Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Biocides; animal or insect repellents or attractants
Reexamination Certificate
1999-12-27
2004-04-06
Levy, Neil S. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Biocides; animal or insect repellents or attractants
C424S406000, C424S407000, C424S078020, C514S407000
Reexamination Certificate
active
06716442
ABSTRACT:
The present invention relates to a procedure for the eradication of parasites, namely parasites of the order of Siphonaptera, especially fleas, such as, for example,
Ctenocephalides felis
and
canis
, but like-wise the other fleas of small mammals such as, for example, rabbits or laboratory animals.
The control of parasites of small domestic mammals, for example dogs and cats, and especially of fleas, is known to be extremely difficult.
Generally, it is attempted to control the animals themselves, either with the aid of flea collars containing various insecticides, or by topical application of preparations based on insecticides.
Nevertheless, the fleas always remain present in the environment of the animal, and especially in the premises of pets, such as domestic premises, kennels or catteries, as well as laboratories keeping animals.
The eradication of fleas in these premises with the aid of pesticides or agents for chemical treatment or the premises is a difficult operation and, except for permanently leaving the premises covered in an insecticidal substance, which can, in the long term, have an undoubted toxicity, reinfestation takes place rapidly.
Thus it only remains to regularly treat the animals with the aid of insecticides having a period of efficacy which is as great as possible, in order to reduce the periodicity and the cost of the treatments.
Thus the use has recently been proposed, for the treatment of fleas and of ticks in small animals, of topical preparations in the form of preparations for spraying or of concentrated preparations for point cutaneous application (spot on) whose active principle is formed by 1-[2,6-Cl
2
-4-CF
3
-phenyl]-3-CN-4-[SO—CF
3
]-5-NH
2
-pyrazole, whose non-proprietary name is fipronil.
In fact, the compounds belonging to the pyrazole, especially phenylpyrazole, families described in the Patents EP-A-295 217 and EP-A-352 944 have turned out to be extremely efficacious against fleas.
The period of anti-flea efficacy of fipronil, in the form of a concentrated solution for point application, called a spot on solution, can exceed 2 to 3 months in dogs and six weeks in cats.
In view of these performances, the users are naturally tempted to prolong the periods between two applications so as to benefit from this effect of long duration.
A possible explanation for the long duration of activity on the animal can be connected to the observation that fipronil dissolves in the sebum and the sweat glands to be released over a long time.
In a communication (Meo N.J. et al.; Proc. Am. Assoc. Vet. Parasitol (41 Meet., 52, 1996)), it was stated that there was a considerable increase in the percentage of non-reappearance of fleas in non-treated premises if the animals frequenting these premises (cats, dogs) received monthly administrations of sprays of the product Frontline® Spray containing fipronil.
The present invention proposes to simplify and to further improve this flea control.
A subject of the invention is thus a procedure for eradication of fleas in domestic or accommodation premises of mammals of small size, especially cats and dogs, characterized in that a concentrated topical preparation for point application, of the spot-on type in an efficaciously parasiticidal quantity of a compound of formula I or, optionally, of formula II is applied periodically to the animal or the animals of the premises considered, according to a monthly periodicity.
The formula I is the following formula:
in which:
R
1
is CN or methyl or a halogen atom;
R
2
is S(O)
n
R
3
or 4,5-dicyanoimidazol-2-yl or haloalkyl;
R
3
is alkyl or haloalkyl;
R
4
is a hydrogen or halogen atom; or an NR
5
R
6
, S(O)
m
R
7
, C(O)—R
7
, C(O)O—R
7
, alkyl, haloalkyl or OR
8
radical or an —N═C(R
9
) (R
10
) radical;
R
5
and R
6
independently are the hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, alkoxycarbonyl or S(O)
r
CF
3
radical; or R
5
and R
6
can together form a divalent alkylene radical which can be interrupted by one or two divalent heteroatoms, such as oxygen or sulphur;
R
7
is an alkyl or haloalkyl radical;
R
8
is an alkyl or haloalkyl radical or a hydrogen atom;
R
9
is an alkyl radical or a hydrogen atom;
R
10
is a phenyl or heteroalkyl group which is optionally substituted by one or more halogen atoms or groups such as OH, —O-alkyl, —S-alkyl, cyano or alkyl;
R
11
and R
12
are, independently of one another, a hydrogen or halogen atom, or optionally CN or NO
2
;
R
13
is a halogen atom or a haloalkyl, haloalkoxy, S(O)
q
CF
3
or SF
5
group;
m, n, q and r are, independently of one another, an integer equal to 0, 1 or 2;
X is a trivalent nitrogen atom or a C—R
12
radical, the three other valencies of the carbon atom being part of the aromatic ring;
with the reservation that when R
1
is methyl, R
3
is haloalkyl, R
4
is NH
2
, R
11
is Cl, R
13
is CF
3
and X is N; or when R
2
is 4,8-dicyanoimidazol-2-yl, R
4
is Cl, R
11
is Cl, R
13
is CF
3
and X is ═C—Cl.
The formula II is the following formula:
where Y is hydrogen or halogen
R
14
is hydrogen or methyl
and Z is —(CH
2
)
n
— with n=1 or 2.
Preferably, in the formula (I),
R
1
is CN or methyl;
R
2
is S(O)
n
R
3
;
R
3
is haloalkyl or ethyl
R
4
is a hydrogen or halogen atom; or an NR
5
R
6
, S(O)
m
R
7
, C(O)R
7
, alkyl, haloalkyl or OR
8
radical or an —N═C(R
9
) (R
10
) radical;
R
5
and R
6
independently are the hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, S(O)
r
CF
3
radical; or R
5
and R
6
can together form a divalent alkylene radical which can be interrupted by one or two divalent heteroatoms, such as oxygen or sulphur;
R
11
and R
12
are, independently of one another, a hydrogen or halogen atom;
with the reservation that when R
1
is methyl, R
3
is haloalkyl, R
1
is NH
2
, R
11
is Cl, R
13
is CF
3
and X is N.
Compounds of formula (I) which will be considered are very particularly those in which R
1
is CN. Compounds will also be considered in which R
13
is haloalkyl, preferably CF
3
, or R
2
is S(O)
n
R
3
with R
3
being haloalkyl or X=C—R
12
, R
12
being a halogen atom. It is also preferred that R
11
is a halogen atom.
A preferred class of compounds of formula (I) is formed by the compounds where R
1
is CN, R
3
is haloalkyl, R
4
is NH
2
, R
11
and R
12
are independently of one another a halogen atom, and/or R
13
is haloalkyl.
The alkyl radicals of the definition of the compounds of formulae (I) generally comprise from 1 to 6 carbon atoms. The ring formed by the divalent alkylene radical representing R
5
and R
6
as well as the nitrogen atom to which R
5
and R
6
are attached is generally a ring with 5, 6 or 7 members.
A compound of formula (I) which is very particularly preferred in the invention is
1-[2,6-Cl
2
-4-CF
3
-phenyl]-3-CN-4-[SO—CF
3
]-5-NH
2
-pyrazole, called fipronil below.
Among numerous other advantageous compounds, it is possible to mention 1-[2,6-Cl
2
-4-CF
3
-phenyl]-3-CN-4-[SO—C
2
H
5
]-5-NH
2
-pyrazole.
The compounds of formula (I) can be prepared according to one or other of the processes described in the Patent Applications WO-A-87/3781, 93/6089, 94/21606 or European EP-A-0 295 117, or any other procedure dependent on the competence of the specialist in chemical synthesis. For the chemical preparation of the products of the invention, the person skilled in the art is considered as having at his disposition, among other things, all the contents of “Chemical Abstracts” and documents which are cited there.
Preferably, in the compound of formula (II) Y=Cl, R
14
=H and n=1, that is to say
1-[(6-chloro-3-pyridinyl)methyl]-4,5-dihydro-N-nitro-1H-imidazol-2-amine or imidaclopride.
The compounds of the formula (II) can be prepared by the corresponding procedures described, for example, in EP-A-0 192 060.
Monthly periodicity is ideally understood as meaning one treatment every month but it is understood that the invention can be practised at a higher rate, for example twice weekly or every three weeks, or optionally, but in a non-preferre
Etchegaray Jean-Pierre
Hunter James S.
Jeannin Philippe
Julia Bruno
Frommer William S.
Frommer & Lawrence & Haug LLP
Kowalski Thomas J.
Levy Neil S.
Merial
LandOfFree
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