Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-10-22
2003-11-25
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S292000, C504S292000
Reexamination Certificate
active
06653342
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a series of new 13-substituted milbemycin derivatives which have valuable acaricidal, insecticidal and anthelmintic activities making them highly useful for protecting plants and animals, which may be human or non-human, from damage by parasites. The invention also provides methods and compositions for using these compounds as well as processes for their preparation.
There are several classes of known compounds with a structure based on a 16-membered macrolide ring, which are obtained by fermentation of various microorganisms or semi-synthetically by chemical derivatization of such natural fermentation products, and which exhibit acaricidal, insecticidal, anthelmintic and antiparasitic activities. The milbemycins and avermectins are examples of two such classes of known compounds, but others exist and are normally identified in the prior art by different names or code numbers. The names for these various macrolide compounds have generally been taken from the names or code numbers of the microorganisms which produce the naturally occurring members of each class, and these names have then been extended to cover the chemical derivatives of the same class, with the result that there has been no standardized systematic nomenclature for such compounds generally.
In order to avoid confusion, a standardized system of nomenclature will be used herein, which follows the normal rules for naming derivatives of organic compounds as recommended by the International Union of Pure and Applied Chemistry (IUPAC), Organic Chemistry Division, Commission on Nomenclature of Organic Chemistry, and which is based on the hypothetical parent compound hereby defined as “milbemycin”, which is that compound represented by the following formula (A):
wherein R
a
and R
b
both represent hydrogen atoms.
For the avoidance of doubt, the above formula (A) also shows the numbering of positions of the macrolide ring system applied to those positions of most relevance to the compounds of the present invention.
The naturally produced milbemycins are a series of macrolide compounds known to have anthelmintic, acaricidal and insecticidal activities. Milbemycin D was disclosed in U.S. Pat. No. 4,346,171, where it was referred to as “Compound B-41D”, and milbemycins A
3
and A
4
were disclosed in U.S. Pat. No. 3,950,360. These compounds may be represented by the above formula (A) in which R
a
at position 13 is a hydrogen atom and R
b
at position 25 is a methyl group, an ethyl group or an isopropyl group, these compounds being designated as milbemycin A
3
, milbemycin A
4
and milbemycin D, respectively. The milbemycin analog having a hydrogen atom at position 13 and substituted at position 25 with a sec-butyl group was disclosed in U.S. Pat. No. 4,173,571, where it was known as “13-deoxy-22,23-dihydroavermectin B
1a
aglycone”.
Subsequently, various derivatives of the original milbemycins and avermectins have been prepared and their activities investigated. For example, 5-esterified milbemycins have been disclosed in U.S. Pat. Nos. 4,201,861, 4,206,205, 4,173,571, 4,171,314, 4,203,976, 4,289,760, 4,457,920, 4,579,864 and 4,547,491, in European Patent Publications No. 0008184, No. 0102721, No. 0115930, No. 0180539 and No. 0184989 and in Japanese Patent Applications Kokai (i.e. as laid open to public inspection) No. 57-120589 and 59-16894.
13-Hydroxy-5-ketomilbemycin derivatives have been disclosed in U.S. Pat. No. 4,423,209. Milbemycin 5-oxime derivatives were disclosed in U.S. Pat. No. 4,547,520 and in European Patent Publication No. 0203832.
Milbemycins having an ester bond at the 13-position are of particular relevance to the present invention and a number of compounds in which the 13-hydroxy group in the compounds of the above formula (A) has been esterified is disclosed in European Patent Publication No. 0186043, which describes esters of a variety of carboxylic acids such as the alkanoic acids. Other milbemycin derivatives having an ester bond at the 13-position, which probably represent the closest prior art, are described in European Patent Publications No. 0246739, No. 0675133 and No. 0765879. These, however, differ from the compounds of the present invention in the nature of the group at the 13-position and, in the case of European Patent Publication No. 0765879, the nature of the group at the 5-position.
The various classes of milbemycin-related macrolide compounds referred to above are all disclosed as having one or more types of activity as antibiotic, anthelmintic, ectoparasiticidal, acaricidal or other pesticidal agents. However, there is still a continuing need to provide such agents with improved activity against one or more classes of agricultural and horticultural pests.
It has now been discovered that the activity of such milbemycin-related derivatives can be improved by appropriately selecting the combination of substituents on the macrolide ring system, especially the substituents at position 13. In particular, it has now been found that the activity of the compounds can be improved upon by appropriate selection of certain highly specific ester groups at the 13 position, as specified below. The compounds of the present invention have been found to have a better pesticidal activity than do the compounds of the prior art, and many of the compounds of the present invention have a very substantially better activity.
BRIEF SUMMARY OF INVENTION
Accordingly, it is an object of the present invention to provide such milbemycin derivatives which have improved activity.
It is another object of the invention to provide methods for preparing such compounds.
It is a still further object of the invention to provide acaricidal, insecticidal and anthelmintic compositions and methods using the said compounds.
Other objects and advantages will become apparent as the description proceeds.
The present invention thus provides compounds of formula (I) and agriculturally, horticulturally, pharmaceutically and veterinarily acceptable salts thereof:
wherein:
R
1
represents a methyl group, ethyl group, isopropyl group or s-butyl group;
R
2
represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms;
R
3
represents a hydrogen atom, an alkanoyl group having from 1 to 6 carbon atoms which may optionally be substituted with 1, 2 or 3 substitutents selected independently from Substituents A defined below, an alkenoyl group having from 3 to 5 carbon atoms which may optionally be substituted with 1 or 2 substitutents selected independently from Substituents A defined below, an alkynoyl group having from 3 to 5 carbon atoms which may optionally be substituted with 1 or 2 substitutents selected independently from Substituents A defined below, an alkylsulfonyl group in which the alkyl moiety has from 1 to 6 carbon, or an alkoxycarbonyl group in which the alkoxy moiety has from 1 to 6 carbon atoms, or
R
2
and R
3
together with the nitrogen atom to which they are attached form a saturated 4- to 6-membered heterocyclic ring group containing one ring nitrogen atom and optionally containing one further ring heteroatom selected from the group consisting of sulfur atoms, oxygen atoms and nitrogen atoms, said saturated heterocyclic ring optionally being substituted with 1 or 2 substituents independently selected from Substituents B defined below;
the moiety -a- together with the carbon atom to which it is attached forms a 3- to 6-membered cycloalkyl group;
Substituents A are selected from the group consisting of halogen atoms, cyano groups, hydroxy groups, alkoxy groups having from 1 to 6 carbon atoms, alkylthio groups having from 1 to 6 carbon atoms, alkanoyloxy groups having from 1 to 6 carbon atoms, amino groups which may optionally be substituted with 1 or 2 substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, alkanoyl groups having from 1 to 6 carbon atoms, alkylsulfonyl groups in which the alkyl moiety has from 1 to 6 carbon and alkoxycarbonyl groups in which the alkoxy moiety has from 1 to 6 carbon atoms,
Nanba Toshihiko
Saito Akio
Sugiyama Yoko
Toyama Toshimitsu
Frishauf Holtz Goodman & Chick P.C.
Owens Amelia
Sankyo Company Limited
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