TW202335661A - 用於動物寄生蟲之防治及預防的可局部投予之調配物 - Google Patents
用於動物寄生蟲之防治及預防的可局部投予之調配物 Download PDFInfo
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- TW202335661A TW202335661A TW112103268A TW112103268A TW202335661A TW 202335661 A TW202335661 A TW 202335661A TW 112103268 A TW112103268 A TW 112103268A TW 112103268 A TW112103268 A TW 112103268A TW 202335661 A TW202335661 A TW 202335661A
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- chloro
- trifluoromethyl
- ethyl
- liquid formulation
- methyl
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- 239000000203 mixture Substances 0.000 title claims abstract description 34
- 238000009472 formulation Methods 0.000 title claims abstract description 29
- 230000002265 prevention Effects 0.000 title abstract description 6
- 244000000054 animal parasite Species 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 88
- 241001465754 Metazoa Species 0.000 claims abstract description 27
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 claims abstract description 24
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 17
- 239000012669 liquid formulation Substances 0.000 claims abstract description 16
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- 239000011737 fluorine Substances 0.000 claims abstract description 11
- 230000002141 anti-parasite Effects 0.000 claims abstract description 10
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims abstract description 9
- 244000045947 parasite Species 0.000 claims description 18
- 239000006184 cosolvent Substances 0.000 claims description 13
- 125000001153 fluoro group Chemical group F* 0.000 claims description 11
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
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- FLEFKKUZMDEUIP-QFIPXVFZSA-N 1-[6-[(5s)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4h-1,2-oxazol-3-yl]spiro[1h-2-benzofuran-3,3'-azetidine]-1'-yl]-2-methylsulfonylethanone Chemical compound C1N(C(=O)CS(=O)(=O)C)CC21C1=CC=C(C=3C[C@](ON=3)(C=3C=C(Cl)C(F)=C(Cl)C=3)C(F)(F)F)C=C1CO2 FLEFKKUZMDEUIP-QFIPXVFZSA-N 0.000 claims description 3
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 claims description 3
- JIMJBSNUFKIEEP-UHFFFAOYSA-N 2-chloro-5-[1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethyl)phenyl]pyrazol-4-yl]-N-cyclopropylpyridine-3-carboxamide Chemical compound FC(F)(F)c1cc(cc(Cl)c1-n1cc(cn1)-c1cnc(Cl)c(c1)C(=O)NC1CC1)C(F)(C(F)(F)F)C(F)(F)F JIMJBSNUFKIEEP-UHFFFAOYSA-N 0.000 claims description 3
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- BPFUIWLQXNPZHI-UHFFFAOYSA-N 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-N-[(methoxyamino)methylidene]-2-methylbenzamide Chemical compound C1=C(C)C(C(=O)N\C=N/OC)=CC=C1C1=NOC(C(F)(F)F)(C=2C=C(Cl)C=C(Cl)C=2)C1 BPFUIWLQXNPZHI-UHFFFAOYSA-N 0.000 claims description 3
- OXDDDHGGRFRLEE-UHFFFAOYSA-N 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4h-1,2-oxazol-3-yl]-n-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]naphthalene-1-carboxamide Chemical compound C12=CC=CC=C2C(C(=O)NCC(=O)NCC(F)(F)F)=CC=C1C(C1)=NOC1(C(F)(F)F)C1=CC(Cl)=CC(C(F)(F)F)=C1 OXDDDHGGRFRLEE-UHFFFAOYSA-N 0.000 claims description 3
- MWMQNVGAHVXSPE-UHFFFAOYSA-N Pyriprole Chemical compound ClC=1C=C(C(F)(F)F)C=C(Cl)C=1N1N=C(C#N)C(SC(F)F)=C1NCC1=CC=CC=N1 MWMQNVGAHVXSPE-UHFFFAOYSA-N 0.000 claims description 3
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- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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Abstract
本發明係有關一種適合局部投予動物之新穎液體調配物,該調配物包含含氟抗寄生蟲活性化合物及磷酸三乙酯,並有關其於防治及預防動物寄生蟲上之用途。
Description
本發明係有關一種適合局部投予動物之新穎液體調配物,該調配物包括含氟抗寄生蟲活性化合物及磷酸三乙酯,並有關其於防治及預防動物寄生蟲上之用途。
相當長期以來已知有現代含氟抗寄生蟲活性化合物(本文亦稱為氟化抗寄生蟲劑),例如:氟雷拉鈉(fluralaner)、阿弗索拉納(afoxolaner)、撒洛倫(sarolaner)、羅替蘭(lotilaner)、芬普尼(fipronil),該等說明於WO2015/067646與WO2015/067647之活性化合物具有良好殺昆蟲與殺蜱蟎效力。然而,許多此等活性化合物在適合局部投予動物之溶劑中之溶解度非常低。為了避免調配物在投藥後從外皮溢流,或為了避免在動物身上留下濕的外皮,活性化合物較佳應溶解在低體積中,此表示大多數需要高達30% w/v的活性化合物濃度。此外,溶劑必需在毒物學上安全且具有高度皮膚相容性。該調配物應無味或具有宜人的氣味。同時從生產觀點而言,閃燃點高於35°C之溶劑有利於使為了防止爆炸所需的費用降至最低。此外,溶解的活性化合物必需在調配物中充份穩定。
N-甲基-2-吡咯烷酮(NMP)為一種用於多種有機化合物之極佳溶劑,亦可用於滴劑調配物。然而,經過歐洲化學品管理局(European Chemicals Agency)ECHA (ECHA/RAC/RES-O-000000 5316-76-01/F)再度評估的結果,NMP於新產品上之用途仍受到質疑。
碳酸丙二酯及碳酸丙二酯與苯甲醇之混合物已確立為具有良好相容性而適合滴劑調配物之溶劑(參見例如:WO9617520)。然而,碳酸丙二酯及碳酸丙二酯與苯甲醇之混合物對上述氟化活性化合物沒有充份溶解性。
磷酸三乙酯迄今尚未被揭示為滴劑調配物之溶劑。WO2016144678說明磷酸三乙酯為油性分散液、懸浮液、乳液、與溶液之液體稀釋劑。
因此,本發明之目的在於提供一種使用對現代氟化抗寄生蟲劑具有充份高溶解性而適合局部投予動物之新穎液體醫藥。此等醫藥所使用之液體調配物應具有下列性質:
1. 良好皮膚相容性
2. 低毒性
3. 高度且長效作用
4. 以> 35°C之高閃燃點較佳。
已驚人地發現,磷酸三乙酯對氟化抗寄生蟲劑具有極佳溶解性
( 表 1) 。磷酸三乙酯對大鼠、狗、與貓具有低毒性及皮膚相容性。130°C之高閃燃點足以安全製造。以選定的氟化抗寄生蟲劑在磷酸三乙酯調配物中的研究顯示,對狗與貓上之跳蚤及各種不同蜱類具有良好且長效的活性。
表1 (溶解度,以% (w/w)表示):
*化合物1與化合物2之定義:見下文。
** 已提出之INN (參見WHO Drug Information, Vol. 31, No. 2, 2017)
磷酸三乙酯 | 碳酸丙二酯 | 83.3% 碳酸丙二酯 16.7% 苯甲醇 | |
化合物2* | 40% | 4% | 14% |
化合物1* | 44% | 5% | 17% |
特格納(tigolaner)** | 52% | 26% | 20% |
比普魯(pyriprole) | 49% | 21% | 28% |
氟滅醯胺(fluxametamide) | 20% | 3% | 6% |
氟雷拉鈉(fluralaner) | 41% | 7% | 13% |
芬普尼(fipronil) | 36% | 11% | 5% |
因此,上述目的藉由下述達成:
一種包含有效對抗寄生蟲之含氟活性化合物、與磷酸三乙酯之液體調配物。
根據另一態樣,本發明係有關一種以本文說明之液體調配物於防治寄生蟲(特定言之動物之體外寄生蟲)上之用途。
咸了解,抗寄生蟲活性化合物(本文亦稱為「抗寄生蟲劑」)意指具有對抗體內寄生蟲或體外寄生蟲或二者之活性化合物。本文說明之液體調配物較佳係指使用具有對抗體外寄生蟲活性之活性化合物。
與本文所使用活性化合物相關之「含氟」(或氟化)特定言之意指活性化合物分子中,每200 u分子量包含至少一個氟原子,較佳為每160 u分子量包含至少1個氟原子,特定言之每100 u分子量包含至少1個氟原子。氟原子可以附接各種不同基團,例如:附接芳香環。較佳係活性化合物分子中為每500 u分子量包含至少1個三氟甲基。咸了解上述數字,如:「每200 u分子量」係指範圍。「每200 u分子量至少一個氟原子」意指分子量至高200 u之分子包含一個氟原子;因此分子量200至400 u之分子則包含至少兩個氟原子,依此類推。亦可據此了解上述含氟活性化合物之較佳實施例中與其中所含氟原子或三氟甲基之相關說明。
根據一項實施例,含氟抗寄生蟲活性化合物具有至少一個包含1至3個,較佳為1或2個選自N、O與S(較佳為選自N與O)之相同或相異雜原子之5-或6-員雜芳香環。
可特別述及下列含氟抗寄生蟲活性化合物:
經取代之苯甲醯胺化合物,其說明於WO 2015067646 A1或WO 2015067647 A1,同時提出:
通式(I)化合物:
(I)
其中
R
1代表H、各情況下視情況經取代之C
2-C
6-烯基、C
2-C
6-炔基、C
3-C
7-環烷基、C
1-C
6-烷基羰基、C
1-C
6-烷氧基羰基、芳基-(C
1-C
3)-烷基、雜芳基-(C
1-C
3)-烷基,或代表視情況經取代之C
1-C
6-烷基,較佳為H或較佳為C
1-C
2-烷基,極特別佳為H或甲基,特定言之H,
該等部份基團如下:
A
1代表CR
2或N,
A
2代表CR
3或N,
A
3代表CR
4或N,
A
4代表CR
5或N,
B
1代表CR
6或N,
B
2代表CR
7或N,
B
3代表CR
8或N,
B
4代表CR
9或N,及
B
5代表CR
10或N,
但A
1至A
4部份基團中不超過三個基團代表N,及B
1至B
5部份基團中不超過三個基團代表N;
R
2、R
3、R
4、R
5、R
6、R
7、R
9與R
10彼此分別獨立代表H、鹵素、氰基、硝基、各情況下視情況經取代之C
1-C
6-烷基、C
3-C
6-環烷基、C
1-C
6-烷氧基、
N-C
1-C
6-烷氧基亞胺基-C
1-C
3-烷基、C
1-C
6-烷基硫基、C
1-C
6-烷基亞磺醯基、C
1-C
6-烷基磺醯基、
N-C
1-C
6-烷基胺基、
N,N-二-C
1-C
6-烷基胺基或
N-C
1-C
3-烷氧基-C
1-C
4-烷基胺基或1-吡咯烷基;
若A
2與A
3部份基團均不代表N時,則R
3與R
4可與其等所鍵結之碳原子共同形成包含0、1或2個氮原子與/或0或1個氧原子與/或0或1個硫原子之5-或6-員環;或
若A
1與A
2部份基團均不代表N時,則R
2與R
3可與其等所附接之碳原子共同形成包含0、1或2個氮原子之6-員環;
R
8代表鹵素、氰基、硝基、各情況下視情況經取代之C
1-C
6-烷基、C
3-C
6-環烷基、C
1-C
6-烷氧基、
N-C
1-C
6-烷氧基亞胺基-C
1-C
3-烷基、C
1-C
6-烷基硫基、C
1-C
6-烷基亞磺醯基、C
1-C
6-烷基磺醯基、
N-C
1-C
6-烷基胺基或
N,N-二-C
1-C
6-烷基胺基;
W 代表O或S,
Q 代表H、甲醯基、羥基、胺基、或各情況下視情況經取代之C
1-C
6-烷基、C
2-C
6-烯基、C
2-C
6-炔基、C
3-C
6-環烷基、C
1-C
5-雜環烷基、C
1-C
4-烷氧基、C
1-C
6-烷基-C
3-C
6-環烷基、C
3-C
6-環烷基-C
1-C
6-烷基、C
6-、C
10-C
14-芳基、C
1-C
5-雜芳基、C
6-、C
10-、C
14-芳基-(C
1-C
3)-烷基、C
1-C
5-雜芳基-(C
1-C
3)-烷基、
N-C
1-C
4-烷基胺基、
N-C
1-C
4-烷基羰基胺基,或
N,N-二-C
1-C
4-烷基胺基;或
代表視情況經多個V取代之不飽和6-員碳環;或
代表視情況經多個V取代之不飽和4-、5-或6-員雜環,其中
V 分別獨立代表鹵素、氰基、硝基、各情況下視情況經取代之C
1-C
6-烷基、C
1-C
4-烯基、C
1-C
4-炔基、C
3-C
6-環烷基、C
1-C
6-烷氧基、
N-C
1-C
6-烷氧基亞胺基-C
1-C
3-烷基、C
1-C
6-烷基硫基、C
1-C
6-烷基亞磺醯基、C
1-C
6-烷基磺醯基,或
N,N-二-(C
1-C
6-烷基)胺基;
T 代表視情況經取代之5-員雜芳香系,其包含不超過2個雜原子(1或2個雜原子),如:四個碳原子與一(1)個雜原子(較佳為一(1)個氮、一(1)個氧或一(1)個硫原子)、或三個碳原子與兩個雜原子(較佳為兩個氮原子、一(1)個氮與一(1)個氧原子,或一(1)個氮與一(1)個硫原子),
及式(I)化合物之鹽類、N-氧化物、與互變異構型。
本發明一項態樣係有關一種式(Ia)化合物
(Ia)
其中
D
1、D
2部份基團彼此分別獨立代表C-R
11或選自N與O之雜原子;
D
3與D
4部份基團彼此分別獨立代表C或代表選自N之雜原子(換言之D
3與D
4部份基團彼此分別獨立代表C或N);
其中不超過一(1)個或兩個選自D
1、D
2、D
3、與D
4之部份基團代表雜原子,其中一(1)個或兩個選自D
1、D
2、D
3與D
4之部份基團中,D
1與D
2代表選自N或O之雜原子,或D
3與D
4代表N;
代表芳香系;及
R
1、A
1、A
2、A
3、A
4、B
1、B
2、B
3、B
4、B
5、R
2、R
3、R
4、R
5、R
6、R
7、R
8、R
9、R
10、R
11、W、Q、V與T係如本文說明之定義,其中不超過一個選自A
1、A
2、A
3、A
4之部份基團代表N,且不超過一個選自B
1、B
2、B
3、B
4與B
5之部份基團代表N;或其中一個或兩個選自A
1、A
2、A
3、A
4之部份基團可代表N,且不超過一個選自B
1、B
2、B
3、B
4與B
5之部份基團代表N;
及式(I)化合物之鹽類、N-氧化物、與互變異構型。
本發明之一項實施例係有關一種式(Ia‘)化合物
(Ia‘)
其中
R
1、R
11、Q、W、A
1、A
2、A
3、A
4、B
1、B
2、B
4與B
5分別如本文中之定義,其中不超過一個選自A
1、A
2、A
3、A
4之部份基團代表N,且不超過一個選自B
1、B
2、B
3、B
4與B
5之部份基團代表N;或其中一個或兩個選自A
1、A
2、A
3、A
4之部份基團可代表N,且不超過一個選自B
1、B
2、B
3、B
4與B
5之部份基團代表N;
D
1與D
2彼此分別獨立代表C-R
11或雜原子,較佳為C-R
11或選自N、O或S之雜原子,更佳為C-R
11或選自N或O之雜原子;
D
3與D
4部份基團彼此分別獨立代表C或選自N之雜原子;
其中不超過一(1)個或兩個選自D
1、D
2、D
3與D
4之部份基團代表雜原子,其中一(1)個或兩個選自D
1、D
2、D
3與D
4之部份基團中,D
1與D
2代表選自N或O之雜原子,或D
3與D
4代表N;
代表芳香系;
及R
8係如本文中定義,較佳為代表全氟化C
1-C
4-烷基。
本發明另一項實施例係有關一種式(Ia‘‘)化合物
(Ia'')
其中
D
1代表C-R
11或選自N或O之雜原子;
D
2代表C-R
11或選自N或O之雜原子;
D
3代表C或N;
D
4代表C或N;
D
5代表C-R
11或N;
其中不超過一(1)個或兩個選自D
1、D
2、D
3、D
4、與D
5之部份基團代表雜原子;
代表芳香系;及
R
1代表H、各情況下視情況經取代之C
2-C
6-烯基、C
2-C
6-炔基、C
3-C
7-環烷基、C
1-C
6-烷基羰基、C
1-C
6-烷氧基羰基、芳基-(C
1-C
3)-烷基或雜芳基-(C
1-C
3)-烷基,或代表視情況經取代之C
1-C
6-烷基,特別佳為H;
該等部份基團如下:
A
1代表CR
2或N,
A
2代表CR
3或N,
A
3代表CR
4或N,
A
4代表CR
5或N,
B
1代表CR
6或N,
B
2代表CR
7或N,
B
3代表CR
8或N,
B
4代表CR
9或N,及
B
5代表CR
10或N,
但A
1至A
4部份基團中不超過三個基團代表N及B
1至B
5部份基團中不超過三個基團同時代表N;
R
2、R
3、R
4、R
5、R
6、R
7、R
9與R
10彼此分別獨立代表H、鹵素、氰基、硝基、各情況下視情況經取代之C
1-C
6-烷基、C
3-C
6-環烷基、C
1-C
6-烷氧基、
N-C
1-C
6-烷氧基亞胺基-C
1-C
3-烷基、C
1-C
6-烷基硫基、C
1-C
6-烷基亞磺醯基、C
1-C
6-烷基磺醯基、
N-C
1-C
6-烷基胺基或
N,N-二-C
1-C
6-烷基胺基;
若A
2與A
3部份基團均不代表N時,則R
3與R
4可與其等所附接之碳原子共同形成包含0、1或2個氮原子與/或0或1個氧原子與/或0或1個硫原子之5-或6-員環,或
若A
1與A
2部份基團均不代表N,則R
2與R
3可與其等所附接之碳原子共同形成包含0、1或2個氮原子之6-員環;
R
8代表鹵素、氰基、硝基、各情況下視情況經取代之C
1-C
6-烷基、C
3-C
6-環烷基、C
1-C
6-烷氧基、
N-C
1-C
6-烷氧基亞胺基-C
1-C
3-烷基、C
1-C
6-烷基硫基、C
1-C
6-烷基亞磺醯基、C
1-C
6-烷基磺醯基、
N-C
1-C
6-烷基胺基或
N,N-二-C
1-C
6-烷基胺基;
R
11分別獨立代表H、鹵素、氰基、硝基、胺基或視情況經取代之C
1-C
6-烷基、C
1-C
6-烷基氧、C
1-C
6-烷基羰基、C
1-C
6-烷基硫基、C
1-C
6-烷基亞磺醯基、C
1-C
6-烷基磺醯基,較佳為H;
W 代表O或S,
Q 代表H、甲醯基、羥基、胺基或各情況下視情況經取代之C
1-C
6-烷基、C
2-C
6-烯基、C
2-C
6-炔基、C
3-C
6-環烷基、C
1-C
5-雜環烷基、C
1-C
4-烷氧基、C
1-C
6-烷基-C
3-C
6-環烷基、C
3-C
6-環烷基-C
1-C
6-烷基、C
6-、C
10-C
14-芳基、C
1-C
5-雜芳基、C
6-、C
10-、C
14-芳基-(C
1-C
3)-烷基、C
1-C
5-雜芳基-(C
1-C
3)-烷基、
N-C
1-C
4-烷基胺基、
N-C
1-C
4-烷基羰基胺基,或
N,N-二-C
1-C
4-烷基胺基;或
代表視情況經多個V取代之不飽和6-員碳環;或
代表視情況經多個V取代之不飽和4-、5-或6-員雜環,其中
V 分別獨立代表鹵素、氰基、硝基、各情況下視情況經取代之C
1-C
6-烷基、C
1-C
4-烯基、C
1-C
4-炔基、C
3-C
6-環烷基、C
1-C
6-烷氧基、
N-C
1-C
6-烷氧基亞胺基-C
1-C
3-烷基、C
1-C
6-烷基硫基、C
1-C
6-烷基亞磺醯基、C
1-C
6-烷基磺醯基,或
N,N-二-(C
1-C
6-烷基)胺基;
及式(Ia‘‘)化合物之鹽類、N-氧化物、與互變異構型。
本發明另一項實施例係有關一種式(Ia‘‘)化合物,其中式(Ia‘‘)化合物為式(I-T3)化合物
(I-T3)
其中R
1、A
1、A
2、A
3、A
4、R
11、B
1、B
2、B
4、B
5、R
8、Q與W分別如本文中之定義,其中不超過一個選自A
1、A
2、A
3、A
4之部份基團代表N,且不超過一個選自B
1、B
2、B
3、B
4與B
5之部份基團代表N;或其中一個或兩個選自A
1、A
2、A
3、A
4之部份基團可代表N,且不超過一個選自B
1、B
2、B
3、B
4與B
5之部份基團代表N。
本發明另一項實施例係有關一種式(Ia‘‘)化合物,其中式(Ia‘‘)化合物為式(I-T2)化合物
(I-T2)
其中R
1、A
1、A
2、A
3、A
4、R
11、B
1、B
2、B
4、B
5、R
8、Q與W分別如本文中之定義,其中不超過一個選自A
1、A
2、A
3、A
4之部份基團代表N,且不超過一個選自B
1、B
2、B
3、B
4與B
5之部份基團代表N;或其中一個或兩個選自A
1、A
2、A
3、A
4之部份基團可代表N,且不超過一個選自B
1、B
2、B
3、B
4與B
5之部份基團代表N。
本發明另一項實施例係有關一種式(Ia‘‘)化合物,其中式(Ia‘‘)化合物為式(I-T4)化合物
(I-T4)
其中R
1、A
1、A
2、A
3、A
4、R
11、B
1、B
2、B
4、B
5、R
8、Q與W分別如本文中之定義,其中不超過一個選自A
1、A
2、A
3、A
4之部份基團代表N,且不超過一個選自B
1、B
2、B
3、B
4與B
5之部份基團代表N;或其中一個或兩個選自A
1、A
2、A
3、A
4之部份基團可代表N,且不超過一個選自B
1、B
2、B
3、B
4與B
5之部份基團代表N。
本發明另一項實施例係有關一種式(Ia‘‘)化合物,其中式(Ia‘‘)化合物為式(I-T22)化合物
(I-T-22)
其中R
1、A
1、A
2、A
3、A
4、R
11、B
1、B
2、B
4、B
5、R
8、Q與W分別如本文中之定義,其中不超過一個選自A
1、A
2、A
3、A
4之部份基團代表N,且不超過一個選自B
1、B
2、B
3、B
4與B
5之部份基團代表N;或其中一個或兩個選自A
1、A
2、A
3、A
4之部份基團可代表N,且不超過一個選自B
1、B
2、B
3、B
4與B
5之部份基團代表N。
本發明另一項實施例係有關一種式(Ia‘‘)化合物,其中式(Ia‘‘)化合物為式(I-T23)化合物
(I-T23)
其中R
1、A
1、A
2、A
3、A
4、R
11、B
1、B
2、B
4、B
5、R
8、Q與W分別如本文中之定義,其中不超過一個選自A
1、A
2、A
3、A
4之部份基團代表N,且不超過一個選自B
1、B
2、B
3、B
4與B
5之部份基團代表N;或其中一個或兩個選自A
1、A
2、A
3、A
4之部份基團可代表N,且不超過一個選自B
1、B
2、B
3、B
4與B
5之部份基團代表N。
本發明另一項實施例係有關本文所述化學式與實施例之化合物,其中R
11代表H,及W代表O。
本發明另一項實施例係有關本文所述化學式與實施例之化合物,其中R
11代表H,及W代表O,及B
3代表C-R
8,R
8代表經鹵素取代之C
1-C
3-烷基(較佳為全鹵化C
1-C
3-烷基,更佳為全氟化C
1-C
3-烷基)或經鹵素取代之C
1-C
3-烷氧基(較佳為全鹵化C
1-C
3-烷氧基,更佳為為全氟化C
1-C
3-烷氧基)。
本發明另一項實施例係有關本文所述化學式與實施例之化合物,其中A
1至A
4及B
1至B
5部份基團係如下列:
A
1代表C-H,
A
2代表CR
3或N,
A
3代表CR
4,
A
4代表C-H,
B
1代表CR
6或N,
B
2代表C-H,
B
3代表CR
8,
B
4代表C-H,及
B
5代表CR
10或N。
本發明另一項實施例係有關本文所述化學式與實施例之化合物,其中R
1代表H。
本發明另一項實施例係有關本文所述化學式與實施例之化合物,其中Q代表經氟取代之C
1-C
4-烷基、C
3-C
4-環烷基、視需要經氰基或經氟取代之C
3-C
4-環烷基、C
4-C
6-雜環烷基、1-氧離子基硫雜環丁烷-3-基、1,1-二氧離子基硫雜環丁烷-3-基、苯甲基、吡啶-2-基甲基、甲基磺醯基或2-側氧基-2-(2,2,2-三氟乙基胺基)乙基。
本發明另一項實施例係有關本文所述化學式與實施例之化合物,其中R
8代表鹵素或經鹵素取代之C
1-C
4-烷基。
本發明再一項實施例係有關本文所述化學式之化合物,其中R
11代表H。
本發明再一項實施例係有關本文所述化學式之化合物,其中R
6、R
7、R
9與R
10彼此分別獨立代表H、鹵素、氰基、硝基、各情況下視情況經取代之C
1-C
4-烷基、C
3-C
4-環烷基、C
1-C
4-烷氧基、
N-烷氧基亞胺基烷基、C
1-C
4-烷基硫基、C
1-C
4-烷基亞磺醯基、C
1-C
4-烷基磺醯基、
N-C
1-C
4-烷基胺基、
N,N-二-C
1-C
4-烷基胺基。
本發明再一項實施例係有關本文所述化學式之化合物,其中R
2、R
3、R
4與R
5彼此分別獨立代表H、鹵素、氰基、硝基、各情況下視情況經取代之C
1-C
4-烷基、C
3-C
4-環烷基、C
1-C
4-烷氧基、
N-C
1-C
4-烷氧基亞胺基-C
1-C
4-烷基、C
1-C
4-烷基硫基、C
1-C
4-烷基亞磺醯基、C
1-C
4-烷基磺醯基、
N-C
1-C
4-烷基胺基或
N,N-二-C
1-C
4-烷基胺基。
本發明再一項實施例係有關本文所述化學式之化合物,其中A
1至A
4及B
1至B
5部份基團係如下列:
A
1代表C-H,
A
2代表CR
3或N,
A
3代表CR
4,
A
4代表C-H,
B
1代表CR
6或N,
B
2代表C-H,
B
3代表CR
8,
B
4代表C-H,及
B
5代表CR
10或N。
本發明再一項實施例係有關本文所述化學式之化合物,其中R
1代表H。
本發明再一項實施例係有關本文所述化學式之化合物,其中R
1代表甲基。
本發明再一項實施例係有關本文所述化學式之化合物,其中Q代表經氟取代或甲醯胺(–C(=O)N(R)
2,其中R彼此分別獨立代表H、C
1-C
3-烷基或經鹵素取代之C
1-C
3-烷基)取代之C
1-C
4-烷基、視需要經氰基或經氟取代之C
3-C
4-環烷基、C
4-C
6-雜環烷基、1-氧離子基硫雜環丁烷-3-基、1,1-二氧離子基硫雜環丁烷-3-基、苯甲基、吡啶-2-基甲基、甲基磺醯基或2-側氧基-2-(2,2,2-三氟乙基胺基)乙基。
本發明再一項實施例係有關本文所述化學式之化合物,其中Q代表2,2,2-三氟乙基、2,2-二氟乙基、3,3,3-三氟丙基、環丙基、環丁基、1-氰基環丙基、反式-2-氟環丙基或順式-2-氟環丙基、氧雜環丁烷-3-基、硫雜環丁烷-3-基、1-氧離子基硫雜環丁烷-3-基、1,1-二氧離子基硫雜環丁烷-3-基、苯甲基、吡啶-2-基甲基、甲基磺醯基或2-側氧基-2-(2,2,2-三氟乙基胺基)乙基。
本發明再一項實施例係有關本文所述化學式之化合物,其中R
8代表鹵素或經鹵素取代之C
1-C
4-烷基。
可述及下列較佳實例:
2-氯-N-環丙基-5-[1-[4-(1,1,1,2,3,3,3-七氟丙烷-2-基)-2-甲基-6-(三氟甲基)苯基]-1H-吡唑-4-基]苯甲醯胺:
2-氯-N-(1-氰基環丙基)-5-[1-[4-(1,1,1,2,3,3,3-七氟丙烷-2-基)-2-甲基-6-(三氟甲基)苯基]-1H-吡唑-4-基]苯甲醯胺:
2-氯-N-環丙基-5-[4-[2,6-二甲基-4-[1,2,2,2-四氟-1-(三氟甲基)乙基]苯基]吡唑-1-基]苯甲醯胺:
2-氯-N-(1-氰基環丙基)-5-[4-[2,6-二氯-4-[1,2,2,2-四氟-1-(三氟甲基)乙基]苯基]吡唑-1-基]苯甲醯胺:
2-氯-5-[3-[2-氯-4-[1,2,2,2-四氟-1-(三氟甲基)乙基]-6-(三氟甲基)苯基]異㗁唑-5-基]-N-環丙基苯甲醯胺:
2-氯-N-(1-氰基環丙基)-5-[3-[2-甲基-4-[1,2,2,2-四氟-1-(三氟甲基)乙基]-6-(三氟甲基)苯基]異㗁唑-5-基]苯甲醯胺:
2-氯-N-(1-氰基環丙基)-5-[1-[2,6-二氯-4-[1,2,2,2-四氟-1-(三氟甲基)乙基]苯基]吡咯-3-基]苯甲醯胺:
2-氯-5-[3-[2-氯-4-[1,2,2,2-四氟-1-(三氟甲基)乙基]-6-(三氟甲基)苯基]吡咯-1-基]-N-環丙基苯甲醯胺:
2-氯-5-[1-[2-氯-4-[1,2,2,2-四氟-1-(三氟甲基)乙基]-6-(三氟甲氧基)苯基]-1H-吡唑-4-基]-N-環丙基-3-吡啶甲醯胺(化合物1):
2-氯-5-[1-[2-氯-4-[1,2,2,2-四氟-1-(三氟甲基)乙基]-6-(三氟甲基)苯基]-1H-吡唑-4-基]-N-環丙基-3-吡啶甲醯胺(化合物2):
可述及之其他抗寄生蟲活性化合物為:已提出為INN特格納(tigolaner)之化合物(亦參見WO2014/122083):
其他抗寄生蟲活性化合物為選自芳基異㗁唑啉類之化合物,可述及之較佳實例為:氟雷拉鈉(fluralaner)(WO2005085216)、阿弗索拉納(afoxolaner)(WO2009126668)、撒洛倫(sarolaner)(WO 2012120399)、羅替蘭(lotilaner)(WO2010070068)或氟滅醯胺(fluxametamide)。
其他抗寄生蟲活性化合物為選自芳基吡唑類之化合物,特定言之比普魯(pyriprole)或芬普尼(fipronil)。本發明調配物較佳為溶液。
調配物中活性化合物含量依該活性化合物而定,且應可以達成良好效力及良好相容性。通常,活性化合物含量為1至60% (w/w),較佳為10至50% (w/w),特別佳為20至40% (w/w)。根據另一項實施例,以高效力活性化合物為例,其含量可為1至30% (w/w),較佳為1至20% (w/w),特別佳為5至10% (w/w)。調配物通常包含至少10% (w/w),較佳為至少30% (w/w),特別佳為至少50%重量比,極特別佳為至少60%重量比之磷酸三乙酯。因此,磷酸三乙酯含量通常為10至95% (w/w),較佳為15至90% (w/w),特別佳為50至80% (w/w)。若使用溶劑混合物(合適共溶劑:參見下文)時,依據另一項實施例,磷酸三乙酯含量亦可降低,例如:5至50% (w/w),較佳為10至40%(w/w),特別佳為15至35% (w/w)。
根據一項實施例,該調配物包含磷酸三乙酯作為唯一溶劑。
其他使用型式中,除了磷酸三乙酯外,包含至少另一種適用於獸醫學之共溶劑。共溶劑應與所選擇量之磷酸三乙酯互溶,且不應對皮膚相容性及毒性有不良效應。較佳不應降低溶解度並改善美容性質。
可述及下列較佳共溶劑:乙酸1-甲氧基-2-丙基酯、2-甲氧基-1,3-二氧雜環戊烷、1-甲氧基-2-丁醇、3,4-己二酮、2-庚酮、2,3-戊二酮、3-己酮、丙酮、月桂氮酮(laurocapram)、乙酸乙酯、1-十二烷基-2-吡咯烷酮、2-戊酮、3-戊酮、3-甲基-2-丁酮、環己酮、丙二醇、聚乙二醇、三醋精、檸檬烯、中鏈三酸甘油酯、油酸乙酯、檸檬酸三乙酯、乙二醇、6-甲基-2,4-庚二酮、2-甲氧基-1-丙醇、第三丁醇、1-丁醇、四甘醇、異丙醇、2-胺基-6-甲基庚烷、異山梨酯二甲基醚、二乙二醇單乙基醚、丙酮縮甘油(solketal)、碳酸二乙酯、3,5-庚烷二酮、2,3-庚烷二酮、乙醇、2-苯氧基乙醇、酞酸二乙基酯、2-乙醯基檸檬酸三丁酯、2,6-二甲基吡啶、磷酸參-(2-乙基己基)酯、4-甲基-2-戊酮、丙二醇單乙基醚乙酸酯、辛基十二烷醇、6-甲基-3,5-庚二烯-2-酮。可述及下列特別佳共溶劑:2-丁酮、2-吡咯烷酮、4-甲基戊-3-烯-2-酮、ε-己內酯、γ-己內酯、1-甲氧基-2-丙醇、二甲亞碸、N,N-二乙基-間-甲苯甲醯胺、苯甲醇、碳酸丙二酯、異山梨酯二甲基醚、2-庚酮、N-甲基己內醯胺、γ-丁內酯、1-辛基-2-吡咯烷酮。
根據本發明調配物中可能使用個別共溶劑或兩種或更多種共溶劑之組合。
通常,共溶劑或共溶劑混合物之比例為1至85% w/w,較佳為20至80% w/w,特別佳為30至75% w/w。根據一項實施例,共溶劑之比例高於磷酸三乙酯之比例;此時,共溶劑之比例通常為40至85% w/w,較佳為50至80% (w/w),特別佳為60至80% (w/w)。
根據另一項實施例,共溶劑之比例低於磷酸三乙酯之比例;此時,共溶劑之比例通常為1至40% w/w,較佳為5至35% (w/w),特別佳為10至30% (w/w)。
所說明調配物亦可包含活性化合物之組合,以藉由協同作用改良活性或擴大活性範圍。
調配物視情況再包含其他醫藥上可接受之輔劑與添加劑,例如:界面活性劑、抗氧化劑、與滲透劑。
合適之界面活性劑為例如:聚山梨酸酯(Tween®)、山梨糖醇酐酯(Span®)、聚氧乙烯硬脂酸酯(Myrj®、Brij®、Cremophor®)、單-或二-硬脂酸甘油酯、泊洛沙姆(poloxamers)(Pluronic F68)、油醯基聚乙二醇-6甘油酯(Labrafil®),等等。界面活性劑通常使用濃度至高5% (w/w),特定言之0.5至5% (w/w)。
合適之抗氧化劑為例如:丁基化羥基甲苯(BHT)、丁基化羥基苯甲醚(BHA)、維生素E,等等,其使用濃度為至高4% (w/w),特定言之0.5至4% (w/w)。
滲透劑可用於例如:若需要活性化合物(群)滲入或通過皮膚時。滲透劑為例如:醇類(尤其指例如:乙醇、異丙醇、苯甲醇、異硬脂醇)、氮雜環烷酮類(尤其指例如:月桂氮酮(laurocapram))、二氧雜環戊烷類(例如:2-壬基-1,3-二氧雜環戊烷)、脂肪酸與衍生物(例如:月桂酸、油酸、庚酸、棕櫚酸、亞油酸、肉豆蔻酸異丙基酯)、酯類(例如:乙酸甲酯、-乙酯、-丁酯、戊酸甲酯與棕櫚酸甲酯、從肉豆蔻酸異丙基酯(C17)至硬脂酸異鯨蠟基酯(C34)之長鏈脂肪酸酯]、尿素與尿素衍生物、吡咯烷酮類(例如:2-吡咯烷酮、N-甲基-2-吡咯烷酮、N-(2-羥乙基)-2-吡咯烷酮、2-吡咯烷酮-5-羧酸)、亞碸類(例如:二甲亞碸)、萜烯類(例如:檸檬烯、1,8-桉葉油醇、橙花三級醇)、甘醇醚類(例如:二乙二醇單乙基醚[Transcutol®])。滲透劑之使用濃度可為1至60% (w/w),例如:1至30% (w/w)、1至20% (w/w)、10至50% (w/w)、20至40% (w/w)或40至60% (w/w)。
製備時,由活性化合物或活性化合物群溶於室溫或升溫下之溶劑或溶劑混合物中。若調配物包含不同溶劑時,該活性化合物或活性化合物群可以先溶於一種溶劑或該等不同溶劑之部份混合物中,較佳為具有最佳溶解性質之溶劑/溶劑混合物中。
夲文所說明調配物計畫用於對抗動物身體內或身體上之寄生蟲,特定言之體外寄生蟲或體內寄生蟲。術語「體內寄生蟲」特別包括蠕蟲與原生動物,如:球蟲。體外寄生蟲通常且較佳為節肢動物,特定言之昆蟲或蟎類。調配物之活性範圍當然會依其中所含之活性化合物或活性化合物混合物而定。
原則上,根據本發明調配物適合防治發生在牲畜、培育、動物園、實驗室、實驗及家庭飼養等動物之動物培育與動物飼養上之寄生蟲。其等有活性對抗寄生蟲之所有或特定發展階段。
農業牲畜包括例如:哺乳動物,如:綿羊、山羊、馬、驢、駱駝、水牛、兔、黇鹿、馴鹿,及尤指牛與豬;或禽類,如:火雞、鴨、鵝,特別指雞。
家庭動物包括例如:哺乳動物,如:倉鼠、天竺鼠、大鼠、小鼠、栗鼠、雪貂,及特定言之狗、貓、籠中鳥;爬蟲類、兩棲類或觀賞魚。
一項明確實施例中,式(I)化合物係投與哺乳動物。
另一項明確實施例中,式(I)化合物係投與鳥類,亦即籠中鳥,或特別指禽類。
根據一項實施例,根據本發明調配物適用於寵物動物,特定言之哺乳動物,較佳為狗或貓。
式(I)化合物於防治動物寄生蟲上之用途係計畫降低或預防疾病、死亡率及減輕已下降之生產效能(以肉、奶、毛、皮、蛋,等等為例),因此可以更經濟且更簡單地達成動物管理及更佳動物健康。
在動物健康相關領域上,本文中之術語「防治」或「預防」意指利用根據本發明調配物,使感染特定寄生蟲之動物中之此等寄生蟲可以減少至無害程度。更明確言之,本文中之「防治」意指式(I)化合物會殺死各寄生蟲、抑制其生長、或抑制其繁殖。
根據本發明調配物計畫供局部投予,其中咸了解「局部」為調配物施用在所治療動物之外表皮,亦即,皮膚。其實例包括:
滴劑施用法,包括施加相當少量調配物(例如:0.1至20 ml,較佳為0.2至10 ml,特定言之0.3至5 ml)至有限的皮膚區域,通常在動物頸部或背部。
淋洗施用法,其類似滴劑施用法。然而,係施加更大量調配物(例如:5至100 ml,特定言之8至50 ml)。
此外,活性化合物可具有全身作用,亦即由有效量活性化合物滲入皮膚,並藉由循環系統分佈在動物體內。
亦可採用非全身性作用:若有任何活性化合物滲入皮膚也是僅有少量。反之,活性化合物係塗佈在動物表面,在此展開其作用。顯然地,非全身性投藥法並不適合以該調配物來對抗體內寄生蟲。
實例:
實例1:
2-氯-5-[1-[2-氯-4-[1,2,2,2-四氟-1-(三氟甲基)乙基]-6-(甲氧基)
苯基]-1H-吡唑-4-基]-N-環丙基-3-吡啶甲醯胺(化合物1) 30.0 g
磷酸三乙酯 87.1 g
117.1 g = 100 ml
實例2:
化合物1 30.0 g
1-甲氧基-2-丙醇 47.4 g
DMSO 15.8 g
磷酸三乙酯 15.8 g
109.0 g = 100 ml
實例3:
2-氯-5-[1-[2-氯-4-[1,2,2,2-四氟-1-(三氟甲基)乙基]-6-(三氟甲基)
苯基]-1H-吡唑-4-基]-N-環丙基-3-吡啶甲醯胺(化合物2) 30.0 g
磷酸三乙酯 85.6 g
115.6 g = 100 ml
實例4:
芬普尼(fipronil) 30.0 g
磷酸三乙酯 70.0 g
100.0 g
實例5:
氟雷拉鈉(fluralaner) 30.0 g
磷酸三乙酯 70.0 g
100.0 g
生物實例:活體內效力數據
(
貓、狗
)
為了測試物質對體外寄生蟲之作用效力,在貓與狗身上實驗性接種(感染)跳蚤與蜱。分析效力時,由處理組動物的數據與未處理對照組動物比較。
每次感染時,在每隻動物身上施加40-50隻蜱與約100隻跳蚤。
以處理當天計算為第0天;因此第一週計算為第0週(第0-6天)。因此,第1週相當於處理後第7-13天,及第8週相當於第56-62天。
讓
跳蚤留在狗或貓身上24或48(±4 h)小時。之後,使用跳蚤梳除下動物身上的跳蚤。收集梳子除下來的跳蚤,並計數。當計算跳蚤數時,將跳蚤分成活跳蚤與死跳蚤。為了計算寄生蟲,僅考慮計算活跳蚤。
讓
蜱留在狗或貓身上48 (±4 h)小時。之後,手動清除動物身上的蜱,視情況使用一把鑷子。收集除下來的蜱,並計數。當計算蜱數量時,將蜱分成活蜱、吸附的活蜱、離身的死蜱、及吸附的死蜱。為了計算寄生蟲,僅考慮計算吸附的活蜱。
採用下列公式計算對抗目標寄生蟲之效力:
效力% = (N2-N1) /N2 X 100。
N1 = 處理組中寄生蟲數量之幾何平均值(寄生蟲數:活跳蚤或吸附的活蜱)
N2 = 未處理組中寄生蟲數量之幾何平均值(寄生蟲數:活跳蚤或吸附的活蜱)
狗與貓之動物實驗中,劑量為每公斤體重使用0.1ml(30% w/v 溶液,相當於30 mg/kg),下表中實例顯示對抗跳蚤(狗蚤屬(
Ctenocephalides))與蜱(革蜱屬
(Dermacentor)、扇頭蜱屬(
Rhipicephalus)與硬蜱(
Ixodes))至少8週之效力。詳細內容可參見下表2:
表2
動物物種 | 調配物 | 對抗 體外寄生蟲 之效力數據 | |||
跳蚤 | 篦子硬蜱 (Ixodes ricinus) | 血紅扇頭蜱 (Rhipicephalus saguineus) | 美洲大革蜱 (Dermacentor variabilis) | ||
狗 | 實例 3 | 9週(100%) 計數24 (±4) h | 9週(100%) 計數48 h (±4) h | 9週(100%) 計數48 h (±4) h | 8週(92%) 計數48 h (±4) h |
狗 | 實例 1 | 8週(100%) 計數24 (±4) h | 10週(100%) 計數48 h (±4) h | 10週(99%) 計數48 h (±4) h | 8週(100%) 計數48 h (±4) h |
狗 | 實例 2 | 8週(100%) 計數24 (±4) h | 10週(100%) 計數48 h (±4) h | 10週(100%) 計數48 h (±4) h | 8週(100%) 計數48 h (±4) h |
貓 | 實例 1 | 8週(100%) 計數24 (±4) h | 8週(100%) 計數48 h (±4) h | 未檢測 | 未檢測 |
無
無
無。
Claims (11)
- 一種液體調配物,其包含抗寄生蟲之含氟活性化合物和至少10% (w/w)之磷酸三乙酯; 其中該液體調配物包含選自下列組成之群組之化合物做為含氟活性化合物: 2-氯-N-環丙基-5-[1-[4-(1,1,1,2,3,3,3-七氟丙烷-2-基)-2-甲基-6-(三氟甲基)苯基]-1H-吡唑-4-基]苯甲醯胺、 2-氯-N-(1-氰基環丙基-5-[1-[4-(1,1,1,2,3,3,3-七氟丙烷-2-基)-2-甲基-6-(三氟甲基)苯基]-1H-吡唑-4-基]苯甲醯胺、 2-氯-N-環丙基-5-[4-[2,6-二甲基-4-[1,2,2,2-四氟-1-(三氟甲基)乙基]苯基]吡唑-1-基]苯甲醯胺、 2-氯-N-(1-氰基環丙基)-5-[4-[2,6-二氯-4-[1,2,2,2-四氟-1-(三氟甲基)乙基]苯基]吡唑-1-基]苯甲醯胺、 2-氯-5-[3-[2-氯-4-[1,2,2,2-四氟-1-(三氟甲基)乙基]-6-(三氟甲基)苯基]異㗁唑-5-基]-N-環丙基苯甲醯胺、 2-氯-N-(1-氰基環丙基)-5-[3-[2-甲基-4-[1,2,2,2-四氟-1-(三氟甲基)乙基]-6-(三氟甲基)苯基]異㗁唑-5-基]苯甲醯胺、 2-氯-N-(1-氰基環丙基)-5-[1-[2,6-二氯-4-[1,2,2,2-四氟-1-(三氟甲基)乙基]苯基]吡咯-3-基]苯甲醯胺、 2-氯-5-[3-[2-氯-4-[1,2,2,2-四氟-1-(三氟甲基)乙基]-6-(三氟甲基)苯基]吡咯-1-基]-N-環丙基苯甲醯胺、 2-氯-5-[1-[2-氯-4-[1,2,2,2-四氟-1-(三氟甲基)乙基]-6-(三氟甲氧基)苯基]-1H-吡唑-4-基]-N-環丙基-3-吡啶甲醯胺(化合物1)、 2-氯-5-[1-[2-氯-4-[1,2,2,2-四氟-1-(三氟甲基)乙基]-6-(三氟甲基)苯基]-1H-吡唑-4-基]-N-環丙基-3-吡啶甲醯胺(化合物2)、 特格納(tigolaner)、氟雷拉鈉(fluralaner)、阿弗索拉納(afoxolaner) (WO2009126668)、撒洛倫(sarolaner)、羅替蘭(lotilaner)、氟滅醯胺(fluxametamide)、比普魯(pyriprole)、以及芬普尼(fipronil)。
- 如請求項1之液體調配物,其中該含氟活性化合物每200 u、較佳為每160 u、特別佳為每100 u 分子量包含至少一個氟原子。
- 如請求項1之液體調配物,其中該含氟活性化合物每500 u分子量包括至少一個三氟甲基。
- 如請求項1-3其中任一項之液體調配物,其具有之活性化合物含量為1-60% (w/w)。
- 如請求項1-3其中任一項之液體調配物,其包含至少10% (w/w)磷酸三乙酯。
- 如請求項1之液體調配物,其包含10至95% (w/w)之磷酸三乙酯。
- 如請求項1-3其中任一項之液體調配物,其包含共溶劑。
- 如請求項7之液體調配物,其包含選自下列之共溶劑:乙酸1-甲氧基-2-丙基酯、2-甲氧基-1,3-二氧雜環戊烷、1-甲氧基-2-丁醇、3,4-己二酮、2-庚酮、2,3-戊二酮、3-己酮、丙酮、月桂氮酮(laurocapram)、乙酸乙酯、1-十二烷基-2-吡咯烷酮、2-戊酮、3-戊酮、3-甲基-2-丁酮、環己酮、丙二醇、聚乙二醇、三醋精、檸檬烯、中鏈三酸甘油酯、油酸乙酯、檸檬酸三乙酯、乙二醇、6-甲基-2,4-庚二酮、2-甲氧基-1-丙醇、第三丁醇、1-丁醇、四甘醇、異丙醇、2-胺基-6-甲基庚烷、異山梨酯二甲基醚、二乙二醇單乙基醚、丙酮縮甘油(solketal)、碳酸二乙酯、3,5-庚烷二酮、2,3-庚烷二酮、乙醇、2-苯氧基乙醇、酞酸二乙基酯、2-乙醯基檸檬酸三丁酯、2,6-二甲基吡啶、磷酸參-(2-乙基己基)酯、4-甲基-2-戊酮、丙二醇單乙基醚乙酸酯、辛基十二烷醇、6-甲基-3,5-庚二烯-2-酮。
- 如請求項7或8中任一項之液體調配物,其包含1至85% (w/w)之共溶劑。
- 如請求項1-3其中任一項之液體調配物,其中該調配物為均質溶液。
- 如請求項1-3其中任一項之液體調配物,其係用於防治動物身體內/上之寄生蟲。
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TW107130928A TWI794282B (zh) | 2017-09-06 | 2018-09-04 | 用於動物寄生蟲之防治及預防的可局部投予之調配物 |
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UA (1) | UA127622C2 (zh) |
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TW202122079A (zh) * | 2019-08-14 | 2021-06-16 | 德商拜耳動物保健有限公司 | 用於控制寄生蟲之組成物 |
MX2022009240A (es) * | 2020-01-29 | 2022-08-16 | Bayer Animal Health Gmbh | Composicion farmaceutica para el control de parasitos en organismos no humanos. |
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DE4443888A1 (de) | 1994-12-09 | 1996-06-13 | Bayer Ag | Dermal applizierbare Formulierungen von Parasitiziden |
JPH08291004A (ja) * | 1995-04-24 | 1996-11-05 | Nippon Kayaku Co Ltd | 害虫防除剤組成物 |
SE517612C2 (sv) * | 1995-12-20 | 2002-06-25 | Rhone Poulenc Agrochimie | Användning av 5-amino-4-etylsulfinyl-1-arylpyrazol föreningar som pesticider |
DE10117676A1 (de) | 2001-04-09 | 2002-10-10 | Bayer Ag | Dermal applizierbare flüssige Formulierungen zur Bekämpfung von parasitierenden Insekten an Tieren |
DE10320505A1 (de) | 2003-05-08 | 2004-11-25 | Bayer Healthcare Ag | Mittel zum Bekämpfen von Parasiten an Tieren |
CN1225978C (zh) | 2003-11-03 | 2005-11-09 | 浙江新农化工有限公司 | 含三唑磷和氟虫腈复配杀虫微乳剂及其制备方法 |
KR101197482B1 (ko) | 2004-03-05 | 2012-11-09 | 닛산 가가쿠 고교 가부시키 가이샤 | 이속사졸린 치환 벤즈아미드 화합물 및 유해생물 방제제 |
EP2072501A1 (en) | 2007-12-21 | 2009-06-24 | Bayer CropScience AG | Aminobenzamide derivatives as useful agents for controlling animal parasites |
TWI455919B (zh) | 2008-04-09 | 2014-10-11 | Du Pont | 製備3-三氟甲基查耳酮(chalcone)之方法 |
EP2379537B9 (en) | 2008-12-19 | 2017-07-12 | Novartis AG | Isoxazoline derivatives and their use as pesticide |
MX311193B (es) | 2010-01-29 | 2013-07-04 | Mitsui Chemicals Agro Inc | Composicion para exterminar parasitos de animales, y metodo para exterminar parasitos de animales. |
CA2828397C (en) | 2011-03-10 | 2015-10-13 | Zoetis Llc | Spirocyclic isoxazoline derivatives as antiparasitic agents |
SI2953942T1 (en) | 2013-02-06 | 2018-03-30 | Bayer Cropscience Ag | Halogen-substituted pyrazole derivatives such as pesticides |
CA2929390C (en) | 2013-11-05 | 2023-02-28 | Bayer Cropscience Aktiengesellschaft | Substituted benzamides for treating arthropodes |
JP6740239B2 (ja) | 2015-03-12 | 2020-08-12 | エフ エム シー コーポレーションFmc Corporation | 複素環置換二環式アゾール殺有害生物剤 |
AR106084A1 (es) * | 2015-09-23 | 2017-12-13 | Syngenta Participations Ag | Benzamidas sustituidas con isoxazolina como insecticidas |
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- 2018-09-04 TW TW112103268A patent/TW202335661A/zh unknown
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KR20200044099A (ko) | 2020-04-28 |
CN111050557B (zh) | 2023-08-01 |
SG11202001304XA (en) | 2020-03-30 |
MX2020002496A (es) | 2020-07-20 |
JP2020532563A (ja) | 2020-11-12 |
CA3074620A1 (en) | 2019-03-14 |
AU2018329158A1 (en) | 2020-03-05 |
PH12020500431A1 (en) | 2020-11-09 |
JP7305620B2 (ja) | 2023-07-10 |
DOP2020000052A (es) | 2020-08-16 |
US20210059986A1 (en) | 2021-03-04 |
RU2020112629A3 (zh) | 2021-12-28 |
TW201919584A (zh) | 2019-06-01 |
US11344532B2 (en) | 2022-05-31 |
UY37867A (es) | 2019-03-29 |
CR20200105A (es) | 2020-04-22 |
EP3651579A1 (en) | 2020-05-20 |
AU2018329158A8 (en) | 2020-03-12 |
CN111050557A (zh) | 2020-04-21 |
CL2020000551A1 (es) | 2020-11-06 |
AR113107A1 (es) | 2020-01-29 |
CO2020002624A2 (es) | 2020-04-13 |
IL272720A (en) | 2020-04-30 |
UA127622C2 (uk) | 2023-11-08 |
BR112020004339A2 (pt) | 2020-09-08 |
WO2019048381A1 (en) | 2019-03-14 |
RU2020112629A (ru) | 2021-10-06 |
TWI794282B (zh) | 2023-03-01 |
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