前苏联专利SU1560059A3 Method of producing avermectine derivatives

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专利摘要:
The invention provides novel compounds having the formula: wherein the broken line at the 22-23 position represents an optional double bond and wherein R' is H or OH and the double bond is absent, or, the double bond is present and R' is absent; R2 is an alpha-branched C3-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group; a C3-C8 cycloalkyl, C5-C8 cycloalkenyl or C5-C8 cycloalkylalkyl group, any of which may optionally be substituted by methylene or one or more C1-C4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may optionally be substituted by one or more C1-C4 alkyl groups or halo atoms; R3 is hydrogen or methyl; R4 is H or 4'-(alpha-L-oleandrosyl)-alpha-L-oleandrosyloxy, with the proviso that when R2 is alkyl it is not isopropyl or sec-butyl, and when R4 is H, R1 is OH, and the double bond is absent, R2 is not 2-buten-2-yl, 2-pentene-2-yl or 4-methyl-2-pentene-2-yl. The compounds are broad spectrum antiparasitic agents having utility as anthelmintics, ectoparasiticides, insecticides and acaricides. The invention also provides a process for producing the novel avermectin and milbemycin derivatives by adding a carboxylic acid or derivative thereof to a fermentation of an avermectin or milbemycin producing organism.
公开号:SU1560059A3
申请号:SU864027887
申请日:1986-07-25
公开日:1990-04-23
发明作者:Пол Гибсон Стив；Скотт Холдом Келвин；Кроссан Гоуди Александр；Десмонд Бу Лок Джон
申请人:Пфайзер Корпорейшн (Фирма)；
IPC主号:

专利说明:

This invention relates to the microbiological industry, in particular the production of antibiotics.
For carrying out the method, a strain of Streptomyces averraitilis NCI B 12121 is used, which is characterized by the following properties.
Cultural-morphological signs.
Spore chains on 1SP4 medium.
Sulfur pigmentation of aerial mycelium on JSP 4 medium.
The lack of clear pigmentation of the substrate mycelium on 1SP 4 medium. The absence of diffusible pigment on the ISP 5 medium.
Melanin formation on 1 SP 6; peptone yeast gel agar. Biochemical properties.
Enzyme activity:
s
Nitrate ReductionEducation
Hippurate Hydrolysis Degradation Products: Guanine
Urea +
Allantoiin +
Growing temperature: 45 ° C
Growth in the presence of: 7% sodium chloride + O, 1% phenol +
O, 0001% tellurium potassium +
Growth on a single source of nitrogen (0.1 wt./vol.%))
L-Cysteine +
L-valin +
L-Phenylalanine +
L-Histidine +
L-Hydroxyproline Potassium Nitrate
Growth on a single carbon source (1 w / v%):
L-Arabinose +
Sucrose +
D-Xylose +
meso-inositol +
Mannitol +
D-Fructose +
L-rhamnose +
Raffinose +
D-Laktoea
Salicin D-Melibiosis +
Sodium acetate
(0.1% w / v) +
Propinnatry
(0.1% wt.%) "
Pyruvate sodium (0.1% w / v) +
(ISP - environments according to the international project on streptomycin (ISP)).
Example 1. Getting 25-cycle lopentyl-avermectin A2.
Suspension of culture on S.avermitilis NCI B 12121 oblique agar is cast in 600 ml of medium containing lactose (12.0 g), bard (8.0 g) and yeast extract (3.0 g) in a three-liter flask, and incubated at 28 for 3 days. This inoculum is used to inoculate 16 L of srd containing soluble starch (640 g), ammonium gulyate (32 g), vtric acidic potassium phosphate (16 g), sodium chloride (16 g), manna 7HO (16 g), calcium carbonate
0
five
0
five
0
five
0
(32 g), soluble yeast extract (6.4 g), iron (II) sulbate x 7Ht 0 (0.016 g), pink sulphate 7 H2O (0.016 g) and CO manganese chloride, 01 6 g), in twenty-liter syrene- tere. The fermented mass is incubated at 28 ° C with stirring at a rate of 250 vol. minutes and serves air at a rate of 15 l / min. The sodium salt of cyclopentacarboxylic acid (1.6 g) is added after 24 hours, and again after 28 and 72 hours of incubation, and the fermentation is continued for 120 hours. After this time, the mycelium is removed by filtration and extracted with acetone: 1N. hydrochloric acid (100: 1, l). The extract obtained is concentrated to approximately 2 L under reduced pressure and extracted with methylene chloride (L). The methylene chloride extract is concentrated to dryness to give the crude product as a mobile oil, which is dissolved in diethyl ester and introduced into a column With silica gel (1 kg). The column was eluted with diethyl ether, collected from 100 ml each. Fractions 20-40 are combined, and the solvent is evaporated, yielding substantially purified material. The product is dissolved in a mixture of methanol and water (4: 1) and chromatographed on a CIS Micro-Bqndapack column (50 cm) in a high-performance liquid chromatograph using the same solvent at a flow rate of 100 ml / min. Fractions 35-50 containing the desired product are combined and rechromatographed on a C18 Zorbax ODS column (21 mm 15 cm), eluting with a mixture of methanol and water (4: 1) at a flow rate of 9 ml / min. The appropriate Lrachia are combined and the solvent is evaporated to give the compound of the formula
AT
50
(one)
where R1 is OH, double bond notes; R4 is cyclopentyl; RS CF3; 4 4- (appalaz-ole and ros sil) -alpha-Z-o le e ro ro il-s,
CH3 x (2)
LO but - - o-h b
sneo sns °
in the form of a white powder with so pl. 150.5-151 ° C. The structure of the product is confirmed by mass spectrometry and NMR data.
WITH.
The fast atom bombardment Mace spectrometry was carried out on a VG model 7070E mass spectrometer using a tri-ethylene glycol matrix with solid sodium chloride, (M + Na) 4 observed at x / e 939 (theoretically 939). Mass spectrometry of an electron impact is carried out on a VG Model 707OF mass spectrometer. The values of t / e for the main Fragments are as follows: 335, 3J7, 275, 25J, 205, 181, J79, J45, 127, 413, 1Л, 96 and 87
NMR C data was obtained on a Brooker Model T1-250 spectrometer for a sample with a concentration of 20 mg / m in deutero-chloroform. Chemical shifts in ppm with respect to tetramethylsilane: 14.1; 15.3; 17.8; 18.5; 19.9; 20.3; 24.6 $ 25.9; 26.2; 29.3; 34.4 (2C), 34.7, 36.7; 37.8; 39.8; 40.5; 41.0; 41.3; 45.8; 56.4; 56.6; 57.8; 67.4; 68.0; 68.7; 69.9; 70.5; 76.0; 77.6 (2C), 78.3; 79.5; 80.7 (2C); 81.8; 94.9; 98.7; 99.8; 117.7; 118.5; 119.8; 125.0; 135.8; 136.3; 137.8; 160.1 173.8.
Example 2. A culture suspension on oblique agar S.avermitilis ATCC 31271 is inoculated in 50 ml of medium containing lactose (1.0 g), bard (0.75 g) and yeast extract (0.25 g) in a 350 ml flask and incubated at 28 ° C for 3 days. This inoculum (4 ml) is used to incubate each of the 50 flasks containing corn starch (2.0 g), soy flour (0.35 g) and yeast extract (0.25 g) with a volume of 350 ml, which is incubated at 28 C.
After 24 hours, sodium cyclopentacarboxylic acid (5 mg) is added to each flask and incubation is continued for the next 5 days. After this, the contents of the flasks are removed and the mycelium is separated.
0
five
0
0
five
with
by niem. The resulting mycelium is extracted with a mixture of acetone: 1N. hydrochloric acid (100: 1) and the acetone extract are concentrated to dryness. The extract is analyzed by high performance liquid chromatography and shows that it contains a product identical to the product of example 1.
Example 3. The inoculum of example 1 is prepared and used to inoculate 50 ml of medium as in example 1, enclosed in a 350 ml flask. After incubation for 24 h, 2-amino-cyclopethyl-acetic acid (cyclopentylglyini) (5 mg) is added and fermentation is continued for another 5 days. The resulting product is isolated, extracting mycelium with acetone and methylene chloride. The extract is analyzed by high performance liquid chromatography, the data of which indicate that the product contains a compound identical to the product of example 1.
Example 4. The reproduction of the conditions of Example 3, except that cyclopentylmethanol was used as a substrate with similar results.
Example 5. The reproduction of the conditions of Example 3, except that cyclopentacarboxylic acid methyl ester was used as a substrate with similar results.
EXAMPLE 6 The reproduction of the conditions of Example 3, except that cyclopentane carboxylic acid dissolved in methanol was used as a substrate, with similar results.
Example 7. Preparation of 25- (Thien-3-yl) -Avermec Tin.
A suspension of culture on S.avermitilis NCIB 12121 oblique agar is inoculated in 600 ml of medium containing lactose (12.0 g), bard (8.0 g) and yeast extract (3S0 g) in a three-Q liter flask and incubated at 28 ° C for 3 days. This inoculum is used to inoculate 16 L of medium containing soluble starch (640 g), ammonium sulfate (32 g), secondary acidic potassium phosphate (16 g), sodium chloride (16 g), magnesium sulfate (16 g), calcium carbonate (32 g), soluble yeast extract (6.4 g), ferrous sulfate (7NO) (0.016 g),
five
0
five
71560059
zinc sulphate 7Н70 (0.016 g) and manganese chloride (0.016 g) located in a twenty-liter fermenter. The fermented mass is incubated at C with stirring at a speed of 250 rpm and air is supplied at a rate of 15 l / min. After 24 hours, thiopheng-carboxylic: acid sodium salt (1.6 g) is added, this addition is
thirty
ten
repeated after 48 and 72 hours, and Fermentationio is continued for 120 hours. Next, the mycelium is removed by filtration and extracted with a mixture of aieton: 1N. hydrochloric acid (100: 1.3x7 l). The resultant extract was concentrated to approximately 2 liters under reduced pressure and extracted with methylene chloride (2–5 liters). The methylene chloride extract is concentrated to dryness to give the crude product as a mobile oil, which is dissolved in diethyl ether and introduced into a silica gel column (1 kg). This column was eluted with diethyl ether, collecting aractions of 200 ml each. Fractions 32-45 are combined and the solvent is evaporated. Before a partially purified material is obtained. The product obtained is dissolved in a mixture of methanol and water (3: 1) and chromatographed on a CIS Micro Bonda-pack column (50 cm) in a high-performance liquid chromatograph using the same solvent at a flow rate of 100 ml / min. Fractions 27-36 containing the desired product are combined and rechromatographed on a CJ8 Zorbax ODS column (21 mm x 25 cm), eluting with a mixture of methanol and water (3: 3) at a flow rate of 9 ml / min. The appropriate fractions are combined and the solvent is evaporated to give the compound of formula (1), where RJ is OH, there is no double bond, R is thienyl-3-yl, K, is CHj, and R. 4 is 4 - (alpha-2- Oleandrosyl) -bala-2-oleondrosiloxy (2) in the form of a white powder with m.p. 167 C. The structure of the product is confirmed by mass spectrometry data as follows.
Mace spectrometry with fast electron bombardment was carried out on a VG model 7070F mass spectrometer using a triethylene glycol sample matrix with solid sodium nitride. (M + Na) is observed at ha / e - 953 (theorem 953).
Mace spectrometry of electron impact is carried out on a mass spectrometer
35
40
45
50
55
VG but 33 19
then 12
on Inla Druchu 30 niku sra pv dl s me 35 1 (n g ff (to the same number i l m sh a r and p el a p tk o (s
eight
VG model 7070F. The t / e values for the main fragments are as follows: 349, 331, 275, 265, 257, 247, 237, 219, 195.145, 127, 113, 95, and 87.
Example 8. Vegetative cell suspension S-avermitilis NCIB 12121 stored at -60 ° C at 10%
five
0
5 Q
five
0
five
0
five
volume / volume of aqueous (2 ml) glycerol, inoculated into 50 ml of medium containing lactose (1.0 g), bard (0.75 g) and yeast extract (0.25 g) in a 30.0 ml conical flask and incubated at 28 ° C for 24 hours with shaking. The inoculum is then added to 600 ml of this medium contained in a three-liter flask, and the mixture is incubated at 28 ° C for 24 hours with shaking. The resulting product was used to inoculate 10 liters of this medium, which was in a 1.6-liter Lörmentere, and incubated for 24 hours at 28 ° C and a stirring speed of 350 rpm with aeration at a rate of 10 l / min. This fermentable mass (600 ml) is used to inoculate 16 liters of medium containing partially hydrolyzed starch (640 g), ammonium sulfate (32 g), potassium hydrogen phosphate (16 g), sodium chloride (16 g), magnesium sulfate 7H40 (16 d) calcium carbonate (16 g), soluble yeast extract (6.4 g), iron (II) 7H20 sulfate (0.016 g), zinc sulfate (0.016 g), and manganese chloride (0, OJ6 g) contained in 20 liter fermenter. The fermented mass is incubated at 28 ° C with stirring at a speed of 350 rpm and aerated at a rate of 15 l / min. After 24 hours, the sodium salt of cyclobutanecarboxylic acid (1.6 g) is added and this addition is repeated after 48 and 72 hours of incubation, and Lementation is continued for J20 hours. After this period of time, the mycelium is removed by filtration and extracted with acetone ( ). This extract is concentrated to approximately 2 L under reduced pressure and extracted with methylene chloride (2 x 5 L). The utechylene chloride is condensed to dryness to give the crude product as a mobile oil. It is placed in isooctane (150 ml), and the solution is extracted with a mixture of methanol (95 ml) and water (5 ml). After evaporation of the methanol extract, a partially purified product is obtained.
The material was divided into individual components by high performance liquid chromatography as follows.
The residue obtained is dissolved in a small amount of methanol and a C-6 Micro-Bondapack chromatography chromatograph (50 mm "50 cm} on a high performance liquid chromatograph using a mixture of methanol / water (4: 1) at a flow rate of 100 ml / min. Fractions - 4 is combined and used in example 9, fractions 5-9 are combined and used in example 10, fractions 1.0-19 are combined and used in example 1-1, and fractions 20-35 are combined and used in example 12.
Example 9. Preparation of 25-ibobutyl-avermectin B2 (R, OH,).
The combined fractions 1-4 of example 8 are evaporated to dryness and the residue is rechromatographed on a CIS Zorbax ODS column (21 cm), eluted with a mixture of methanol and water (3: 1) at a flow rate of 9 ml / min. The appropriate fractions are combined, the solvent is evaporated and the product obtained is subjected to final purification on a column (10.5 cm), eluting with a mixture of methylene chloride and methanol (98: 2) at a flow rate of 4 ml / min. The appropriate fractions are combined and the solvent is evaporated to give the compound of formula (I), where C is OH, there is no double bond, R is cyclobutyl, RS is H, and R4-4 is (alpha-g-oleandrosyl) alpha g oleandrostox (2) in the form of a white powder with so pl. 1JO-112 ° C
The structure of the obtained product was confirmed by mass spectrometry as follows.
Fast electron bombardment face spectrometry was performed on a VG model 7070E mass spectrometer using a triethylene glycol sample matrix with solid sodium chloride (M + + Na) was observed at m / e 91J (theoretically 91 i).
Electron impact Mace spectrometry was performed on a VG Model 707OF mass spectrometer. Values u / e for the main fragments: 321, 303, 26J, 257.237, 219, 209, J 91 f JJ9,
167,145, J27, J13, 1JI, 95 and 87.
Example 10. Preparation of 25-cyclobutyp-avermectin A2 (ROH,)
Combined fractions 5-9 of example 8 are evaporated to dryness, and the residue
ten
20
jc
25 h.
l 35
45
50
.
60059Y
chromatographed twice on a CIS Zorbax ODS capsule (21 mm x 25 cm), eluted with a mixture of methanol. and water (77:25) with a flow rate of 9 ml / min. The corresponding Fractions are combined to Gchgaa to form a compound of the formulas ;, (1), where Rf is OH, there is no double bond, R is cyclobutyl, Ke is CH3, and K 4 is 4 - (al-fa- oleandrosyl) -alc -2, - epeandros 1-loxy (2) in the form of a white powder with m.p. 135-14 ° C.
The structure of the product is confirmed by mass spectrometry as follows.
Fast electron bombardment mass spectrometry sweat on a VG model 7070E mass spectrometer using a triethylene glycol sample matrix with solid sodium chloride (M + + Na) + was observed at m / e 925 (theoretically 925).
Electron impact nass spectrometry was performed on a VG model 7070F spectrometer. The values of t / e for the main Fragments follow. Junze are: 596, 454, 321, 303, 275, 237, 219, 191.179, 167, 145, 127, 133, ill, 95 and 87.
Example I. Preparation of 25-uhK lobutyl-avermectin B1 (there are 22.23 double bonds, R3 H).
The combined fractions 10-19 of example 8 are evaporated to dryness, and the residue is dissolved in methanol and chromatographed on a C18 Zorbax ODS column, eluting with a mixture of methanol and water (4: 1) at a flow rate of 9 ml / min. The appropriate fractions are combined and the solvent is evaporated to afford a product, which is rechromatographed on a Silica Zorbax SIZ column (21 mm 25 cm), eluting with a mixture of dichlrrmethane and methanol (98.5: 1.5) at a flow rate of 9 ml / min. The appropriate fractions are combined and the solvent is evaporated to form a compound of formula (1), where R is absent, a double bond is present, R g is cyclobutane, R3 is H, aR4-4 - (aly a-oleandrosyl) alpha-oleandrosiloxy, in white powder with t.pp. . The structure of the obtained product was confirmed by mass spectrometry as follows.
Mace spectrometry with fast-electron bombardment is carried out on a VG model 7070E mass spectrometer using a sample matrix of three 11
,five
15
ethylene glycol and solid sodium chloride (M + Na) + is observed at r / e 898 (theoretically 803)
Mace electron spectrometry was carried out on a VG model 7070E mass spectrometer. The values of ta / e for the main fragments are as follows: 303, 261, 257, 219, 391, 1 $ 7, L27, 113, 111, 95, and 87. tO
Example 12. Preparation of 25-cyclobutyl-avermectin A1 (there is a double bond 22.23 RS CH3).
The combined fractions 20-35 of example 8 are evaporated to dryness and the residue is chromatographed on a C18 Zor-bx ODS column (21 cm) at a flow rate of 9 ml / min. The appropriate fractions are combined, the solvent is evaporated, and the product obtained is repeated — Q is chromatographed on a 5 μm Silica Sperisorb column (10.5 mm “25 cm), eluting with a mixture of dichloromethane and methanol (98.5: 1.5) at a flow rate of 4 ml / min
By combining the appropriate fractions, followed by evaporation, a compound of the formula (1) is obtained, where R is absent, a double bond is present, Ig is shklobutyl, R-androsiloxy,
12 as a white powder
25
from m.p. 131-5 C.
The structure of the obtained product was confirmed by mass spectrometry as follows.
Mace spectrometry with fast electron bombardment is carried out on a VG model 7070E mass spectrometer, using a sampler triple ethylene glycol with solid nitrihloride (M + Na) 1 used at We 951 (theoretically 951.).
. Electron impact mass spectrometry was carried out using a VG model 7070F mass spectrometer. The t / e values for the main Fragments are: 624.480, 347, 329, 375, 263, 245, 235, 217, 205.193, 179, J45, 127, 113, 111, 95, and 87.
Example 14. Preparation of 25-cyclohexyl avermectin A2.
Reproduce the medium and conditions of Example 1 with the exception that the sodium salt of cyclohexanecarboxylic acid is used as a substrate to obtain the compound of formula (1), where R ,, is OH, R is cyclohexyl, RJ is CH, a R. - 4 - (alpha-oleandroxyl) -alAlCH3, a Rq 4- (alpha-Z-oleandrosyl) -alpha-oleandrosiloxy, in the form of a white powder with m.p. 120-124 ° C. The structure of the obtained product was confirmed by mass spectrometry as follows.
A fast electron bombardment mass spectrometry is carried out on a VG model 7070E mass spectrometer using a matrix of a sample of triethylene glycol with solid sodium chloride. (M + Na) + is observed at m / e 907 (theoretically 907).
Mace spectrometry of electron impact is carried out on a VG model 707OF m spectrometer. The values of t / e for the main fragments are: 578, 303, 2755 257, 219, 191, 167, 145, 127, 113.1 P, 95 and 87.
Example 13. Obtaining 25- (cyclohex-3-enyl) avermectin A2.
Reproduce the medium and conditions of Example 1, except that the salt of 3-cyclohexanoic acid is used as a substrate to form a compound of formula (1), where R ,, is OH, there is no double bond, cyclohex-3-enyl , R3 - CH3, a R 35
40
Rl3Q Z-oleandrosiloxy, in the form of a white powder with so pl. A2-117 ° C.
The structure of the obtained product was confirmed by mass spectrometry as follows.
A fast electron bombardment mass spectrometry is performed on a VG model 7070E mass spectrometer using a triethylene glycol sample matrix with a solid sodium chloride. (H-Wa) is observed at m / e 953 (theoretically 953).
Mace electron spectrometry was carried out on a VG model 7070F mass spectrometer. The t / e ds values for the main fragments are: 624.482, 349, 331, 275, 265, 247, 237, 219, 207.195, 179, 145, 127, 113, 111, 96, and 87.
Example 15. Preparation of 25- (1-methylthioethyl) avermectin A2.
Reproduce the medium and conditions of Example 1 with the exception that the sodium salt of 2-methylthiopropionic acid is used as a substrate to obtain a compound of formula (1), where R ,, is OH, R.Ј is 1-methylthioethyl, RJ 50
55
SNE, a R4-4 - (alpha-g-oleandroxyl) - alpha-g-oleandroxyloxy in the form of white - 4 (- (alpha - α - oleandrosyl) - alpha z - oloh powder with mp 134-138 ° s
1560059
androsyloxy,
12 as a white powder
five
15
tO
Q
25
from m.p. 131-5 C.
The structure of the obtained product was confirmed by mass spectrometry as follows.
Mace spectrometry with fast electron bombardment is carried out on a VG model 7070E mass spectrometer, using a sampler triple ethylene glycol with solid nitrihloride (M + Na) 1 used at We 951 (theoretically 951.).
. Electron impact mass spectrometry was carried out using a VG model 7070F mass spectrometer. The t / e values for the main Fragments are: 624.480, 347, 329, 375, 263, 245, 235, 217, 205.193, 179, J45, 127, 113, 111, 95, and 87.
Example 14. Preparation of 25-cyclohexyl avermectin A2.
Reproduce the medium and conditions of Example 1 with the exception that the sodium salt of cyclohexanecarboxylic acid is used as a substrate to obtain the compound of formula (1), where R ,, is OH, R is cyclohexyl, RJ is CH, a R. - 4 - (alpha-oleandroxyl) -alla
Z-oleandrosiloks, in the form of a white powder with so pl. A2-117 ° C.
The structure of the obtained product was confirmed by mass spectrometry as follows.
A fast electron bombardment mass spectrometry is performed on a VG model 7070E mass spectrometer using a triethylene glycol sample matrix with a solid sodium chloride. (H-Wa) is observed at m / e 953 (theoretically 953).
Mace electron spectrometry was carried out on a VG model 7070F mass spectrometer. The t / e values for the main fragments are: 624.482, 349, 331, 275, 265, 247, 237, 219, 207.195, 179, 145, 127, 113, 111, 96, and 87.
Example 15. Preparation of 25- (1-methylthioethyl) avermectin A2.
Reproduce the medium and conditions of Example 1 with the exception that the sodium salt of 2-methylthiopropionic acid is used as a substrate to obtain a compound of formula (1), where R ,, is OH, R.Ј is 1-methylthioethyl, RJ
SNE, a R4-4 - (alpha-g-oleandroxyl) - alpha-g-oleandroxyloxy as a white powder with m.p. 134-138 ° C.
The structure of the obtained product was confirmed by the mass spectrum metrically as follows.
Fast electron bombardment spectrometry was performed on a VG Model 7070E mass spectrometer using a matrix of a sample of triethylene glycol with solid sodium chloride, (M + Na) was observed at temperature 945 (theoretically 945).
Waste electron impact spectrometry was carried out on a VG model 7070F mass spectrometer. The value of tl / e for the main fragments are 341, 323, 275, 257, 239 2JI, J79, 187, 145, 127, PZ, JJJ, 95 and 87.
Example 16. Getting 26- (2- methylcyclopropyl) avermectin A2,
Reproduce the medium and conditions of Example 1 except that the sodium salt of 2-methylcyclopropanecarboxylic acid is used as a substrate to obtain the ENT compound.
mules (1), where cyclopropyl,
Ri Kz OH, Kg - 2-methyl- CHj, R4 - 4- (alpha-Z-oleand ros yl) -alpha-Z-oleandroxyloxy, in the form of a white powder with m.p. 147-150 ° C.
0
0
five
five
va, 2-methyl-pectanova, 2-picl-proclc-propionic, iiklohechtankarO) oval, 4,4-difluorocyclog xancap- bonone, 4-methylcyclohexanecarboxylic, 3-cytylcyclohexanecarboxylic, cyclopentene-3 carboxylic acid, 3-cytylcyclohexanecarboxylic, cyclopentanecarboxylic acid, 3-cytylcyclohexanecarbonic acid, cyclohexanecarboxylic acid, 3-ketacyclohexanecarboxylic acid, cyclohexanecarboxylic acid, 4-difluoro-cyclo-xylohexanecarboxylate tetraparidrol Iran-4-carbonIB thiophene-2-carboxylic, 3 ™ leryluxusna and 2-chloro-thio (Len-4-carboxylated.
Example 18. Getting 25-cycle lobutyl-22,23-dihydroavsrmektin B1.
The product of Example 1 1 in benzene is hydrogenated in the presence of tris (trignylphosphine) apium chloride according to the method EPA-A - 0001689 to obtain the corresponding compound of Formula (1), where H is and no double bond is present.
Example 20 Liquid composition
The product obtained by the method of any of the preceding examples was dissolved in polyethylene glycol (average molecular weight 300) to obtain a solution containing 400 µg / ml for use as a liquid composition.
Example 21. Antihelminthic activity assessed against Sae
The structure of the obtained product is under 30 norhab ditis elegans, using in
vitro screening test. The products of examples 1, 7, 9-16 kill 100% black vey in a concentration of 0.1 mg / ml.
This is indicated by mass spectrometry as follows.
Fast electron bombardment jiacc spectrometry was performed on a VG model 707 OE mass spectrometer, USING the matrix of the sample of triethylene glycol with solid sodium chloride, (M + Na) 4 was observed at ha / e 925 (theoretically 925).
Electron impact mass spectrometry was carried out on a VG model 7070F mass spectrometer. The t / e values for the main fragments are: 596, 454, 303, 275, 237, 219, 209, 191, 179, 167, U5, 127, 113, 111, 96, and 87.
Example 17. Reproduce the method of Example J except that the sodium salts of the following carboxylic acids are used as the substrate together with cyclopentacarboxylic acid, to obtain the corresponding 25-substituted avermectins of formula (1), where Rf is OH, there is no double bond or where there is a double bond, and T1 is absent, R, - H or OH, a 4 - (alcBa-oleandrosyl) -, alpha-Z-oleandro-ploxy: 2-methylvalerian, 2,3-dimethylmasl, 2 - methylhexane, 2-methylpent-4-eno-
norhab ditis elegans using in
vitro screening test. The products of examples 1, 7, 9-16 kill 100% black vey in a concentration of 0.1 mg / ml.
Example 22. Fabulous thicidal activity.
Activity against an adult domestic fly Musca domestica is demonstrated using a standard test procedure in which flies are anesthetized with carbon dioxide and O, I μl of acetone containing the test compound is placed on the thorax of female flies. The products of examples 1.7 and 9-16. All kill 100% of the treated flies in doses of 0.01 μg per fly.

权利要求:
Claims (6)
[1]
Using the method allows to obtain drugs with a broad spectrum anti-parasitic effect. Invention Formula
J. Method for preparing avermectin derivative of general formula I
to,
CH3
CHS
151560059
dashed line in position 22z t t
ten
3 represents a possible double bind;
Rt is H or OH and there is no double bond at position 22-23 or a double bond is present and absent
Rt alpha branched C3-C «is alkyl with the proviso that it is not isopropyl or secondary butyl, alkenip, alkynyl, alkaline to yl, il and alkylthioalkyl group, and alkyl and alkylalkyl groups in which the alkyl group represents an alpha branched C-C is an alkyl group, or a Cj-C-cycloalkyl, or a C J. -C g-cycloalkynyl jn group, at. any id of them can be replaced by methylene or one or more C ,, -C 4, -alkyl sludge and g groups, or haloatoms, or thienyl-25 group ,;
R3 is H or CH e;
R4-4 - (/ - g-oleandrozil) / - 2 oleandrosyloxy group of formula 30
sixteen
five
0
five
concluding that Strepomyces avermitilis NCIB 12121 strain is cultured in a nutrient medium in the presence of a carboxylic acid total
° PMy ™ R, C02H,
or its sodium salt, or its methyl ester, and the desired product of general formula I is isolated, where R 1 is OH and there is no double bond at position 22-23 or there is a double bond and there is no Rf and, if necessary, the last compound is reduced obtaining the desired product, where R is H and there is no double bond.
[2]
2. The method according to claim, characterized by the fact that RI means a C, -, or C-cycloalkyl or cycloalkenyl group, which if necessary can be replaced by one or more G C 1 -C 4 alkyl groups.
[3]
3. A method according to claim 2, wherein R-i is cyclopentyl or cyclohexyl.
[4]
4. A process according to claim 1, wherein R h is cyclobutyl.
[5]
5. The method according to claim 1, wherein R.J is 3-thienyl.
[6]
6. A method according to claim, wherein R .31 is 1-methylthioethyl.
P p and o p and there:
07.27.85 - on PP. 2 and 3J
05/02/86 on P.A .;
09.08.85- according to claim 5;
04/24/86 - according to claim 6.
em on point

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同族专利:

公开号 | 公开日

CN1007266B|1990-03-21|

NO165881C|1991-04-24|

AU6056986A|1987-05-14|

YU134186A|1987-12-31|

NO863014L|1987-01-28|

HK65793A|1993-07-16|

MA20746A1|1987-04-01|

NO165881B|1991-01-14|

PH23081A|1989-04-10|

HUT44081A|1988-01-28|

EP0214731A3|1987-07-22|

NO1995009I1|1995-11-17|

EP0214731B1|1991-01-02|

PL260806A1|1987-11-16|

NL950011I1|1995-12-01|

NO863014D0|1986-07-25|

AU572402B2|1988-05-05|

CA1339480C|1997-09-30|

PL153429B1|1991-04-30|

ES8800986A1|1987-12-01|

IE58640B1|1993-10-20|

OA08370A|1988-02-29|

DE3676396D1|1991-02-07|

FI87367B|1992-09-15|

ES556466A0|1987-12-01|

EP0214731A2|1987-03-18|

FI87367C|1992-12-28|

YU44294B|1990-04-30|

IL79523A|1990-02-09|

DK353486A|1987-01-28|

BG46601A3|1990-01-15|

NL950011I2|1997-03-03|

CN86105218A|1987-03-04|

US5089480A|1992-02-18|

LU88788I2|1996-11-05|

GR861965B|1986-11-26|

IE861983L|1987-01-27|

PT83070A|1986-08-01|

NZ216980A|1988-10-28|

CY1719A|1994-05-06|

HU195856B|1988-07-28|

UA6345A1|1994-12-29|

DK169036B1|1994-08-01|

JPH0637501B2|1994-05-18|

AP8600040A0|1986-08-01|

AP37A|1989-03-11|

PT83070B|1989-02-28|

DK353486D0|1986-07-25|

SK278513B6|1997-08-06|

US5451511A|1995-09-19|

JPS6229590A|1987-02-07|

FI863065A0|1986-07-25|

FI863065A|1987-01-28|

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法律状态:

优先权:

申请号 | 申请日 | 专利标题

GB858518999A|GB8518999D0|1985-07-27|1985-07-27|Antiparasitic agents|

GB858520069A|GB8520069D0|1985-08-09|1985-08-09|Anti-parasitic agents|

GB868610063A|GB8610063D0|1986-04-24|1986-04-24|Antiparasitic agents|

GB868610862A|GB8610862D0|1986-05-02|1986-05-02|Antiparasitic agents|LV931372A| LV5626A3|1985-07-27|1993-12-23|Achievement of Avermectin Derivative Acquisition|

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