EXHIBIT 1018
`
`

`

`(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2009/0312387 A1
`Sirinyan et al.
`(43) Pub. Date:
`Dec. 17, 2009
`
`US 20090312387A1
`
`(54) COMPOSITION FOR CONTROLLING
`PARASITES ON ANIMALS
`
`(75)
`
`Inventors:
`
`Kirkor Sirinyan, Bergisch
`Gladbach (DE); Andreas Turberg,
`Haan (DE)
`
`Correspondence Address:
`BAYER HEALTHCARE LLC
`P.0.BOX 390
`SHAWNEE MISSION, KS 66201 (US)
`
`(73) Assignee:
`
`(21) Appl. No.:
`
`BAYER ANIMAL HEALTH
`GMBH, LEVERKUSEN (DE)
`12/520,169
`
`(22) PCT Filed:
`
`Dec. 14, 2007
`
`(86) PCT No.:
`
`PCT/EP2007/010980
`
`§ 371 (0X1),
`Jun. 19’ 2009
`(2): (4) Date:
`Foreign Application Priority Data
`
`(30)
`
`Dec. 27, 2006
`
`(DE) ...................... 10 2006 061 537.9
`,
`, Cl
`'fi
`_
`Publication
`as51 cation
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 31/415
`(2006.01)
`A61P 33/00
`(52) us. Cl. ........................................................ 514/407
`(57)
`ABSTRACT
`The invention relates to novel compositions for controlling
`parasites on animals, comprising an N-phenylpyrazole in a
`formulation comprising aliphatic cyclic carbonates.
`
`

`

`US 2009/0312387 A1
`
`Dec. 17, 2009
`
`solvents and spreading agents, an additive which can improve
`the good arthropodicidal efficacy properties of the N-phe-
`nylpyrazoles.
`[0005] The invention relates to novel compositions for con—
`trolling parasites on animals, comprising an N-phenylpyra-
`zole in a formulation comprising:
`[0006]
`an aliphatic cyclic carbonate
`[0007]
`an aliphatic cyclic or acyclic polyether.
`[0008] The arthropodicidal compositions according to the
`invention are novel and, compared to the formulations hith-
`erto described, have considerably better and longer-lasting
`efficacy, with simultaneously improved user and target ani-
`mal safety profile.
`[0009] To the person skilled in the art, N—phenylpyrazoles
`are known per se as arthropodicidally active compounds, for
`example from the documents mentioned above, which are
`incorporated herein by way of reference.
`[0010] Preferred phenylpyrazoles are those of the formula
`(I):
`
`(I)
`
`R4
`
`R5
`
`N(
`
`\N
`
`R6
`
`R3
`
`/ I"
`
`\ R
`
`2
`
`in which
`
`X represents :N— or C—Rl,
`R1 and R3 independently of one another represent halogen,
`R2 represents halogen, C H-haloalkyl, S(O),,CF3 or SFS,
`n represents 0, 1 or 2,
`R4 represents hydrogen, cyano or a radical of the formula
`
`Y A
`
`...
`
`[0011]
`
`or one of the cyclic substituents below:
`
`N
`/N
`/ \ Y O
`Y ’0 NJ R22
`N—
`/
`
`O
`
`O
`
`.
`
`RS represents hydrogen, C2_4-alkynyl, C2_4—alkenyl
`[0012]
`which may optionally be mono- or polysubstituted by halo-
`gen or C1_3-alkyl, or R5 represents Cl _4—a1kyl-(C=O)——,
`C1_4-alky1-S—, C,_4-haloalkyl-S—-, —S(=O)——C,_4-
`alkyl or —S(=NH)——C 1 _4-alky1, optionally halogen-sub—
`stituted phenyl, optionally halogen-substituted furyl, the
`radical —NR14R15, an oxiranyl radical which is optionally
`mono- or polysubstituted by C1 A-alkyl or C1_4-haloalkyl,
`
`COMPOSITION FOR CONTROLLING
`PARASITES ON ANIMALS
`
`[0001] The invention relates to novel compositions for con-
`trolling parasites on animals, comprising an N—phenylpyra-
`zole in a formulation comprising aliphatic cyclic carbonates.
`[0002] N-Phenylpyrazoles and their good insecticidal and
`acaricidal activity are known from US 2006014802 A1,
`W02005090313 A1,
`FR2834288A1, WOO9828277,
`U806069157, W0200031043, DE19824487, W009804530,
`WOO9962903, EPOO933363, EP00911329, WOO9856767,
`U805814652, W009845274, WO9840359, W009828279,
`W009828278, DE19650197, WOO9824767, EP00846686,
`EP00839809, W009728126, EP00780378, GB02308365,
`U805629335, W009639389, US05556873, EP00659745,
`USOS321040, EP00511845, EP—A-234119, EP-A-2951 17
`and WO 98/24769. In spite of this abundance ofapplications
`with numerous N-phenylpyrazole structures, there is a supe-
`rior structure type which, for most indications, shows, by
`comparison, the best activity. 1-[2,6-Dichloro-4—(trifluorom—
`ethyl)pheny1]-3-cyano-4-[(trifluoromethyl)-su1phiny1]-5—
`aminopyrazole (INN: fipronil) is generally acknowledged to
`be the most effective compound of this class for controlling
`most parasites.
`[0003] N-Phenylpyrazoles have been marketed as ecto-
`parasiticides for more than 10 years (Hunter, J. S., 111, D. M.
`Keister and P. Jeannin. 1994. Fipronil: A new compound for
`animal health. Proc. Amer. Assoc. Vet. Parasitol. 39th Ann.
`
`Mtg. San Francisco, Calif. Pg. 48.). They are distinguished by
`good and broad activity and acceptable compatibility. It is
`known that the existing formulations having a high content of
`DEE (Transcutol) contain a strong transdermal (FR 1996-
`11446 A; Sicherheitsdatenblatt [Safety data sheet]: ISO/DIS
`11014/29 CFR 1910.1200/ANSI Z400.1 Printing date Oct.
`23, 2001: FRONTLINE® TOP SPO'ITM: fipronil 9.7% w/w)
`component. This facilitates, via the formulation, penetration
`into the sebaceous glands and the epithelium (Skin distribu-
`tion of fipronil by microautoradiography following topical
`administration to the beagle dog. Cochet, Pascal; Birckel, P. ;
`Bromet—Petit, M.: Bromet, N.: Weil, A.; European Journal of
`Drug Metabolism and Pharmacokinetics (1997), 22(3), 211-
`216.). Via sebum excretion from the sebaceous glands, a high
`concentration in the sebaceous glands may contribute to a
`long—lasting availability of the active compound If the active
`compound is carried along. However, in the case of the cus-
`tomary formulations, penetration of N—phenylpyrazoles into
`the circulation is also likely, since each hair follicle is sup-
`plied by a blood vessel and the follicles are thus separated
`from the circulation only by a very thin area (Transfollicular
`drug delivery——Is it a reality? Meidan, Victor M.; Bonner,
`Michael C.; Michniak, Bozena B.; International Journal of
`Pharmaceutics (2005), 306(1-2), 1—14). Thus, the availability
`ofthe active compound on the animal is limited, to, both with
`respect to duration and concentration, since the active com-
`pound passes into the circulation and its available concentra—
`tion in the sebum is lowered accordingly.
`[0004] This disadvantage ofthe formulation ofthe prior art
`was to be reduced by modifying the basic properties of the
`formulation without losing the positive efficacy properties. To
`this end, by intensive analyses and test series, we have now
`surprisingly identified, from a large number of additives,
`
`

`

`US 2009/0312387 A1
`
`Dec. 17, 2009
`
`[0033] R2 preferably represents C1_3-haloa1kyl or SFS.
`g
`y
`[0034] R4 preferably represents hydro en, c ano or a radi-
`ca] of the formula
`
`Y i
`
`,
`
`or a cyclopropyl radical which is optionally mono- or
`polysubstituted by halogen, C1_4-a]kyl or C M-haloalkyl,
`[0013] R6 represents hydrogen, C1_4-alkylcarbonyl or a
`radical —NR16R17,
`[0014] R7 represents hydrogen, C1_4-alkyl, CIA-alkyl-S—-
`or —NR9R1°,
`[0015] Y represents :8, =0, =NH, =N—C1_4-alkyl,
`=N—OH or
`
`[0016] R8 represents Cl _4-a1kyl,
`[0017] R9 and R10 independently of one another represent
`hydrogen, hydroxy] or C1 _4-a1kyl,
`[0018]
`R11 represents hydrogen, C1_4-a1ky], —COO—Cl_
`4-alkyl or —CONR12R13,
`[0019] R12 and R13 independently of one another represent
`hydrogen or CIA-alkyl,
`[0020] R14 and R15 independently of one another represent
`hydrogen, C 1 _4-alkyl, C1_4-haloa1kyl or C 1 4-alkyl—SOZ—,
`[0021]
`R16 and R1 7 independently of one another represent
`hydrogen, C1 4-alkoxy or C 1 A-alkyl, where the C M—alkyl
`may optionally be substituted by phenyl, pyranzinyl or
`pyridyl, where phenyl, pyranzinyl or pyridyl may be mono-
`or polysubstituted by hydroxyl, C r_4-alkyl, Cl_4-haloalkyl
`and/or C M-alkoxy, or
`[0022] R“5 and R17 represent C1_4-alkylcarbonyl, C1 4-
`alkoxycarbonyl, C1_4-a1koxy—CH-alkylcarbony] or
`the
`radical —(C:=O)NR2°R21 or
`the group
`represent
`[0023] R16
`and R17
`together
`=CR18R19 which is attached by a double bond to the
`nitrogen,
`[0024] R18 and R19 independently of one another represent
`phenyl which is optionally mono- or polysubstituted by
`hydroxyl, CIA-alkyl, C1_4-haloalkyl and/or C1_4-alkoxy,
`and/or R18 and R19 represent hydrogen, CIA-alkyl, C1 4-
`alkenyl or C1_4-alkoxy, where CM-alkyl, C1_4-alkeny1 or
`CM-alkoxy may optionally be substituted by phenyl
`which is optionally mono- or polysubstituted by hydroxyl,
`CM-alkyl, CM-haloalkyl and/or C1_4—alkoxy,
`[0025] R20 and R21 independently of one another represent
`hydrogen, C M—alkyl or phenyl which is optionally mono-
`or polysubstituted by hydroxyl, C 1 A—alkyl, C1_4-haloalkyl
`and/or C1_4-a1koxy,
`[0026]
`R22 represents C1_4-alkyl.
`[0027] Halogen preferably represents fluorine, chlorine,
`bromine or iodine, in particular fluorine, chlorine or bromine.
`[0028] C1_4-Alky1 represents straight—chain or branched
`alkyl having 1
`to 4 carbon atoms, such as, for example,
`methyl, ethyl, n-propyl, isopropyl, n—butyl, sec-butyl, tert-
`butyl.
`or
`straight—chain
`represents
`[0029] CM-Haloalkyl
`branched alkyl having 1 to 4 carbon atoms which is substi-
`tuted by one or more identical or different halogen atoms; this
`also includes perhaloalkyl compounds. Preference is given to
`fluoroalkyls. Examples are —CF2H, —CF3, —CH2CF3,
`—CF2CF3.
`[0030]
`Preferably,
`meanings:
`[0031] X preferably represents C—RI.
`[0032] R1 and R3 independently of one another preferably
`represent chlorine or bromine.
`
`the substituents have the following
`
`[0035]
`
`or one of the cyclic substituents below:
`
`/
`Rn
`
`[0036] R5 preferably represents hydrogen, C2_3-alkynyl,
`C2_3-alkenyl which may optionally be monosubstituted by
`halogen or C1_3-a1kyl, or R5 preferably represents CH-
`alkyl—(C=O)——,
`C,_3-a1kyl-S——,
`Cl_3-haloalkyl—S—-,
`——S(:O)—Cl_3-alkyl
`or —S(=NH)-—~Cl_3-alkyl,
`optionally halogen-substituted phenyl, optionally halogen-
`substituted furyl, the radical ——NR14R15, an optionally
`C1_3-haloalkyl-substituted oxiranyl radical or a cyclopro-
`pyl radical which is optionally mono- or polysubstituted by
`halogen, C1_4-a1kyl or C1_4-haloa1kyl.
`[0037] R6 preferably represents hydrogen, CM—alkylcar-
`bonyl or a radical —NR16R17.
`[0038] R7 preferably represents hydrogen, C1 4-alkyl, C 1-4-
`alkyl-S— or —NR9R1°.
`[0039] Y preferably
`represents
`=N—~OH or
`
`:8, =0, =NH,
`
`O
`/=N
`\Rs.
`
`[0040] R8 preferably represents C1_3 -a]kyl.
`[0041] R9 and R10 independently of one another preferably
`represent hydrogen, hydroxyl or C1_3-a1kyl.
`[0042]
`R11 preferably represents hydrogen, CM-alkyl or
`—CONR12R13 .
`
`R12 and R13 independently of one another prefer-
`[0043]
`ably represent hydrogen or Cid—alkyl.
`[0044] R14 and R15 independently of one another prefer-
`ably represent hydrogen, CH-alkyl, C1_3-haloalkyl or
`C,_3—alky1—SOZ—.
`[0045] R16 and R17 independently of one another prefer-
`ably represent hydrogen, C1_3—alkoxy or Cm-alkyl, where
`the C1_3-a1ky1 may optionally be substituted by phenyl,
`pyrazinyl or pyridyl, where phenyl, pyrazinyl or pyridyl
`may be mono- or disubstituted by hydroxyl, C1_3-a1kyl,
`C1_3-haloa1kyl and/or Cl_3-a1koxy, or
`[0046] R16 and R17 represent CM-alkylcarbonyl, CM—
`alkoxycarbonyl, C1 4-alkoxy-C1_4-alkylcarbonyl or the
`radical ——(C:O)NR2°R21 or
`the group
`represent
`[0047] R16
`and R17
`together
`=CR18R19 which is attached by a double bond to the
`nitrogen.
`[0048]
`R18 and R19 independently of one another prefer-
`ably represent phenyl which is optionally mono- or disub-
`stituted by hydroxyl, C1,3-alkyl, CH-haloalkyl and/or
`C1_3-alkoxy, and/0r R18 and R19 represent hydrogen, C1_3-
`
`

`

`US 2009/0312387 A1
`
`Dec. 17, 2009
`
`-continued
`
`tux
`
`Cl
`
`Cl
`
`F
`EP00659745
`
`F F
`
`N\\
`
`N113
`
`C1
`
`F
`S7Q
`o
`N‘A‘
`
`C1
`
`°\
`
`F
`U805556873
`N
`N
`\\
`\\s\
`N: \N
`
`N
`
`F F
`
`Cl
`
`Cl
`
`F F
`
`F
`WOO9639389
`Salt with 2,4,6-t1'imethyl—benzenesulphonic acid
`
`N O\\
`
`fif/N\N\
`
`N
`
`C1
`
`C1
`
`F
`
`F F
`
`U8056293 35
`
`alkyl, C 1_3-a1ker1yl or C1_3-alkoxy, where C ,_3-alkyl, CH-
`alkenyl or C1_3-alkoxy may optionally be substituted by
`phenyl which is optionally mono— or disubstituted by
`hydroxyl, CH-alkyl, C M-haloalkyl and/or CH-alkoxy.
`
`[0049] R20 and R21 independently of one another prefer-
`ably represent C1-3-a1kyl or phenyl which is optionally
`mono- or disubstituted by hydroxyl, C1_3-alkyl, Cid-ha-
`loalkyl and/or C1_3-alkoxy.
`
`[0050] R22 preferably represents C1_3-a1kyl.
`[0051] Particularly preferably, the substituents in formula
`(I) have the meaning below:
`
`[0052] X represents C-le.
`[0053]
`R1 and R3 each represent C1.
`[0054] R2 represents CF3.
`[0055] R4 represents CN, .—C(:S)NH2 or -C(fl)CH3.
`[0056]
`RS represents —SCHF2, —S(:O)CF3, —S(:O)
`CH3, —S(=O)CH2CH3 or represents the l-lrifluorom-
`ethyloxiranyl radical.
`
`[0057] R6 represents an amino group or one of the radicals
`below
`
`/N I
`
`/N
`
`[0058] Preferred examples of compounds which can be
`used according to the invention are listed below:
`
`N\\
`
`F
`
`o\\s7<F
`
`F
`
`N“—
`
`cl—\Q\oo
`
`/
`
`F
`
`EPOOS l l 845
`F
`
`\
`
`/
`N\ N
`
`c1
`
`F F
`
`N\\
`
`S7<F
`
`F
`
`\
`
`/
`N\N
`
`N—
`
`C1
`
`C1 —
`
`F
`F
`
`F
`
`U805321040
`
`o
`
`/o
`
`

`

`US 2009/0312387 A1
`
`Dec. 17, 2009
`
`-continued
`
`N \
`
`\
`
`N: \
`N
`
`N
`C1
`
`C1
`
`F F
`
`F
`EP00846686
`
`N\\
`
`Br
`
`«J N
`
`N
`
`W009824767
`
`N
`
`F
`
`F
`
`ssx
`/
`\
`N
`\N
`
`N
`
`C1
`
`C]
`
`F
`
`,
`
`F
`F
`DE19650197
`
`\N O
`
`\N
`
`\_
`
`\\S_MN
`CI?CI
`
`F
`
`W009828278
`
`-continued
`
`
`
`EPOO780378
`
`\
`
`N
`
`o
`
`F
`
`F
`
`i / xx
`/N\N\
`N
`
`C1
`
`C1
`
`\
`
`WOO9728126
`
`N\\ O\\s/\
`
`(AA
`
`c1
`
`'
`
`Cl
`
`F
`EP00839809
`
`F F
`
`

`

`US 2009/0312387 A1
`
`Dec. 17, 2009
`
`5
`
`-continued
`
`O\ / o
`N
`\\S
`
`C1
`
`F
`
`F
`F
`W00985 6767
`
`N
`
`o
`\\S/
`
`/
`N\
`
`\
`
`N
`
`N
`(:1
`
`o
`
`\N
`|
`
`Cl
`
`F
`
`F
`
`F
`EP00911329
`
`%
`N/\N\
`N
`C1
`
`C1
`
`F F
`
`F
`EP00933363
`
`o\
`
`N
`
`N
`o=<
`N/
`N
`/ \ \N
`01
`
`o\
`\s
`
`F
`
`F
`
`F
`
`\ N—
`
`\o
`(:1 <
`
`F
`
`F
`F
`WOO9962903
`
`H
`
`\
`
`N/
`\N
`
`N
`C1
`
`-continued
`
`N
`
`O
`\\S
`
`\
`
`N/
`\N
`
`\
`
`N
`
`C1
`
`s
`
`C1
`
`F
`
`F
`F
`WOO9828279
`
`I/\o
`O
`
`N/
`\
`
`\
`
`N
`
`c1
`
`S/
`
`N
`c1
`
`F
`F
`F
`W009840359
`
`F
`
`SA
`\
`>1
`N
`
`:1
`
`c1
`
`/ \
`
`/N
`
`F
`
`woo9s45274
`o\
`\s/\
`
`N
`\\
`
`\
`
`N/
`\N
`
`N
`Cl
`
`F
`
`F
`F
`USOSS 14652
`
`F F
`
`01
`
`

`

`US 2009/0312387 A1
`
`Dec. 17, 2009
`
`6
`
`N\
`\
`N/
`
`\N
`
`C1
`
`-continued
`
`0
`
`\ N>\N
`
`C1
`
`F
`
`F
`
`F
`
`F
`
`F
`
`F
`F
`
`F
`
`F
`FR2834288 A1 20030704
`
`\E o
`Ng/ \
`
`\\
`
`C1
`
`C1
`
`F—s—F
`F/ \F
`F
`w02005090313 A1 20050929
`
`[0059] Particularly preferred examples of compounds
`which can be used according to the invention are:
`
`N—
`
`S—CHF2
`
`\
`
`/
`N\
`
`N
`
`C1
`
`If!
`C1
`
`N
`\
`/
`
`CF3
`
`pyriprole
`
`-continued
`
`N\
`\
`N/
`
`o
`\
`
`\N
`
`Cl
`
`N
`C1
`
`F
`F
`F
`W009804530
`
`S
`
`N
`
`(:1
`
`O\\SJ\FF
`
`\N
`
`N
`
`c1
`
`F F
`
`F
`W0200031043, DE19824487
`
`N\
`
`\
`
`/ 0
`
`_
`
`/
`\
`
`N
`
`\
`
`N
`
`Cl
`
`C1
`
`C1
`
`F F
`
`F
`U806069157
`O
`0
`v
`
`N\
`
`N
`
`C1
`
`N
`C1
`
`F F
`
`F
`WOO9828277
`
`

`

`US 2009/0312387 A1
`
`Dec. 17, 2009
`
`-continued
`
`N_
`
`S—CHZF
`
`N/
`\N
`
`\
`
`Cl
`
`i]
`Cl
`
`N
`
`\
`/
`N
`
`I
`
`HzN
`
`C1
`
`\S
`\
`
`\CF3
`
`NHz
`C1
`
`/
`N
`\N
`
`CF3
`
`pyrafluprole
`
`N—
`
`S—CHFZ
`
`N
`
`\
`
`\ N
`
`C1
`
`N /
`Cl
`
`c1:3
`5-mino—4—trifluorornethyl-
`sulphinyl— 1—(2,6—dichloro-
`4—trifluoromethylphenyl)—
`3-miocarbamoylpyrazole
`
`\
`
`o
`
`0
`
`CF;
`
`vanilliprole
`
`S
`
`\CF3
`
`N
`
`\
`
`\N
`
`NH2
`
`N
`
`\\
`N
`
`Cl\©/CJ
`
`(31:3
`
`fipronil
`
`O
`
`/
`
`\N
`
`NH:
`
`O\\S4d
`Cl\ : ,Cl
`
`CF:
`acetoprole
`
`\
`\o
`
`N
`
`c1
`
`Cl
`
`Z
`
`F
`
`F
`
`F
`
`ethiprole
`0
`
`run-sh”
`
`N
`
`NH2
`
`ZO / /
`: ,Cl
`
`CF;
`JP08311036, Takeda
`
`Cl,
`
`[0060] An example of a very particularly preferred
`N—arylpyrazole is fipronil.
`[0061] A filrther example of a very particularly preferred
`N-arylpyrazole is 5-amino-4-trifluoromethylsulphinyl-1-(2,
`6-dichloro-4-trifluoromethylphenyl)-3-thio-carbamoylpyra—
`zole.
`
`[0062] Depending on the nature and arrangement of the
`substituents, the active compounds may, if appropriate, be
`present in various stereoisomeric forms, in particular as enan-
`tiomers and racemates. According to the invention, it is pos—
`sible to use both the pure stereoisomers and mixtures thereof.
`[0063]
`If appropriate, the active compounds can also be
`employed in the form of their salts, pharmaceutically accept-
`able acid addition salts and basic salts being suitable.
`[0064]
`Suitable pharmaceutically acceptable salts are salts
`of mineral acids or organic acids (for example carboxylic
`acids or sulphonic acids). Examples which may be mentioned
`are salts of hydrochloric acid, sulphuric acid, acetic acid,
`glycolic acid, lactic acid, succinic acid, citric acid, tartaric
`acid, methanesulphonic acid, 4-toluenesulphonic acid, galac-
`turonic acid, gluconic acid, embonic acid, glutamic acid or
`aspartic acid. Suitable pharmaceutically acceptable basic
`salts are, for example, the alkali metal salts, for example the
`sodium or potassium salts, and the alkaline earth metal salts,
`for example the magnesium or calcium salts.
`[0065]
`It is furthermore also possible to use the active com-
`pounds in the form of their solvates, in particular hydrates.
`Solvates are to be understood as meaning both the solvates, in
`particular hydrates, of the active compounds themselves and
`the solvates, in particular hydrates, of their salts.
`[0066] As solids, the active compounds may, in certain
`cases, form various crystal modifications. Advantageous for
`the use in medicaments are stable modifications having suit—
`able solubility properties.
`[0067] Unless indicated otherwise, percentages are to be
`understood as percent by weight based on the weight of the
`finished preparation.
`[0068] Usually, the compositions comprise the arylpyra-
`zole in amounts of from 1 to 27.5% by weight, preferably
`from 5 to 20% by weight, particularly preferably from 7.5 to
`15% by weight.
`[0069] The aliphatic cyclic carbonate is preferably ethylene
`carbonate or propylene carbonate, it also being possible to use
`mixtures.
`
`[0070] The amount of aliphatic cyclic carbonate in the for-
`mulation can be varied widely in the range of from 10% by
`weight to 70% by weight, preferably from 12.5 to 50% by
`weight, particularly preferably from 15 to 40% by weight.
`[0071] Aliphatic cyclic and/or acyclic ethers are com-
`pounds known per se. Preferably, they are ethers derived from
`diols having up to 8 carbon atoms, such as, for example,
`ethylene glycol, diethylene glycol, propylene glycol, dipro-
`pylene glycol. In the acyclic ethers, one or both OH groups
`carry a CM-alkyl group, preferably, only one OH group is
`etherified; particularly preferred examples are: diethylene
`glycol monoethyl ether, diethylene glycol monopropyl ether,
`dipropylene glycol monopropyl ether. Preferred 5- or 6-mem-
`bered cyclic ethers have a ring oxygen and 4 or 5 ring carbon
`atoms and optionally carry a CM-alkyl substituent; prefer-
`ably, they carry a free OH group either directly on the ring or
`on the C1_4-a1kyl
`substituent. A particularly preferred
`example is tetrahydrofurfuryl alcohol. The amount of ali-
`phatic, cyclic and/or acyclic ether in the compositions accord-
`ing to the invention can be varied within wide limits of from
`
`

`

`US 2009/0312387 A1
`
`Dec. 17, 2009
`
`20 to 77.5% by weight, with amounts in the range of from 25
`to 65% by weight and amounts in the range offrom 25 to 50%
`by weight being particularly preferred and very particularly
`preferred, respectively.
`[0072] According to a preferred embodiment, the compo-
`sitions according to the invention may additionally comprise
`one or more esters ofa dihydric or trihydric alcohol having up
`to three carbon atoms with organic fatty acids having 6 to 18
`carbon atoms. As alcohol component, the esters used accord-
`ing to the invention contain a di- or trihydric alcohol having
`up to three carbon atoms, such as, for example, ethylene
`glycol, propylene glycol or glycerol. In general, at least two,
`preferably all, hydroxyl groups of the alcohol are esterified.
`The acid components of the esters are fatty acids having 6 to
`18 carbon atoms, which may be straight—chain, branched and
`also mono- or polyunsaturated. It is possible to use mixed
`esters or else mixtures of various types of esters. Preferred
`triglycerides are caprylic/caprinic acid triglycerides and also
`carprylic/caprinic/linoleic acid triglycerides. Preference is
`likewise given to esters of propylene glycol with caprylic
`and/or caprinic acid (propylene glycol octanoate decanoate).
`Particularly preferably, these glycerol or propylene glycol
`esters ofcaprylic/caprinic acidhave aviscosity range (20° C.)
`of 008-1 .3 Pas, and preferably 0.08-0.40 Pa's. It is also
`possible to use their polyethylene oxide-, polypropylene
`oxide- and/or propylene carbonate—modified derivatives hav-
`ing the viscosity range mentioned. Examples which may be
`mentioned are propylene glycol dicaprylate, propylene gly-
`col octanoate decanoate having a Viscosity range of009-0. 1 2
`Pas, caprylic/caprinic diglyceryl succinate having a mean
`viscosity of 0.23 Pa-s, medium-chain caprylic/caprinic trig-
`lycerides having a Viscosity of 0.27-0.30 Pa's.
`[0073] The liquid formulations according to the invention
`may comprise one or more of the esters mentioned above.
`Usually, the compositions according to the invention com-
`prise the ester or the ester mixture in proportions of from 0 to
`40% by weight, preferably from 1 to 35% by weight, particu-
`larly preferably from 1 to 12.5% by weight and very particu-
`larly preferably from 2.5 to 7.5% by weight.
`[0074]
`If appropriate, customary organic or inorganic anti-
`oxidants may be used for stabilizing the formulations men-
`tioned. Suitable inorganic antioxidants are, for example, the
`sulphites and bisulphites, in particular sodium bisulphite.
`Preference is given to phenolic antioxidants, such as anisole,
`butylated hydroxytoluene and hydroxyanisole, and their mix-
`tures with one another. Usually, from 0.01 to 1% by weight,
`preferably from 0.05% to 0.5%, particularly preferably from
`0.075 to 0.2% by weight are used.
`[0075] The formulation ingredients mentioned, in particu-
`lar the organic esters, may be stabilized against possible
`hydrolytic degradation using acidifying agents. Suitable
`acidifying agents are pharmaceutically acceptable acids, in
`particular carboxylic acids, such as, for example, succinic
`acid, tartaric acid, lactic acid or citric acid. Their preferred
`amount is in the range of from O to 0.5% by weight, but
`preferably from 0 to 0.2% by weight.
`[0076]
`Polymeric surfactants based on polymethoxysilox-
`anes having a low surface tension of <30 mN/m, preferably
`<22 mN/m, can be used as further formulation auxiliaries for
`improving the spreadability. Such surfactants are known
`ethoxylated and/or propoxylated, preferably neutral or par-
`ticularly preferably cationic formulation auxiliaries. An
`example of a preferred polymeric auxiliary which may be
`mentioned is the methoxysilane/ethylene oxide copolymer
`
`Belisil Silvet L 77 from Bayer GE Siliconics GmbH. The
`amount of these formulation auxiliaries may be varied within
`wide limits in the range of from 0.01 to 1.0% by weight. The
`preferred range is from 0.2 to 0.4% by weight.
`[0077]
`If appropriate, the formulations may comprise fiJr—
`ther pharmaceutically acceptable auxiliaries and additives.
`[0078] The compositions according to the invention may
`also comprise one or more further active compounds as com-
`bination partners for the arylpyrazoles. Preferred examples of
`such active compounds for combinations which may be men-
`tioned are: growth inhibitors, such as, for example, chitin
`biosynthesis inhibitors, such as, for example, benzoylpheny-
`lureas (for example triflumuron, lufenuron); phenyloxazo-
`lines (for example etoxazole); juvenile hormone analogues
`(for example methoprene, hydroprene, pyriproxifen) and also
`mixtures of these active compounds with one another. Their
`amount may be varied within wide limits in the range offrom
`0.1 to 7.5% by weight, but preferably from 0.25 to 5.0% by
`weight, particularly preferably from 0.25 to 2.5% by weight.
`[0079] The formulations according to the invention may
`also comprise synergists. Synergists in the sense ofthis appli-
`cation are to be understood as meaning compounds which for
`their part do not have the desired activity, but which, as
`mixing partners,
`increase the activity of the active com-
`pounds. Piperonyl butoxide, MG 264, verbutin, S,S,S -tributyl
`phosphorotrithioate may be mentioned here in an exemplary
`manner.
`
`[0080] The compositions according to the invention are
`environmentally compatible and have a low toxicity which is
`reduced compared to that of known compositions. Accord-
`ingly, they are user—friendly and furthermore distinguished by
`their easy handling. The compositions have a favourable
`flashpoint of >70° C. and can therefore be manufactured in
`simple plants which do not require additional measures to
`protect against explosions.
`[0081] Having favourable homeotherm toxicity, the com-
`positions ofthe invention are suitable for controlling parasitic
`arthropods, in particular insects and arachids, very particu-
`larly fleas and ticks, encountered on animals, in particular
`homeotherms, particularly preferably mammals. These ani-
`mals may be domestic animals and useful animals and also
`zoo animals, laboratory animals, test animals and pets.
`[0082] The compositions described herein are used in par-
`ticular against ectoparasites on pets and useful animals.
`[0083] The compositions ofthe invention are active against
`all or individual stages of development of the pests and
`against resistant and normally sensitive pest species.
`[0084] The pests include:
`[0085]
`from the order of the Anoplura, for example, Hae-
`matopinus spp., Linognathus spp., Solenopotes spp., Pedicu-
`lus spp., Pthirus spp.,
`from the order of the Mallophaga, for example, Trimenopon
`spp., Menopon spp., Eomenacanthus spp., Menacanthus
`spp., Trichodectes spp., Felicola spp., Damalinea spp., Bovi-
`cola spp.,
`fi'om the order of the Diptera, suborder Brachycera, for
`example, Chrysops spp., thanus spp., Musca spp., Hydro-
`taea spp., Muscina spp., Haematobosca spp., Haematobia
`spp., Stomoxys spp., Fannia spp., Glossina spp., Lucilia spp.,
`Calliphora spp., Auchmeromyia spp., Cordylobia spp.,
`Cochlz'omyia spp., Chrysomyia spp., Sarcophaga spp., Wohl-
`fizrtia spp., Gasterophilus spp., Oesteromyia spp., Oedema-
`gena spp., Hypoderma spp., Oestrus spp., Rhinoestrus spp.,
`Melophagus spp., Hippobosca spp.,
`
`

`

`US 2009/0312387 A1
`
`Dec. 17, 2009
`
`from the order of the Diptera, suborder Nematocera, for
`example, Culax spp., Aedes spp., Anopheles spp., Culicoides
`spp., Phlebotomus spp., Simulium spp.;
`from the order ofthe Siphonaptera, for example, Ctenocepha-
`[ides spp., Echidnophaga spp., Ceratophyllus spp., Pulex
`Spp-;
`from the order ofthe Metastigmata, for example, Hyalomma
`spp., Rhipicephalus spp., Boophilus spp., Amblyomma spp.,
`Haemaphysalis spp., Dermacentor spp., Ixodes spp., Argus
`spp., Ornithodorus spp., Otobius spp.;
`from the order of the Mesostigmata, for example, Dermanys-
`sus spp., Ornithonyssus spp., Pneumonyssus spp.;
`from the order of the Prostigmata, for example, Cheyletiella
`spp., Psorergates spp., Myobia spp., Demodex spp., Neotrom-
`bicula spp.;
`from the order of the Astigmata, for example, Acarus spp.,
`Myocoptes spp., Psoroptes spp., Chorioptes spp., Otodectes
`spp., Sarcoptes spp., Notoedres spp., Knemidocoptes spp.,
`Neoknemidocoptes spp., Cytodites spp., Luminosioptes spp.;
`[0086] Particular emphasis may be given to the action
`against fleas (Siphonaptera for example, Ctenacephalides
`spp, Echidnaphaga spp., Ceratophyllus spp., Pulex spp.),
`ticks (Hyalomma spp., Rhipicephalus spp., Boophilus spp.,
`Amblyomma spp., Haemaphysalis spp., Dermacentor spp.,
`Ixodes spp., Argas spp., Ornithodorus spp., Otobius spp.) and
`the Diptera mentioned above (Chrysops spp., Ybbanus spp.,
`Musca spp., Hydrotaea spp., Muscina spp., Haematobosca
`spp., Haematobia spp., Stomoxys spp., Fannia spp., Glosst'na
`spp., Lucilia spp., Calliphora spp., Auchmeromyia spp.,
`Cordylobia spp., Cochliomyz‘a spp., Chrysomyia spp., Sar-
`cophaga spp., Wohlfartia spp., Gasterophilus spp., 0ester-
`omyia spp., Oedemagena spp., Hypoderma spp., Oestrus
`spp., Rhinoestrus spp., Melophagus spp., Hippobosca spp.).
`[0087] The useful and breeding animals include mammals,
`such as, for example, cattle, horses, sheep, pigs, goats, cam-
`els, water buffalo, donkeys, rabbits, fallow deer, reindeer,
`fur-bearing animals, such as, for example, mink, chinchilla,
`raccoon, birds, such as, for example, hens, geese, turkeys,
`ducks.
`
`[0088] The laboratory animals and test animals include
`mice, rats, guinea pigs, rabbits, golden hamsters, dogs and
`cats.
`
`[0089] The pets include dogs and cats.
`[0090] Particular emphasis is given to application on cat
`and dog.
`[0091] Application can take place both prophylactically
`and therapeutically.
`[0092]
`Preferably, the liquid formulations according to the
`invention are suitable for spot—on, pour-on or spray applica—
`tion, where the spray application may be carried out, for
`example, using a pump spray or an aerosol spray (pressurized
`spray). For specific indications, the formulations may also be
`used after dilution with water as a dip; in this case, the for-
`mulation should contain emulsifying additives.
`[0093] The preferred application forms are pump spray,
`pour-on and spot-on. The spot-on application is very particu-
`larly preferred.
`[0094] The formulations according to the invention are dis-
`tinguished by excellent compatibility with customary
`“single-dose” plastic tubes and by their storage stability in
`various climate zones. They have low viscosity and can be
`applied without any problems.
`[0095] The liquid formulations according to the invention
`can be prepared by mixing the appropriate amounts of the
`
`components with one another, using, for example, conven-
`tional stirring tanks or other suitable instruments. If required
`by the ingredients, it is also possible to operate under a pro-
`tective atmosphere or with other methods of excluding oxy-
`gen.
`
`EXAMPLES
`
`Example 1
`
`100 ml of liquid formulation consisting of
`[0096]
`10.0 g of 5-amino-4—trifluoromethylsulphinyl-1-(2,
`[0097]
`6—dichloro-4-trifluoromethyl—phenyl)-3 -thiocarbam-
`oylpyrazole
`[0098]
`72.7 g of diethylene glycol monoethyl ether
`[0099]
`25.0 g of propylene carbonate
`[0100]
`5.0 g of propylene glycol octanoate decanoate
`[0101]
`0.1 g of butylated hydroxytoluene
`[0102]
`0.2 g of butylated hydroxyanisole
`
`Example 2
`
`100 m1 of liquid formulation consisting of
`10.5 g of fipronil
`57.75 g of dipropylene glycol monomethyl ether
`40.0 g of propylene carbonate
`5.0 g of propylene glycol octanoate decanoate
`0.1 g of butylated hydroxytoluene
`0.2 g of butylated hydroxyanisole
`
`Example 3
`
`100 ml of liquid formulation consisting of
`10.5 g of fipronil
`72.75 g of dipropylene glycol monomethyl ether
`25.0 g of propylene carbonate
`5.0 g of propylene glycol octanoate decanoate
`0.1 g of butylated hydroxytoluene
`0.2 g of butylated hydroxyanisole
`
`[0103]
`[0104]
`[0105]
`[0106]
`[0107]
`[0108]
`[0109]
`
`[0110]
`[0111]
`[0112]
`[0113]
`[0114]
`[0115]
`[0116]
`
`Example 4
`
`100 ml of liquid formulation consisting of
`[0117]
`10.0 g of 5-amino—4-trifluoromethylsulphinyl-1—(2,
`[0118]
`6-dichloro-4—trifluoromethyl-phenyl)-3 -thiocarbam-
`oylpyrazole
`[0119]
`57.7 g of diethylene glycol monoethyl ether
`[0120]
`40.0 g of propylene carbonate
`[0121]
`5.0 g of propylene glycol octanoate decanoate
`[0122]
`0.1 g of butylated hydroxytoluene
`[0123]
`0.2 g of butylated hydroxyanisole
`
`Example 5
`
`100 m1 of liquid formulation consisting of
`[0124]
`11.4 g of fipronil
`[0125]
`60.0 g of diethylene glycol monoethyl ether
`[0126]
`25.0 g of propylene carbonate
`[0127]
`5.0 g of propylene glycol octanoate decanoate
`[0128]
`0.12 g of butylated hydroxytoluene
`[0129]
`0.2 g of butylated hydroxyanisole
`[0130]
`0.25 g of Silvet L 77 from Bayer GE Siliconics
`[0131]
`GmbH
`
`

`

`US 2009/0312387 A1
`
`Dec. 17, 2009
`
`Comparative Example
`
`[0132] A commercially available 10% fipronil spot-on for-
`mulation from Merial Ltd., 3239 Satellite Blvd., Duluth, Ga.
`30096-4640, USA.
`
`Biological Examples
`
`[0133] The tested formulations were metered out exactly
`by weight to ensure better comparability. To this end, 20
`pipettes of the fipronil-containing commercial preparation
`(comparative example) were emptied into a glass bottle and
`likewise blinded using a code.
`[0134] All samples were applied as a single spot to the neck
`(cats and smaller dogs) using Eppendorf pipettes (volume up
`to 0.95 ml). For application volumes of more than 1 ml, the
`volume was halved and applied to the neck as two spots at a
`distance of about 10 cm.
`[0135]
`Further laboratory tests for the activity against fleas
`and ticks according to Examples 2 and 4 show that the prepa-
`rations in the abovementioned formulations according to the
`invention have very good and long-lasting action against ticks
`and fleas which, in the tests, is consistently superior to the
`prior art. Furthermore, the preparations in the abovemen-
`tioned formulations according to the invention are distin-
`guished in that they are tolerated by target animal and user,
`and they are thus highly suitable for controlling fleas and ticks
`on small animals. Thus, for example, a formulation according
`to Example 2 and a formulation according to Example 4 are,
`after oral ingestion, 2x and 3x better tolerated, respectively,
`than formulations of the prior art.
`A. Activity Against Fleas (Ctenocephalidesjklis) on Dogs
`[0136] Between days-4 and -1, dogs are infested 1-2 times
`with about 100 adult unfed Ctenocephalides felis per dog.
`The fleas are placed on the neck of the animal.
`[0137] On day 0, the success of the infestation on the dog is
`examined by checking the awake animals for fleas. The num-
`ber of live fleas is noted.
`
`[0138] After the fleas have been counted, the animals are
`treated. The dogs