Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-14
2002-02-12
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S367400
Reexamination Certificate
active
06346542
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a new composition comprising pesticidal compounds having a chiral center, which chiral center cooperates with an adjacent amino group.
Although chirality usually arises from the presence of a carbon atom to which four different atoms or groups are attached, other atoms, including sulphur, can also give rise to chiral centers.
2. Background Art
It is known from, inter alia, EP-A-0 295 117 and Hatton et al U.S. Pat. No. 5,232,940, that certain N-phenylpyrazole compounds are useful for the control of arthropod, plant nematode, helminth and protozoan pests. These compounds include N-phenylpyrazoles having an optionally substituted amino group attached to the 5-position. Such substituted amino groups include amino substituted by one or two groups selected from alkyl and alkanoyl. Compounds of interest include those having a cyano group attached to the 3-position and a group RS(O)
n
attached to the 4-position, R being selected from alkyl and haloalkyl and n being 0, 1 or 2. When the group RS(O)
n
represents a sulfoxide, RS(O), the resulting compounds are generally chiral compounds which exist as a mixture of two enantiomers (also known as enantiomeric isomers).
Among the compounds in the above-mentioned publications is listed 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinylpyrazole, which is depicted as the following formula (A):
This compound is presently used commercially to control pests in, for example, agriculture, public health and animal health, and is known as fipronil.
SUMMARY AND OBJECTS OF THE INVENTION
The compound of formula (A), although it does not contain any chiral carbon atoms, is a racemic mixture of enantiomers by virtue of the —S(O)CF
3
group. The existence of the enantiomers has not been previously disclosed. The known racemic mixture causes emesis in animals to which it is administered orally.
It is desirable in the control of arthropod pests on animals for compounds to be orally administered. Investigation of the class of N-phenylpyrazoles having an optionally substituted amino group attached to the 5-position of the pyrazole ring has now shown that the level of emetic effect of such oral administration is influenced by a combination of parameters: the presence or absence of substitution on the 5-position; the nature of the substitution; and the chirality of the sulfoxide group on the 4-position.
Placement of an acetyl group on the 5-amino group in formula (A) causes a dramatic increase in toxicity and emesis. At a dose of 10 mg/kg in dogs, both enantiomers have caused emesis in about two-thirds of the animals. However, the (S) enantiomer has caused 100% mortality in testing whereas the (R) enantiomer has caused 33% mortality. Although monosubstitution on the 5-amino group by acetyl causes an increase in emetic activity and mortality, it has been discovered that addition of a methyl substituent on the amino group and replacement of acetyl by ethoxyacetyl or tetrahydrofur-2-oyl can reduce both emetic activity and mortality.
Such chemical modification of the 5-amino group can, however, be avoided by separation of the compound of formula (A) into its component (R) and (S) enantiomers. In contrast to the 5-acetylamino enantiomers [where the (S) enantiomer has caused 100% mortality], it is the (S) enantiomer of the 5-amino compound which is the better of the two enantiomers in that it has lower emetic activity. The (S) enantiomer of the 5-amino compound also possesses a second advantageous property. Improved long term control of ticks can be obtained by its use. For example, at a dose of 10 mg/kg administered orally to dogs, the (S) enantiomer at 23 days after administration has been found 85% effective, compared to only 71% effectiveness for the (R) enantiomer (corresponding to only 15% of ticks remaining instead of 29%).
An object of the present invention is to provide a composition comprising 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinylpyrazole which is substantially enriched in an enantiomer.
Another object of the invention is to provide a composition which is generally safer to use in veterinary medicine or agriculture or public health.
Another object of the invention is to provide a composition which when administered orally to animals is substantially non-emetic, most preferably when about 70% or more of the animals so treated are free of emesis.
These objects are met in whole or in part by the present invention. The present invention provides a composition comprising (S)-5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinylpyrazole and (R)-5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinylpyrazole wherein the composition is enriched in the (S) enantiomer.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
By the term “non-emetic” is meant a composition that does not generally elicit emesis from an animal when a protective, preventative or cleaning dose is administered to said animal. By the term “substantially non-emetic” is meant that, generally, when a composition of the invention is administered to a population of animals, more than 70% (or at least ⅔) of the animals are free of emesis. Preferably, more than 80%, most preferably more than 90%, of said population is free of emesis.
By the term “enriched” is meant wherein the (S):(R) weight:weight ratio is at least approximately 1.05 or higher. Preferably, the composition of the invention is substantially enriched in the (S) enantiomer. By the term “substantially enriched” is meant wherein the (S):(R) weight: weight ratio is at least approximately 1.5 or higher.
In a further aspect of the invention, the (S):(R) weight:weight ratio is at least approximately 2 or greater, preferably at least approximately 5 or greater, most preferably at least approximately 10 or greater.
For greater clarity, the structures of (S)-5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinylpyrazole and (R)-5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinylpyrazole are depicted below as formulas (B) and (C), respectively. The optical configurations of formulas (B) and (C) are assigned by the use of the Cahn-Ingold-Prelog system as generally described in
Advanced Organic Chemistry
, J. March, 3
rd
edition, pp. 96-97, Wiley Interscience, NY, 1985. Such depictions are generally understood by those skilled in the art.
The composition of the invention may further comprise a carrier for use in veterinary medicine, animal health, agriculture, or public health. Such compositions as generally described in EP-A-0 295 117 and Hatton et al U.S. Pat. No. 5,232,940, but comprising the (S) and (R) enantiomers substantially enriched in one enantiomer [preferably enriched in the (S) enantiomer], in a pesticidally effective amount (in place of the known racemic mixture), together with a carrier, preferably in a substantially non-emetic amount, are useful herein. See Hatton et al U.S. Pat. No. 5,232,940, incorporated by reference herein in its entirety and relied upon.
The present invention also provides a method of controlling pests at a locus which method comprises applying a composition according to the present invention in a pesticidally effective amount at the locus, preferably in an amount which is also substantially non-emetic.
Compound A may be prepared according to the methods described in EP-A-0 295 117 and Hatton et al U.S. Pat. No. 5,232,940.
In one aspect of the invention, the composition may be prepared by separating the enantiomers of fipronil in whole or in part by, for example, use of column chromatography or reverse-phase column chromatography using a substantially optically active (or “chiral”) stationary phase as known to those skilled in the art.
In another aspect of the invention, the enantiomers may be separated by a process which comprises:
(a) reacting compound (A) with a compound (EF) wherein:
E is an
Aventis CropScience S.A.
Burns Doane Swecker & Mathis L.L.P.
Ramsuer Robert W.
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