Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Fungus
Reexamination Certificate
1999-06-23
2002-08-20
Naff, David M. (Department: 1651)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Fungus
C435S041000, C435S117000, C435S171000, C435S254100, C435S911000
Reexamination Certificate
active
06436395
ABSTRACT:
SUMMARY OF THE INVENTION
The present invention relates to the use of sordarin and derivatives thereof in controlling phytopathogenic fungi in crops; to agrochemical compositions containing the compounds; and to fermentation processes for the production of sordarin as well as the microorganisms used therein.
BACKGROUND OF THE INVENTION
The control of phytopathogenic fungi is of great economic importance since fungal growth on plants or on parts of plants inhibits production of foliage, fruit or seed, and the overall quality of a cultivated crop. In fact, without crop protection, greater than 75% of the world's food production would be lost. Even so, 12% is still lost to plant diseases. Because of the vast economic ramifications of fungal infection in agricultural and horticultural cultivations, a broad range of fungicidal and fungistatic products have been developed for general and specific applications. However, the widespread use of agricultural fungicides frequently induces resistance to currently available agents; thus, there exists a need to discover new antifungal compounds that are outside of the known chemical classes of agricultural fungicides, and/or act by a different mechanism than the available agents.
Sordarin (I, wherein Z is (d)) is an antifungal antibiotic isolated from the ascomycete
Sordaria araneosa
(see GB 1,162,027 and
Helvetica Chimica Acta
, 1971, 51:119-20). Other compounds having the sordarin skeleton have also been reported as antifungal agents. Japanese Kokai J62040292 discloses the compound zofimarin (I, wherein Z is (e)) isolated from
Zopfiela marina
sp.; Japanese Kokai J06157582 discloses the compound BE-31405 (I, wherein Z is (f) and R
a
is acetyl) isolated from Penicillium sp.; and SCH57404 (I, wherein Z is (f) and R
a
is methyl) is reported in
J. Antibiotics
, 1995, 48:1171-1172. Semi-synthetic sordarin derivatives are reported in PCT Applications WO96/14326 and WO96/14327. While the aforementioned compounds all have been referred to as antifungal agents, the only uses mentioned in the literature have been for treatment of human and/or animal mycotic diseases. There is no teaching or suggestion that sordarin and derivatives thereof are effective against phytopathogenic fungi, or that they are suitable for agricultural applications.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides in one aspect a method for controlling phytopathogenic fungi which comprises administering to a plant in need of such control an antifungal effective amount of a compound of formula (I)
and wherein Z is a tetrahydropyrano group selected from
and salts and solvates (e.g. hydrates) or metabolically labile derivatives thereof, wherein
R
a
is OC(O)CH
3
or CH
3
;
R
1
is hydrogen, halogen, hydroxyl, C
1-4
alkoxy or acyloxy;
R
2
and R
3
may each independently represent hydrogen, C
1-6
alkyl or C
1-4
alkoxy C
1-4
alkyl, or
R
2
and R
3
may together with the carbon atom to which they are attached represent C═O, C═S or C
3-8
cycloalkyl;
R
4
is hydrogen or CH
2
R
7
(where R
7
is hydrogen, hydroxyl, C
1-4
alkoxy or a group OCOR
8
in which R
8
is C
1-4
alkyl or aryl);
R
5
and R
6
may each independently represent hydrogen, C
1-6
alkyl or C
1-4
alkoxy C
1-4
alkyl, or
R
5
and R
6
may together with the carbon atom to which they are attached represent C═O, C═S or C
3-8
cycloalkyl; n is zero or 1;
X and Y may each independently represent oxygen, sulfur or CR
9
R
10
(where R
9
and R
10
may each independently represent hydrogen, C
1-6
alkyl, C
1-4
alkoxy or C
1-4
alkoxyC
1-4
alkyl or R
9
and R
10
may together with the carbon atom to which they are attached represent C═O, C═S, C
3-8
cycloalkyl or C═CHR
11
where R
11
represents hydrogen or C
1-4
alkyl); or when X or Y is oxygen and n is zero then —Y—CR
2
R
3
or —X—CR
2
R
3
— respectively may also represent —N═CR
3
— or —NR
12
—CR
2
R
3
—(where CR
2
and R
3
are C═O and R
12
is C
1-4
alkyl an acyl group COR
13
where R
13
is C
1-6
alkyl) or when Y is oxygen and n is zero X may be represent the group CR
11
(wherein R
11
has the meanings defined above) which is attached to the pyran ring by a double bond;
R
15
is hydrogen, halogen, azido, C
1-6
alkyl, hydroxy, C
1-6
alkoxy (optionally substituted by 1 or 2 hydroxy or a ketal thereof or 1 or 2 C
1-3
alkoxy groups), arylC
1-4
alkoxy, C
3-6
alkenyloxy, a group OCOR
18
(where R
18
is arylC
1-4
alkoxy or a C
1-10
alkyl group optionally containing one or two double bonds) or C
1-6
alkoxycarbonyl C
1-4
alkoxy, and R
16
represents hydrogen or R
15
and R
16
may together with the carbon atom to which they are attached represent C═O or C═CH
2
;
R
17
is CH
2
R
19
where R
19
is hydrogen, hydroxyl, C
1-4
alkoxy or a group OCOR
20
in which R
20
is C
1-4
alkyl); and
W is oxygen, sulfur, or CH
2
; and the dotted line in group (a) indicates the optional presence of an additional bond;
R
1a
is hydrogen, halogen, hydroxyl or C
1-4
alkoxy;
R
2a
hydrogen, halogen, hydroxyl, C
1-10
alkoxy, C
1-10
alkylthio, C
1-6
alkoxyC
1-4
alkoxy, arylC
1-6
alkyloxy, arylC
3-6
alkenyloxy, azido, NR
5a
COR
5a
(where each R
5a
is independently hydrogen or C
1-6
alkyl), OR
6a
(where R
6a
is a cyclic ether containing 4 to 8 atoms linked to the oxygen atom via a ring carbon atom adjacent to the ring oxygen atom) or a group Y
a
C(═O) —X
a
—R
7a
where Y
a
is oxygen, sulfur or NH, X
a
is either a bond, an oxygen atom or a moiety NR
8a
in which R
8a
is hydrogen or C
1-6
alkyl, and R
7a
is C
1-10
alkyl optionally containing one or two double bonds, aryl, arylC
1-4
alkyl, arylC
2-4
alkenyl, haloC
1-6
alkyl, or C
1-6
alkoxyC
1-4
alkyl), and R
3a
represents hydrogen, or
R
2a
and R
3a
may together with the carbon atom to which they are attached represent C═O or C═NOR
9a
(where R
9a
is C
1-6
alkyl); and
R
4a
is hydroxyl, C
1-6
alkoxy or OC(═O)R
7a
(where R
7a
is as defined above); with the proviso that when R
1a
represents a hydroxyl group in the axial configuration and R
4a
is methoxy then R
2a
cannot represent a group in the axial configuration selected from hydroxyl and OCOCHCH
Z
═CH—CH
E
═CHCH
3
.
In another aspect the present invention provides an agricultural composition for use in controlling phytopathogenic fungi which comprises an antifungal effective amount of a compound of formula I and an agriculturally acceptable carrier.
Another aspect of the present invention provides a process for the production of sordarin which comprises:
cultivating a sordarin producing strain of
Rosellinia subiculata
in a nutrient medium containing assimilable sources of carbon and nitrogen; and
isolating sordarin.
Another aspect of the present invention provides a biologically pure culture of
Rosellinia subiculata
having the identifying characteristics of ATCC 74386.
A further aspect of the present invention provides a process for the production of sordarin which comprises:
cultivating a sordarin producing strain of a fungus having the identifying characteristics of ATCC 74387 in a nutrient medium containing assimilable sources of carbon and nitrogen; and
isolating sordarin.
Another aspect of the present invention provides a biologically pure culture of a fungus having the identifying characteristics of ATCC 74387.
In the application, unless otherwise specified, the following definitions apply:
The term “control” or “controlling” includes prophylactic use (i.e. to protect against infection) and curative use (i.e. to eradicate infection).
The term “plants” include whole live plants or parts thereof, foliage, flowers, seeds, fruits, and other materials derived from plants. The term also includes roots of the plant via application of the active ingredient to the soil.
The term “composition”, as in agricultural or agrochemical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any tw
Bills Gerald F.
Dombrowski Anne W.
Horn Wendy S.
Jansson Richard K.
Rattray Mark
Lee Shu Muk
Merck & Co. , Inc.
Naff David M.
Rose David L.
Ware Deborah K.
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