is a process for producing compounds of formula 1 and 2, which comprises culturing Saccharopolyspora strain LW107129 (NRRL 30141) in a suitable medium. The formula 1 and 2 compounds are extracted from the fermentation broth and from the mycelium with polar organic solvents. The compounds may be further purified by techniques well-known in the art, such as column chromatography.
The formula 1 and 2 compounds where R5 is a group having one of the formulas 4a through 4i are useful for the control of mites, ticks, and insects. Therefore, insecticidal and acaricidal compositions and methods for reducing the populations of insects, mites, and ticks using these compounds are also a part of this invention.
Compounds of formula 1 and 2 where R5 is hydrogen (C17-pseudoaglycones) are useful as intermediates in the preparation of insecticidal and miticidal compounds. For example, these compounds can be glycosylated at the C-17 hydroxyl group. The glycosylation may be carried out by chemical synthesis or by microbial bioconversion, using procedures described, for example, in U.S. Pat. No. 5,539,089.
DETAILED DESCRIPTION OF THE INVENTION
Culture Description
The novel strain producing the compounds of the invention has been given the designation LW107129. Culture LW107129 was isolated from a soil sample composed of soils collected at numerous sites. The culture has been deposited in accordance with the terms of the Budapest treaty at the Midwest Area Regional Research Center, Agricultural Research Service, United States Department of Agriculture, 815 North University Street, Peoria, Ill. 61604. The strain was deposited on Jun. 9, 1999, and was assigned deposit number NRRL 30141.
Culture Characteristics
Saccharopolyspora strain LW107129 produces aerial mycelium and bright white spores on the following media: Bennett's, ISP2 and ISP5. Colonies are cream to light tan in color and the substrate mycelium can take on a light brown color, particularly on ISP4 & ISP5. Strain LW107129 does not sporulate on ISP3 and ISP4. No pigments were produced on any medium tested. The mycelium of strain LW107129 undergoes fragmentation in liquid culture.
Morphological Characteristics
Strain LW107129 produces ovid spores in chains of up to 50 spores. The spores are encased in a spore sheath and the spore surface is hairy with infrequent spines.
Physiological Characteristics
Saccharopolyspora strain LW107129 is able to produce acid from the following substrates: D-arabinose, m-erythritol, D-fructose, D-glucose, glycerol, D-mannitol, D-mannose, L-rhamnose, D-ribose and trehalose. Strain LW107129 cannot produce acid from adonitol, L-arabinose, dextrin, dulcitol, ethanol, D-galactose, glycogen, inositol, lactose, maltose, melezitose, melibiose, raffinose, salicin, D-sorbitol, L-sorbose, sucrose, xylitol and D-xylose. Strain LW107129 is able to assimilate several organic acids including acetate, citrate, formate and succinate but not benzoate, butyrate, oxalate or tartrate. Strain LW107129 is able to hydrolyze tyrosine and urea but not adenine, casain, esculin, hippurate, hypoxanthine, starch or xanthifle. LW1071
Gilbert Jeffrey R.
Graupner Paul R.
Hahn Donald R.
Karr Laura L.
Lewer Paul
Dow AgroSciences LLC
Levy Neil S.
Stuart Donald R.
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