Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-11-20
2002-10-22
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S030000
Reexamination Certificate
active
06469067
ABSTRACT:
The present invention relates to preparations for veterinary medicine, which contain a combination of 1-[4-chloro-3-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenyl]-3-(2,6-difluorobenzoyl)urea [hereinafter compound (B)] and a further active ingredient of formula (i) below from the avermectin class. It also relates to the use of these two components in the production of veterinary preparations and their joint usage in a method of controlling ecto- and endo-parasites on productive livestock, domestic animals and pets.
1-[4-chloro-3-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenyl]-3-(2,6-difluorobenzoyl) including the preparation thereof, is known from European Published Specification EP-0.079,311. This compound has in the following the name “compound B”.
In the context of the invention, the active ingredient from the avermectin class is a macro-cyclic compound of formula (i)
wherein
R
1
is hydrogen or one of radicals
R
2
is —CH(CH
3
)—CH
3
, —CH(CH
3
)—C
2
H
5
, —C(CH
3
)═CH—CH(CH
3
)
2
or cyclohexyl; R
3
is hydrogen or hydroxy if the bond between atoms 22 and 23 represents a double bond, or is hydrogen or the group ═N—O—CH
3
if a single bond is present between atoms 22 and 23; and R
4
is HO— or HO—N═, in free form or in the form of a physiologically acceptable salt.
Typical representatives of compounds of formula (i) are:
1) Ivermectin is a mixture of two compounds of formula (i), wherein R
1
is the radical
and R
3
is hydrogen steht, whereby atoms 22 and 23 are linked by a single bond and R
2
is either —CH(CH
3
)—CH
3
or —CH(CH
3
)—C
2
H
5
; both of them, including their preparation, are known from EP-0,001,689. Ivermectin is preferred in the context of the present invention.
2) Doramectin is a compound of formula (i), wherein R
1
is the radical
and R
3
is hydrogen, whereby atoms 22 and 23 are linked by a double bond and R
2
is cyclohexyl. Doramectin is described e.g. in EP-0,214,731 and EP-0,276,131.
3) Moxidectin, also known as LL-F28249&agr; is a compound of formula (i), wherein R
1
and R
3
are hydrogen, whereby atoms 22 and 23 are linked by a single bond and R
2
signifies —C(CH
3
)═CH—CH(CH
3
)
2
. Moxidectin is known from U.S. Pat. No. 4,916,154.
4) Selamectin is 25-cyclohexyl-25-de(1-methylpropyl)-5-deoxy-22,23-dihydro-5-(hydroxyimino)avermectin B1 monosaccharide and thus a compound of formula (i), wherein R
1
is the radical
R
2
signifies cyclohexyl, R
3
is hydrogen, whereby atoms 22 and 23 are linked by a single bond and R
4
is HO—N═. Selamectin is known e.g. from: ECTOPARASITE ACTIVITY OF SELAMECTIN; A novel endectocide for dogs and cats. A Pfizer Symposium, held in conjunction with The 17th international Conference of the World Association for the Advancement of Veterinary Parasitology, Aug. 19, 1999. Copenhagen, Denmark.
The compounds of formula (i) are known from the said publications or are obtainable analogously to known agents.
As is known, the life cycles of the different parasites, which can infest humans or animals, are very complex, which makes it difficult to control them in many cases. In addition, multiple diseases are often a problem that has not yet been satisfactorily resolved. In particular in warmer regions, herd animals such as cattle and sheep, are often infected by an epidemic of helminths and other worm diseases. These diseases in themselves are frequently life-threatening. In many ways, these animals which are already weakened by the endoparasites are additionally infested by ectoparasites, in particular ticks, which often appear en mass and further weaken these animals and form an additional stress factor. The animals which are already weakened by the worms take up even less nourishment because of these plagues, lose weight even more rapidly and require intensive treatment and attention. Moreover, ticks may be infected with various kinds of pathogens, and transmit them particularly easily to host animals that are already weakened and whose immune system is also weakened. There is therefore a vital need to provide preparations which successfully eliminate both the parasitic worms and ticks.
Typical helminthic diseases in the context of the present invention are those caused by members of the nematode class. These include for example the families Filariidae and Setariidae, and the genera Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostumum, Oesophagostonum, Chabertia, Trichuris, especially
Trichuris vulpis
, Strongylus, Trichonema, Dictyocaulus, Capillaria, Strongyloides, Heterakis, Toxocara, especially
Toxocara canis
, Acaridia, Oxyuris, Ancylostoma, especially
Ancylostoma caninum
, Uncinaria, Toxascaris and Parascaris; Dirofilaria, especially
Dirofilaria immitis
(heartworm).
Ticks can feed exclusively from the blood of one host or also from the blood of different hosts. The attach themselves firmly to the host animal and suck its blood. The fully engorged females drop from the host animal and then lay a large number of eggs in a suitable niche in their surroundings. The developing larvae then search for a new host animal in order to develop into adults via the nymph stage, and in turn fully engorge themselves with blood. Certain species feed on two and some on three host animals during their lifecycle.
Ticks of importance in this instance are above all those which belong to the genera Amblyomma, Boophilus, Hyalomma, Ixodes, Rhipicephalus and Dermacentor, especially the species Boophilus microplus and
B. annulatus
, and most especially
B. microplus
. They are responsible for the transmission of numerous diseases which can affect humans and animals. The diseases which are mostly transmitted are bacterial, protozoan, rickettsial and viral. The pathogens of such diseases are transmitted especially by ticks which feed on more than one host. These diseases can lead to the debilitation or even death of the host animals. In most cases they cause considerable economic damage, for example by diminishing the value of meat from livestock, damaging the usable skin, or reducing milk production.
Ticks of the above species are traditionally controlled on otherwise healthy host animals by treating the infested animals with an acaricidally active composition depending on the type of infestation involved, i.e. by curative means. The occurrence of ticks, for example on pasture land, is heavily dependent, however, on seasonal weather conditions, and the ultimate infestation of the host animals itself depends also on their resistance to the ticks. This means that preventative control of the ticks is difficult and time-consuming, since inter alia the severity of infestation by the pests can only be estimated with difficulty. In the case of animals that have already been weakened by other parasites, e.g. the above-mentioned worms, effective control of the ticks is particularly important. Here, preparations are preferred, which show marked contact action, i.e. either kill the ticks upon contact with the pelt or skin, or induce them not to attach themselves and suck blood. With weakened animals, it is especially important that they are not additionally stressed by the anti-tick treatment, and that they are not treated with a number of veterinary preparations, the side effects of which might accumulate. Mass-produced, suitably-adapted, well-tolerated broad-band preparations might provide a remedy.
It is becoming increasingly difficult to synthesise or to isolate from natural sources new classes of active ingredient, which are equal to the active substances already available or even superior to them. Many of the known active ingredients in the field of animal health show exceptionally marked activity against certain target parasites. Unfortunately, their activity is usually restricted either to external or internal parasites only, or they have substantial gaps in their spectrum of activity in one respect or another. For treatment of already weakened animals, however, it would be desirable to provide broad-band preparations, which cover a broad spectrum of
Bouvier Jacques
Kolly Catherine
Kung John W.
Lee Michael U.
Novartis AG
Weddington Kevin E.
LandOfFree
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