Method of producing derivatives of 13-haloidmylbemicine or their salts, or their esters

专利摘要:
Derivatives of milbemycins D, A3 and A4 and of the corresponding sec-butyl compound have a halogen atom at the 13-position; at the 5-positon, they have an oxygen (keto) atom, an oxime group or a substituted oxime group. They may be prepared from known compounds by any appropriate combination of halogenation, ketonization and oximation, and are of use as anthelmintic, acaricidal and insecticidal agents.
公开号:SU1537140A3
申请号:SU4027577
申请日:1986-05-30
公开日:1990-01-15
发明作者:Сато Кацуо；Янаи Тосиаки；Китано Норитоси；Нисида Акира；Фрай Бруно；Оъсалливан Энтони
申请人:Санкио Компани Лимитед (Фирма)；
IPC主号:

专利说明:

The invention relates to a process for the preparation of 13-halo-milbemycin derivatives, or their salts, or their esters, which exhibit anthelmintic, acaricidal and insecticidal activity, and can be used in agriculture.
The purpose of the invention is to obtain new milbemycin derivatives,
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giving higher acaricidal activity.
The method is illustrated by the following examples.
Milbemycins meet the formula A
D,
ABOUT
de R, methyl (milbemycin A-J); R, is ethyl (milbemycin A4) and R, is isopropyl (milbemycin D). These compounds can be isolated from Streptomyces Strain B-41-146 cultures.
Example 1. 13p-Fluoro-5-keto milbemycin A 4.
70 mg of diethylaminosulfurfluoride are added dropwise to a solution of 560 mg of 13-hydroxy-5-ketomylbemycin A4 in 25 ml of methylene chloride, maintaining the temperature at -60 ° C, and the mixture is stirred for 15 minutes. At the end of this time, the reaction mixture is poured into water and extracted with ethyl acetate. The organic extract is dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue is purified on a silica gel chromatography column to obtain 320 mg (yield 57%) of the title compound.
Infrared Absorption Spectrum (KBGMSs 1: 3450, 1735, 1715, 1680.
Mass spectrum (t / g): 559 (M), 541, 521.
NMR spectrum (CDC13) 0 ppm: 2.6 (1H, multiplet), 3.09 (1H, triplet of doublets, J 2.6 and 10.1 Hz); 3.88 (W, singlet); 4.02 (1H, singlet); 4.40 (1H, doublet of doublets, J = 99 and 47.6 Hz); 4.75 (2H, multiplet); 5.2-5.5 (3N, multiplet); 5.75-5.9 (2H, multiplet); 6.54 (1H, multiplet).
Example 2. 13 (-Hpor-5-keto-milbemycin A.
47 µl of thionyl chloride is added dropwise to a solution of 235 mg of 13-hydroxy-5-ketomylbemycin 40 ml of dry benzene under ice cooling conditions.
and the mixture is stirred at room temperature for 2 hours. The reaction mixture is then poured into water and then treated in the same manner as described in Example 1, to give 100 mg (yield 41%) of the desired compound.
Mass spectrum (t / g): 574 (M +), 6.538.
NMR spectrum (SOSTS) & ppm: 4.12 (1H, doublet, J 11.0 Hz); 4.75 (2H, multiplet); 4.95 (1H, multi-PLRT); 5.2-5.5 (2H, m} chintlet); 5.6 - 5.9 (2H, multiplet); 6.54 (1H, multiplet).
Example 3. 13ft-bromo-5-keto-milbemycin AJ.
The procedure described in Q Example 2 was repeated, except that 280 mg of 13-hydroxy-5-ketomyl bemycin A and 80 mg of phosphorus tribromide were used to obtain 90 mg (yield 29%) of the desired compound. 5 Infrared Absorption Spectra (KBr) O, KCCM-: 3450, 1715, 1680.
NMR spectrum (BSCS) b4 ppm: 4.30 (1H, doublet, J 11.0 Hz); 5.2-5.5 (3N, multiplet); 5.75-5.90 (2H, 0 multiplet); 6.54 (1H, multiplet).
Example4. 13 A-Iod-5-keto-milbemycin A c ..
45 mg of trimethylsilyl chloride are added under a nitrogen stream to a solution of 194 mg of GZ-hydroxy-5-ketomylbemicin A and 66 mg of sodium iodide in 15 ml of acetonitrile, the mixture is stirred at room temperature for 8 hours. The reaction mixture is poured into water and then treated in the same manner as described in Example 1, to give 96 mg (yield 41%) of the target compound.
Infrared absorption spectra (KBr) cm-; 3460, 1735, 1715, 1685.
NMR spectrum (HSCC) Ј ppm: 3.06 (1H, triplet of doublets, J = 2.6 and 9.5 Hz); 4.58 (1H, doublet, 0 Hz).
Example 5. 13 ft-Fluoro-5-keto- ® milbemycin D.
0.60 g of activated manganese dioxide is added to a solution of 170 mg of 13-fluoromylbemycin D in 3 ml of methylene chloride at room temperature, and the mixture is vigorously stirred for 10 minutes and the insoluble part is washed with methylene chloride. Filtrate and washing solutions
singlet).
EXAMPLE 7: 13 ft-Chloro-5-ketotomylbemycin A} oxime.
39 mg of 13-chloro-boemicine AJS 0.10 g of activated manganese dioxide and 10 mg of hydroxylamine hydrochloride react in the same way as described in example 7, to give 15 mg (38% yield) of the desired compound.
Mass spectrum (t / g): 575 (M), 557.
NMR spectrum (CDC13) ft ppm: 3S26 (1H, multiplet); 4.09 (111, doublet, J 10.6 Hz); 4.67 (1H, Singpet).
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evaporation is combined and terminated.
under reduced pressure. The residue was purified on a silica gel column to obtain 151 mg (yield: 89%) of the intended compound.
Mass Spectrum (ha / g): 573 (Mf), 555
Example 13 p-Fluoro-5-keto-milbemycin D oxime.
150 mg of 1Z-fluoro-5-ketomyl bemycin (prepared as described in Example 5) and 36 mg of hydroxyl min hydrochloride are added to 3 ml of ethanol and the mixture is stirred at 70 ° C for 90 minutes. The reaction mixture is then cooled and concentrated by evaporation under reduced pressure. Benzene is added to the residue and water is azeotropically removed in situ. The residue was purified by silica gel column chromatography to obtain 90 mg (yield 58%) of the target compound.
Mass spectrum (t / g): 587 (M +), 321.274.
NMR spectrum (CDC13) Ј ppm: 3.07 (1H, doublet of doublets, J 1.9 and 9.5 Hz); 4.40 (1H, doublet of doublet top, J 10.0 and 47.6 Hz); 4.67 (1H,
P milbemycin D oxime.
119 mg 13 chloromylbemipine D and 0.80 g activated manganese dioxide are reacted in the same manner as described in Example 5 to give 13 ft-chloro-5-ketomyl bemycin D, 46 mg hydroxylamine hydrochloride is added to the reaction mixture and the mixture is treated with such in the same manner as described in Example 6, to give 97 mg (yield 80%) of the desired compound.
Mass Spectrum (ha / g): 603 (M +).
NMR spectrum (CDC1,) 8 ppm: 3.07 (1H, doublet of doublets, J 2.0 and 9.5 Hz); 4.09 (1H, doublet, 6 Hz 4.67 (1H, singlet).
Example 8. 13 p-Chloro-5-ke








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Example 9. 13 ft-Fluoro-5-ketomethylbemycin A oxime.
A solution of 268 mg of 1Z-fluoro-5-ketomyl-bemycin A4. (prepared as described in Example 1) in 4 ml of methanol and 4 ml of dioxane are added dropwise to a solution of 166 mg of hydroxylamine hydrochloride in 3 ml of water, and the mixture is stirred at room temperature for 8 hours. After this time, the reaction mixture is poured into water and extracted with ethyl acetate. The extract is dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography to obtain 182 mg (yield 66.4%) of the target compound.
Infrared Absorption Spectrum (KBG) s, ks cm 1: 3450, 1740, 1720, 1710.
Mass spectrum (t / g): 573 (mb, 555, 540.
NMR (COCF) 8 ppm: 3.95 (1H, singlet); 4.41 (1H, doublet of doublets, J 10.3 and 47.6 Hz); 4.67 (1H, singlet); 7.73 (1H, sipglet).
Example 10. 13B-Xpor-5-ketomethylbemycin A oxime.
103.8 mg of 13-chloro-5-ketomyl bemicia per Aq. (prepared as described in Example 2) and 75 mg of hydroxylamine hydrochloride are treated in the same 5 manner as described in Example 9 to obtain 63.4 mg (yield 59.5%) of the desired compound.
Mass spectrum (t / g): 589 (M), 571.
NMR spectrum (CDC1,) ppm: 3.94 (1H, singlet); 4.09 (1H, doublet, J 10.3 Hz); 4.67 (1H, singlet); 7.91 (1H, singlet).
Example 11. 13 th-Iodo-5-keto milbemycin A4. oxime
68 mg 13-under-5-ketomylbemycin Ac. and 35 mg of hydroxylamine hydrochloride are treated in the same manner as described in Example 9 to obtain 48 mg (yield 69%) of the target compound.
Infrared Absorption Spectrum (KBG) Max 3400, 1735, 1720, 1710.
NMR spectrum (CDCl1) f ppm: 3.95 5 (1H, singlet); 4.58 (1H, doublet, J = 11.0 Hz); 4.67 (1H, singlet); 7.86 (1H, singlet).
Example 12. 13/3-Fluoro-5-Ketomellbemycins A4 + j 5-0-methyloxime.
129 mg of a 2.3: 1 mixture by weight of 13-fluoro-5-ketomyl bemycin A and A3 and 115 mg of 0-methylhydroxylamine hydrochloride are reacted in the same manner as described in example 9, to give 108 mg (yield 80%) of the desired compound.
Infrared absorption spectrum (KBG)) s / s cm-: 3470, 1715.
LMR spectrum (CDCl1) Ј ppm: 3.91 (1H, singlet); 4.00 (3N, singlet; 4.40 (1H, doublet of doublets J, 9.9 and 48.0 Hz); 4.56 (1H, singlet).
Example 13. 13 P-Fluoro-5-ketomylbemycin A 4 + 3 5-0-carboxymethyl-oxime.
Repeat the procedure described in Example 12, but using 0-carboxi-methyl-hydroxylamine hydrochloride, to obtain a mixture of 2.8: 1 of the desired compound.
Mass spectrum ha / g: 557 (M), 551, 539, 525.
NMR (ppm): 4.42
(1H, doublet of doublets, J 9.7 and 47.5 Hz); 6.4 (1H, broad singlet) Example 14, 13/3-Fluoro-5-keto-milbemycin A 4 + 3 5-benzyloxime.
Repeat the procedure described in Example 12, but using 0-benzylhydroxylamine hydrochloride, to obtain a mixture of 7.3: 1 of the desired compound.
Mass Spectrum {b / g 663 (M +), 649, 605, 556.
NMR spectrum (CDC13) S ppm: 3.88 (1H, singlet); 4.40 (1H, doublet of doublets, J 9.5 and 47.5 Hz); 4.60 (1H, singlet).
Example 15. 13 | 3-Chloro-5-ketomellbemycin A4 5-0-acetyloxime.
7.7 mg of 1,4-diazobicyclo (2,2,2) octane and 5.4 µl of acetyl chloride are added to a solution of 40.5 mg of 13-chloro-5-ketomyl bemycin A oxime (prepared as described in Example 10), in 1.5 ml of acetonitrate, and the mixture is stirred at room temperature for 6 hours. After that, the reaction mixture is poured into water and extracted with ethyl acetate. The extract is dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue is purified on a chromatographic pad with silica gel to give 33.5 mg (yield 77.2%) of the desired compound. Mass spectrum (t / g): 631 (,) 88.
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NMR spectrum (CDC13) Ј ppm: 2.24 (EF, singlet); 3.93 (1H, singlet); 4.10 (1H, doublet, J - 10.6 Hz); 4.60 (1H, siigtttet).
When pore 16. 13 /} - Chloro-5-ketomellbemycin A 5-0- (M, M-dimethyl-carbamoyl) oxime.
100 mg of 13-chloro-5-ketomylbemycin A 4. oxime (prepared as described in example 10) and 19 μl of M, M-dimethylcarbamoyl chloride are treated in the same way as in the analog in example 15, with iv , 6 41 (yield 72%) of the title compound.
Mass spectrum (ha / g): 536 (Mf-124), 519, 501.
NMR spectrum (CDC13) Ј ppm: 2.99 (6H, singlet); 3.94 (1H, singlet); 4.10 (1H, doublet 10.6 Hz); 4.57 (1H, singlet); 4.71 (2H, singlet).
Example 17. 13 3-Hpor-5-ketomethylbemycin A 5-0- (M-methylcarbamoyl) oxime.
0.30 ml of methyl isocyanate was added to a solution of 100 mg of 1Z-chloro-5-ketomylbamycin A4 oxime (2 ml of tetrahydrofuran obtained as described in example, and the mixture was left to stand for 8 hours, sealed.
Thereafter, the solvent is distilled under reduced pressure to obtain 95.7 mg (yield 87%) of the target compound.
Mass Spectrum) (ha / g): 589 (),
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NMR spectrum (CDC13) J ppm: 2.93 (3F, doublet, J 4.7 Hz); 3.87 (1H, singlet); 4.09 (1H, doublet, J 10.6 Hz); 4.67 (1H, singlet).
Example 18. 13 | 3-Fluoro-5-keto-milbemycin A 5-0- (M, M-dimethylcarbamoyl) oxime.
57 mg of 13-fluoro-5-ketomyl bemycin A oxime (prepared as described in Example 9) and 12 μl of M, i-dimethylcarbamoyl chloride are treated in the same manner as described in Example 15 to give 49 mg (76% yield) target compound.
Mass spectrum (t / g): 644 (M 1), 626, 600, 582.
NMR spectrum (CDCl1) oh ppm: 2.99 5 (6H, singlet); 3.96 (1H, singlet); 4.41 (1H, doublet of doublets, J 9.9 and 47.6 Hz); 4.57 (1H, singlet); 4.72 (2H, singlet).
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Example 19. 13 p-Fluoro-5-ketomylbemycin A4 5-0-pivaloyl oxime.
15 µl of triethylamine and 14 µl of pivaloyl chloride are added to a solution of 57 mg of 13 A-fluoro-5-ketomylbemycin A oxime (prepared as described in Example 9) in 10 ml of benzene and the mixture is then stirred at room temperature for 3 hours. this reaction mixture was worked up in the same manner as described in Example 15 to obtain 52 mg (yield 79%) of the intended compound.
Mass spectrum (t / g): 657 (M), L39.574.
NMR spectrum (CDC1) Ј ppm: 1.29 (9H, singlet); 3.99 (1H, singlet); 4.41 (1H, doublet of doublets, J 9.9 and 47.6 Hz); 4.57 (1H, singlet); 4.72 (2H, singlet).
Example 20 „13-Fluoro-5-keto-milbemycin A 44J 5-0-octanoyloxime, (stage E).
Repeat the procedure of example 15, but using octanoyl chloride and a mixture of 1 3 (3-fluoro-5-ketomylbemitsinov A4 + 5 oximes (prepared according to the method of example 9), to obtain a mixture of 2.0: 1 of the desired compound.
Mass spectrum (.t / g): 699 (M +), 685.
NMR (ppm: 4.41 (1H, doublet of doublets, J 10.1 and 48.4 Hz); 4.58 (1H, singlet); 4.8 (1H, broad singlet).
Example 21: 13-Fluoro-5-keto-milbemycins A4 + 5 5-0-hexadecanoyloxime.
Repeat the procedure of example 15, but using hexadecanoyl chloride and a mixture of 13-fluoro-5-ketomylbemicin A 4 43 oximes (prepared according to the method of example 9), to give a mixture of 1.0: 1 target compounds.
Mass spectrum (ha / g, Ats): 811 (Mf).
NMR spectrum (CDC13) & h / min: 3.95 (1H, singlet); 4.43 (1H, doublet of doublets, J 9.9 and 48.0 Hz); 4.58 (1H singlet).
EXAMPLE 22. 13 P-Fluoro-5-keto-milbemycin A 4 + .j 5-0-acetyloxime.
The procedure of example 15 is repeated, but using a mixture of 13-fluoro-5-ketomyl bemycin A, + e oximes (prepared according to the method of example 9), to obtain a mixture of 1.8: 1 target compounds.
SRI.
Mass spectrum (t / g, Hell): 615 (Mf). NMR spectrum (SZS13) $ ppm: 3.96 (1H, singlet): 4.43 (1H, doublet
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doublets, J 8.7 and 48.0 Hz); 4.60 (1H, singlet).
Example 23. 13 p-Fluoro-5 ke tomylbemycin A 5-O-propionyloxnm.
The procedure of Example 15 is repeated, but using propionyl chloride, to give the desired compound. Mass spectrum (ha / g): 645 (M), 589. NMR spectrum (CDC1,) ppm: 4.11 (1H, doublet, J - 10.4 Hz); 4.61 (1H, singlet); 4.96 (1H, singlet). Example 24. 13/3-Fluoro-5-ke-tomylbemycin A h 5-O-p-toluenesulfonyl oxime.
The procedure of Example t5 is repeated, but using 13-fluoro-5-ketonylbemycin A4 oxime (prepared as described in Example 9) and p-toluenesulfonyl chloride, to give the desired compound.
Mass spectrum (ha / g): 517 (M + -2U, 503, 455.
NMR spectrum (CDCl1) J ppm: 2.44 (3N, singlet); 3.84 (1H, singlet); 4.41 (1H, doublet of doublets, J 10.0 and 47.2 Hz); 4.54 (1H, singlet).
Example 25. 13/3-Fluoro-5-ketomethyl bemicyc A4 5-0- (pentaacetyl-glhjonoyl) oxime.
The procedure described in Example 15 is repeated, but using 13-fluoro-5-ketomyl bemycin Ac. oxime (prepared as described in Example 9) and pentaacetylgluconyl chloride, to give the desired compound.
Mass spectrum (t / g): 615 (), 573.
NMR spectrum (CDC13) Ј ppm: 3.90 (1H, singlet); 4.1-4.4 (5H, multiplet); 4.52 (1H, singlet).
PRI me R 26. 13-Brom-5-keto-milbemycin A,) ..
While cooling with ice, 20 µl of bromomethylsilane is added dropwise to a solution of 27 mg of 13-hydroxy-5-keto-milbemicin A4 in 15 ml of dry methylene chloride, and the mixture is then stirred at room temperature overnight. The reaction mixture was poured into water and processed according to the procedure of Example 1 to obtain 52 mg (19.2%) of the title compound.
Example 27. 38 µl of methyl iodide is added dropwise to 104 µl of triphenyl phosphite at room temperature and the mixture is stirred for 1 Cho. To the mixture diluted with 2 ml of methylene chloride, is added dropwise
a solution of 224 mg of 13-hydroxy-5-keto-milbemycin Aq in 2 ml of methylene chloride. The whole mixture was stirred overnight and then poured into water, after which it was treated according to the method of Example 1, to obtain 76 mg (28%) of 13-iodo-5-ketomyl bemycin A $.
Example 28 o A mixture of 70 μl of 2-chloro-3-ethylbenzoxazoline tetrafluoroborate and 34 mg of tetraethylammonium chloride in methylene chloride is stirred for 15 minutes under ice-cooling.
30 µl of triethylamine and 56 mg of 13-hydroxy-5-ketomyl bemycin A are added to the mixture obtained above, and then the resulting mixture is stirred overnight. The reaction mixture was poured into water and treated according to the procedure of Example 1 to obtain 25 mg (43%) of 13-chloro-5-ketomellbemycin A.
The compounds of formula (I) show a strong acaricidal activity against, for example, developed individuals, adults and Tetranychus, Raponychus cells and Schlechtendal mites, which parasitize on fruit trees, vegetables and flowers. They are also active against Ixodidac Dermanyssida and Sarcoptidae, which parasite animals. In addition, they are active against exoparasites, such as Oestrus, Lucilia, Hypoderma, Gautrop hilus, lice and fleas, which parasitize animals and birds, especially livestock and poultry, domestic insects, such as cockroaches and house flies, and various harmful: insects in agriculture and horticulture such as the Lepidoptera caterpillar and the caterpillar. They are also effective against Meloido gyne, in the soil, Bursaphelenchus and Phi zoglyphis. They are also effective against insects of the Coleoptera genus: Homoptera, Heteroptera, Diptera, Thysanoptera, Orthoptera, Anoplura, Siphonaptera, Mallophage, Thusanura, Isoptera, and Psocoptera, Hymenoptera.
The compounds of the formula I can equally be used to control other harmful insect plants, especially insects, which damage plants by absorbing them. Compounds can be used to protect both ornamental and industrial crops, especially cotton (t0e. Against Spodoptera
littoralis and Heliothis virescens) as well as the grasses (for example, against Leptinotarsa decemlincata and Myzus
persicae) and rice crops (for example, against Chilo supperessalic and Laodelphak) „
The activity of the proposed compounds is clearly expressed as somatic,
and contact. The compounds of the formula I are very effective against sucking insects, especially against the sucking insects of the Hovnoptera series and most particularly against families.
5 Aphididae (such as Aphis fabae, Aphis craccivora and Myzus persicae), which is difficult to control using known compositions.
The compounds of formula 1 may be
0 has also been used to treat all plant methods (as well as seeds from which such plants grow and the environment containing such plants) in order to protect them from insects, such as those described above in the examples. Such plants include cereals (for example, corn and rice), vegetables (for example, potatoes or soy), fruits or other
0 plants (e.g. cotton).
The compounds of formula I can be similarly used to protect animals from various ectoparasites by applying compounds to animals or to the environment in which animals are found, for example, where the herd is kept, in stalls, in a slaughterhouse, on pasture, and when walking. to any other place that is infected. The compounds may also be applied to the external parts of the animals, preferably prior to infection.
In addition, compounds of the formula
with I are effective against various parasitic worms. These parasites can infect livestock, poultry and pets (such as a pig, sheep, goat, cow, horse, dog, cat and bird) and can cause significant economic damage. Among worms (worms) in particular, serious infections often cause nematodes.
Some parasitic individuals of the genus Nematodirus Cooperia and Ocsophugostomum infect the intestines, while some individuals of the genus Haemonchus and Ostertogia parasitize in the stomach,
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and parasites belonging to the genus Dicty ocaulus are in the lungs. Parasites belonging to the Filar idae and Setariidae families are found in internal tissues and organs, such as the heart, blood vessels, subcutaneous tissues and lymphatic vessels. The compounds of formula I are active against all these parasites.
The compounds of formula I are also effective against parasites that infect humans. Typical parasites that are commonly found in the human food tract are parasites of the genera Ancylostroma, Necator, Ascaris, Strongyloides. Trichinella, Capillaria, Trichuris and Enterobius Compounds are also active against parasites of the genera Wuchereria, Brugia Onchocerca and Loa of the Filariidae family (which are found in blood, tissues and organs other than the alimentary tract, and are important medical). Dracunculus and parasites of the genera Strongyloides and Trichinella, which especially affect the exo-intestinal canal.
The form of the compositions and the nature of the carriers or diluents used in them strongly depends on the actual use of the composition. For example, when the proposed compounds are to be used as antihelmintics, they are preferably used orally, parenterally or topically, and the form of the chosen composition corresponds to the actual route of administration.
For oral administration, the present composition is preferably in the form of a drinking liquid comprising a non-toxic solution or suspension, preferably an aqueous, active compound in admixture with a suspending agent (such as bentonite), a wetting agent or other diluents. Drinking also mainly contains anti-foam agents. The active compound is in the drink in an amount of 0.01-0.5 wt.%, More preferably 0.01-0.1 wt.%.
Compositions for oral administration may also be in the form of dry solids, preferably in dosage form, such as capsules, pills or tablets, containing the target amount of active 5
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foot joint. These compositions can be prepared by mixing the active compound to homogeneity with suitable diluents, fillers, disintegrating agents and / or binding agents, for example starch, lactose, talc, magnesium stearate and vegetable oil. The weight and Q content of the preparation can vary widely depending on the nature of the animal being treated, the degree of infection, the nature of the parasite and the animal body weight of the animal being treated.
The compounds can also be used as an additive to animal feed, in which case they can be uniformly dispersed in the feed, used as a top dressing, or used as a pellet. The content of the active compound in the feed is preferably 0.0001-0.02% in order to achieve the target antitinmintic activity.
For parenteral administration, the compound of formula I is preferably dissolved or suspended in a liquid diluent, preferably in a vegetable oil, such as peanut oil or cottonseed oil. When the compound is used in the form of a salt, the liquid carrier may be water or another aqueous medium. Depending on the animal being treated, the administration can be subcutaneous or in the preventricles, muscle or respiratory tract. Such preparations normally contain the active compound at a concentration of 0.05-50 wt.%.
The compounds of formula I can also be applied topically in a mixture with a suitable carrier, such as dimethyl sulfoxide or a hydrocarbon solvent. Such preparations are applied directly to a part of the surface of the animal by spraying (e.g., with a spray gun or as a spray), wetting (e.g. with a swab), dipping into a solution or manually (e.g. wiping).
5 The dose of active compound may vary depending on the nature of the animal being treated, the nature and degree of steam.
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ziticheskogo infection. However, the best results for oral administration are achieved when the dose is 0.01-100 mg, more preferably 0.5-50 mg per 1 kg of body weight. The compound may be administered in a single dose or in divided doses over a relatively short period, such as 1-5 days.
When the composition of the invention is intended for use in agriculture or horticulture, it is possible to use variously shaped compositions. For example, it can be formed as dusts, coarse dusts, soluble powders, microgranules, fine microgranules, wettable powders, dilutable emulsions, emulsion concentrates, aqueous or oily suspensions or solutions (which can be directly sprayed or diluted), aerosols or capsules, for example, in a polymeric shell. The carriers used may be natural or synthetic or organic or inorganic; the carrier is typically used to provide access of the active compound to the substrate being treated, and in order to facilitate storage, transportation or operation with the active compound. Solid, liquid or gaseous carriers can be used, selected from well-known carriers in this technical field for using compositions of this type. Such compositions can be prepared by standard methods, for example, uniformly mixing and / or grinding the active ingredient (s) with a carrier or diluent, for example, a solvent, a solid carrier or, optionally, a surface active agent.
Suitable solvents include aromatic hydrocarbons, preferably Cg-C fractions of petroleum distillate, such as mixtures of xylene or substituted naphthalenes; phthalic acid esters, such as dibutyl or dioxyethyl phthalate; aliphatic hydrocarbons, such as cyclohexane or paraffins; alcohol and glycols or esters h. sshn dineniy, such as a pokazat, ethylene





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glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether; ketones, such as cyclohexanone; highly polar solvents, such as M-methyl-2-pyrrslidone, dimethyl sulfoxide or N, N-n, HMe tilformamide, optionally epoxidized vegetable oils, such as epoxidized coconut oil or joel oil; and water.
Solid carriers that can be used, for example, in dusts of plip di perfurm chips, include natural general fillers, such as calcite, talc, kaolin, montmorillonite or attapulgitis. In order to improve the physical properties of the composition, it is also possible to add highly dispersed silicic acid or highly dispersed absorbent polymers. Suitable granular absorbent carriers may be porous (such as pumice, crushed brick, sepiolite or bentonite) or non-porous (such as calcite or sand). A wide range of pre-ground organic or inorganic materials can also be used; examples include dolomite and ground plant residues.
Surface-active agents that can be used are well known in this technical field and may be non-ionic, cationic or anionic agents that have good emulsifying dispersing and wetting properties. Mixtures of such agents can also be used.
The compositions may also contain stabilizers, antifoaming agents, viscosity regulators, binders and adhesives, or any combination thereof, as well as fertilizers or other active substances to achieve special effects.
Pesticide compositions will typically contain 0.01-99% by weight, more preferably 0.1-95% by weight of active compound, 1-99.99% by weight of solid or liquid additive and 0-25% by weight, more preferably from 0 , 1-25 wt.% Surface-active agent. Since industrial products are usually solid in the form of concentrated compositions, they are usually diluted before use to a concentration of 0.01-0.001 wt.% (10-1 ppm).
Examples 26-28 demonstrate the activity of the proposed compounds. All separations in column chromatography were performed by gradient elution, in which the eluents were mixtures of hexane and ethyl acetate in the range from 10: 1 to 2: 1.
Example 29. Antigelmintic activity against Dilofilaria imitis.
As test animals, dogs weighing 8-17 kg were used, infected with Dilofilaria imitis. Each dog was orally or subcutaneously injected with a sufficient amount of a composition prepared as described below to provide 0.05 kg of the test compound per
1kg body weight. Test compositions were prepared by mixing 1.0 g of each test compound with 0.1 g of 2,6-di-tert-butyl-p-cresol, 10 ml of dimethylacetamide and enough polyethylene glycol (PEG-400) to make 100 ml
by volume of the drug. A blood test was taken from each dog immediately before applying the composition and then 7 and 14 days after application.
0.02 ml of blood was stained with Giemsa solution and the number of microscopic microscopes was evaluated microscopically and the average of four glass plates was determined.
The results are presented in table 1.
PRI me R 30 Acaricidal action against Boophilus microplus.
Fatted female ticks of the species Boophilus microplus were fixed dorsally with double-sided adhesive tape on polyvinyl chloride panels in rows, each row containing 10 ticks. Each compound of examples 7.9 and 19 was tested as follows.
One series of mites was treated by injection at doses of 0.0005-5 mg of the test compound dissolved in
2 or 1 µl of the solvent per individual. Compound efficacy was evaluated by determining the IRq0 value, i.e. dose, stopping reproduction in 90% of female ticks 30 days after treatment. Based on data from 10
five
0
five
0
five
0
five
0
five
To the ranks of TR, j0, all tested compounds were effective at doses of 0.005-0.05 µg per series of ticks.
PRI me R 31. Acaricidal activity against Tetranychus urt-icae.
Primary sheets of plants of the species Vigna sinensis were infected with mites sensitive to organic phosphates (Tetranychus urticae). One day after infection, infected plants were sprayed with a Hisuho spray in 7 ml portions of the test solution containing the test compound at a concentration in the range of 0.3-30 ppm, at a dose rate of 3.5 mg of the test solution per 1 cmolite. Gastrophees of the day Duration of the examination of the presence of adult ticks using a binocular microscope with the registration of live and dead individuals. Two plants were used for each concentration and each compound. During the test, the plants were kept in a greenhouse at 25 ° C.
The results are presented in table 2.
Comparative tests of compounds of the formula I and known analogues in structure and action.
The compounds of examples 9 and 10 show IR 0 activity at doses of 0.05 ppm and 0.005 h / ml, respectively, against Boophilus microplus (the activity value at 11C0, which is the dose that in 90% of the ticks cease reproducing after processing.).
In contrast, the known compounds 13-fluoromylbemycin A show IRa0 activity at doses of 0.5 ppm and 0.05 ppm, respectively, i.e. effective dose of known compounds is 10 times higher than that of compounds I.
In Example 28, test data are given for compounds of Examples 15,16,18, 19,20,21,22, and 23, which are esterified with oxime derivatives. At the same time, it is obvious that their activity does not depend on the form in which they are present, in the form of acids or in the form of esters. Having an active principle, their esters with other acids are also active.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining the derivatives of 13-halo-imidhemycin of general formula I
Rj is methyl, ethyl or isopropyl; X is a halogen atom, Y is an oxygen atom or a group of the general formula
N-ORЈ, where R is a hydrogen atom, C, -C6-alkyl, their salts, or their esters, characterized by the fact that the general formula II
CHi BUT
H3S
where R has the indicated meanings;
Z is either an oxygen atom, or a hydroxy group and a hydrogen atom, is halogenated with a halogenating agent to replace the hydroxy group in the 13 position by a halogen atom and in the case when the Z-hydroxy group and the hydrogen atom, the corresponding compound with manganese dioxide; and the compounds of formula I are isolated, where Y is an oxygen atom, or are subjected to lysis with a compound of formula III.
K2OMNg
where Rg has the indicated values, if R is a hydrogen atom, and if necessary with its ester, and the compound of formula I is isolated, where Y is a group of the formula NOR2, or, if R2 is a hydrogen atom, it is converted into a salt or complex ether.
Table 1
thirty
The mortality rate at the dose, h / m
zziizii :::::;
98
Table 2
35
89
80
100
100
100
100
100
100
80
98
97
36 55 63 56 33 83 87 89 45 55 Y
21
1: 5-ketomylbemycin A .;
2: 5-ketomylbemycin A oxime;
3: 5-ketomylbemycin A4.5-0-M, M dimethylcarbamoyl / - oxime; 4: 5-ketomylbemycin A4 5-0-pivaloyl oxime.
153714022
Continuation of table 2

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法律状态:
2005-01-10| REG| Reference to a code of a succession state|Ref country code: RU Ref legal event code: MM4A Effective date: 20020531 |

优先权:

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申请号 | 申请日 | 专利标题

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JP11862985|1985-05-31|

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