Method of producing polycyclic ester antibiotic or its pharmaceutically acceptable cation salt

专利摘要:
A new acidic polycyclic antibiotic UK-61,689 has the formula: or a pharmaceutically acceptable cationic salt thereof. The antibiotic and its cationic salts are active against a variety of microorganisms and are effective in controlling coccidiosis, enteritis and swine dysentery as well as being effective in promotion of growth and/or improving efficiency of feed utilisation in swine and ruminants.
公开号:SU1510718A3
申请号:SU874203084
申请日:1987-07-31
公开日:1989-09-23
发明作者:Кроссан Гоуди Александр；Дерек Артур Волш Найджел
申请人:Пфайзер Лимитед (Фирма)；
IPC主号:

专利说明:

mules
OSI,
soon
CH,
qHbJ
SNS
The invention relates to a method for producing a new polycyclic essential antibiotic IR-61.689 G (LC, 4S, 5S, 6R, 7S, 22S, 2S, 5S, 6R) - / 22,27-didetoxy-2,6,22-tridemethyl-5, 11-di-0-dimethyl-6-methoxy-22 - / - (tet-, raguidro 5-methoxy-6-methyl-2H-pyran-2yl) -oxy-lomomycin A7, which exhibits strong anticocciidal activity and It can be used to treat many infectious animal diseases.
I The purpose of the invention is to obtain a new antibiotic with valuable

cm
315107184
biologically active properties of 1.25 hours. The reaction mixture is poured into
and less toxicity. Separation funnel, lower oil. Example 1. To a solution, a 15.0 g layer is removed and mixed with dopol (0.0147 ol) pure antibiotic with an acetonitrile-58.8852 mixture in acetonitrile / water / nitrile / water 95: five. Acetonitrile-water
() (400 ml) were added 3.07 layers were combined and treated with sat (0.0161 mol) p-toluenesulfonate with aqueous bicarbonate (400 ml),
acid. The reaction is controlled by a mixture. The mixture is then concentrated to a dense.
thin-layer chromatography to Textosiropa under vacuum, dissolved in
pores until optimal mixture of diethyl ether / ethyl acetate
The yield of the desired product is about 3: 1 (21) and washed with saturated water for 3 hours. The reaction mixture is treated with sodium bicarbonate. Organic and solid solid or aqueous bicarboxylic layer is dried over sulfate
sodium hydroxide and evaporated in vacuo to 15 sodium and concentrate to a full kodo of dry residue. Formed solid brown oil. The purification is usually carried out by dissolving the substance in diethyl watered with a countercurrent extra ether and washed with saturated water. When extracting a mixture is used.
sodium bicarbonate solution, 1: 1 bicar-hexane / ethyl acetate as non-washings are extracted with diethyl-polar phase and a mixture of methanol / water
lovy ether and all ether layers of volume 3: 2 as the polar aqueous phase.
Drain and wash successively. Evaporation of the organic extracts with water and saturated sodium chloride. gives a plastic solid, the ether solution is dried over non-triturated with isopropyl sodium sulfate and evaporated with 2 $ ethyl ether, yielding IR-61.689 in
under vacuum to dryness. Sodium salt form, 10 g, so that the reaction product is 17069 following reactionary 170 C. The product obtained is identical
contains IK-61.689 as the main compound IK-61.689 obtained
component, but is contaminated by the original method of example 1, as shown by CIK-58 .852 and other by-products, comparison of thin-layer chroma data. The crude product is purified by chromatography and NMR.
graph on silica gel followed by Example 3. Distilled
by recrystallization from isopropyl hydrogen-deionized water (200 ml) of added ether to obtain 4.2 g (32%) of 1J-61.689 to hydrochloric acid to obtain
in the form of sodium salt, tp.175- -35Р 2,5. Sodium salt IK-61 .689
176 C; , 3 (c 0.5, MeOH); (0.3b g) is dissolved in 100 ml dichloro
C-13 NMR (CDCl1); MD: 179.15; methane, and washed with a neutral dis107, 45; 103.18; 97.74; 96.96; 86.92; tilirovannoi water and concentrates84, 60; 84.20; 82.27; 82.01; 80.88; with by drying under vacuum to 8080; 79.86; 74.80; 74.55; 73.07; REPORTS 0.225 g (76.85%) of free acid, 70.06; 67.71; 66.89; 39.11; 56,81; lots in the form of a non-white solid substance 45, 40; 39.82; 38.93; 36.46; 33.81; va (tr.133-143). Its infrared
 33.71; 33.54; 33.42; 33.13; spectrum (KBG) shows a wide band
32.44; 32.26; 30.56; 27.58; 26.90; weak absorption of carboxylic acid.
26.84; 26.11; 23.23; 18.40; 17.53; .Infrared spectrum of sodium salt
16.99; 12.13; 11.04; 10,42.IK-61.689 showed a sharp strong peak
Example 2. Crude fer-carboxylate at 1600 cm. Mentation extract (methylisobutyl-IR-58.852: (LC, 4S, 5S, 6R, 7S, 22S / 2S,
ketone) (11) containing the antibiotic 5S, 6R /) - 22,27-didemethoxy-2,6 22IK-58 .852; (approximately 25 g), concentrate trememethyl-5,11-di-0-demetsh-1-6-mecrite under vacuum up to 680 g. Dense-5,22-bis / tetrahydro-5-methoxy-6the masloid is added to a mixture of ace-methyl-2H-pyran-2-yl) oxy / -lonomycinA. Tonitrile / Water 95: 5 (5.61) and forming an Antibiotic IK-B1.689, it exhibits a milky, milky emulsion of the treatment-absorbing effect on the growth of large
p-toluenesulfonic acid amounts of gram-positive micro (78.2 g) at one time. To the extent of organisms. In Table 1, the rivers are summarized, the reaction is going on, the emulsion is gradually the results of in vitro experiments. For these
divided into two distinct layers that each organism was inoculated with
rye is vigorously stirred for a series of test tubes containing nutritional
515
medium and different concentrations of antibiotic JK-61.689 to determine the minimum concentration of the compound in µg / ml, which inhibits the growth of the organism for 24 hours (MIC).
Data on the effectiveness of antibiotic IK-61 .689 and its salts against coccidiol infections in chickens were obtained as follows. Groups of 3-5 day old uninfected white cockerel leggorn are fed with a diet containing antibiotic IK-61.689 or its sodium and / or potassium salt, evenly distributed in the feed. After keeping on this diet for 24 hours, each chicken is inoculated per.OS with the oocysts of the tested Eimeria species. Other groups of 3-5 day old chickens are fed the same diet, but without antibiotic IK-61.689 or its salts. They are also infected after 24 hours and. used as a control group for infection. Another group of 3-5 days old chickens are fed the same diet without antibiotic IK-61.689 and do not infect coccidia. They are used as a normal control. The treatment results are assessed after five days in the case of E. acervulina and for days for all other species.
The parameter used to measure anticocciidal activity is lesion values from 0 to 4 for E.tenella (j.E.Lyuch, NEW Method for Anticoccidial Activity); and from 0 to 3 for other species on the modification of the counting system developed by J.Jchuson U W.U.Reid (Anti-coccidial Drugs-Sesion Scoring Tech- nique in Battery and Floor Pen Experiment in Chin).
Relative values are obtained by dividing the lesion size of each test group by the lesion value of the control infection group.
The antibiotic IK-61.689 and its cationic salts show a high activity against coccindial infections in poultry. When introduced in chicken feed in quantities of 15 to 120 ppm, these compounds are effective in controlling infection caused by Eimeria tenella, E.acervalina, E.maxima, E.brunetti and E.uec atrix,
The diet of animals is usually directly determined when they are fed.
According to the methodology, studies of the digestion of food in ruminants in vitro changes occurring in food under the action of microorganisms are measured more quickly and with greater accuracy to assess the diet of animals (UK Patent No. 1197826). This method includes the use of a device in which animal digestive processes are conducted and studied in vitro. Animal feed, inoculum. the rumen and various growth promoters are introduced, and the outputs from the laboratory device under carefully controlled conditions and the changes that occur are continuously recorded during the consumption of food by microorganisms. An increase in the content of propionic acid in the rumen fluid indicates that the desired result in the process of chewing food is caused by the growth promoter included in the composition of the feed. Changes in the content of propionic acid are expressed as a percentage of the content of propionic acid in the control rumen fluid. Long-term studies of the in vivo feeding process were carried out, which showed a significant correlation between the increase in prolionic acid content in the rumen fluid and the improvement in animal performance.
Scar fluid is taken from the fistula of a cow fed with a commercial diet for feeding and hay. } The rumen's fluidity is immediately filtered and 10 ml of lt is added to a 50-mm conical flask containing 400 mg of a standard substrate (68% corn starch + 17% cellulose + 15% soy bean extract), 10 ml buffer pH 6.8 and test compound Flasks are filled with oxygen-free nitrogen for about 2 minutes. and incubated in a shaking water bath at 39 ° C for about 16 hours. All experiments were repeated three times.
After incubation, 5 ml of the sample is mixed with 1 ml of 25%. metaphosphoric acid. After 10 minutes, 0.25 ml of formic acid was added and the mixture was centrifuged at 1500 rpm for 10 minutes. Samples are then analyzed; using gas-liquid chromotography according to the method of D.W.Kellog.
The height of the peaks for acetic, propio-j, and butyric acids is determined by
for samples from untreated and processed incubation flasks.
In the study in this method in vitro, the antibiotic IK-61,689 with a content of 20 micrograms per millimeter gives an increase of about 80% of the production of propionic acid compared with that obtained in the control solution without the addition of the antibiotic IK-61.689. Compounds that stimulate the production of CRP (rumen propionic acid) improve food utilization in ruminants such as cattle and sheep, and also have a similar effect on monogastric animals such as pigs. The antibiotic IK-61.689 can be introduced into an animal by including food as in the form of free acid; 20 the amount of agent in the finished food is moni
lots, and in the form of a salt, such as sodium or potassium salt, or mixtures thereof. Alternatively, an unrefined or dried fermentation broth containing antibiotic IK-61.689 may be introduced into the feed in the desired cone; centration. The antibiotic IK-61.689 can also be used at the right dose when using an appropriate device for the long-term preparation of a drug .30 intended to measure constant doses of drugs.
When used to treat poultry coccidiosis, the proposed antibiotic is administered orally in a sub-. 35 running carrier. It is most convenient to simply administer the drug to drinking water or to poultry feed, so that the therapeutic dose of the agent is swallowed with a daily dose of water or 40 feed. The agent can be directly metered into the drinking water, preferably in the form of a liquid water-soluble concentrate (such as an aqueous solution of a water-soluble salt), or directly added to the feed in pure form or in the form of a premix or concentrate. used to introduce the agent into the feed. Suitable carriers may be liquid or solid, as required, such as water, various food additives be adjusted by mixing the appropriate proportion of the premix with feed to obtain the desired concentration of therapeutic agent.
Highly effective concentrates can be obtained by the manufacturer of feedstuffs on protein carriers, such as soybean oil and other food products for the manufacture of concentrated additives that are suitable for direct feeding of poultry. In such cases, the bird receives a normal diet. Alternatively, such concentrated supplements can be added directly to poultry feeds in order to obtain a balanced ready meal containing a therapeutically effective amount of the compound.
The mixtures are prepared according to standard procedures, for example, in a double-shell mixer, in order to achieve homogeneity.
Applied doses of the proposed antibiotic may vary depending on various circumstances. 45 Permanent use in a low dose during the growth period, i.e. in the out of 6–12 weeks} chickens life is an effective preventive measure. When treating an established infection, higher doses may be needed. The posture used in the feed is usually in the range of 15-120 ppm. When used in drinking water, the postures must be such as to provide
50
Applied doses of the proposed antibiotic may vary depending on various circumstances. 45 Permanent use in a low dose during the growth period, i.e. in the Excess 6–12 weeks of chickens ’life is an effective preventive measure. When treating an established infection, higher doses may be needed. The posture used in the feed is usually in the range of 15-120 ppm. When used in drinking water, the postures must be such as to provide
products, such as soybean oil, flaxseed oil, kukuluznye.vatka and mine-55, however, the same daily dose of intake, i.e. Rural mixtures, usually used 15-120 ppm, taking into account the ratio, SWING. in poultry feeds. Particularly equal to the ratio of the average daily, an effective carrier is a good food intake to the average daily feed of birds, i.e. ma.pa portion daily water consumption.
this feed. The carrier facilitates uniform distribution of the active material in the feed with which the premix is mixed. This is important as it requires only a small concentration of this potent agent. It is essential that the connection is completely
mixed in premix and then with feed. The agent may be dispersed or dissolved in a suitable oil vehicle such as soybean oil, corn oil, cottonseed oil, and the like.
or in a volatile organic solvent and then mixed with the carrier. Preferably, the proportion of active material in the concentrate can vary over a wide range, since
It can be adjusted by mixing the appropriate proportion of premix with feed to obtain the desired concentration of therapeutic agent.
Highly effective concentrates can be obtained by the manufacturer of feedstuffs on protein carriers, such as soybean oil and other food products for the manufacture of concentrated additives that are suitable for direct feeding of poultry. In such cases, the bird receives a normal diet. Alternatively, such concentrated supplements can be added directly to poultry feeds in order to obtain a balanced ready meal containing a therapeutically effective amount of the compound.
The mixtures are prepared according to standard procedures, for example, in a two-part mixer, in order to achieve homogeneity.

Applied doses of the proposed antibiotic may vary depending on various circumstances. Continuous use at a low dose during the growth period, i.e. in the out of 6–12 weeks} chickens life is an effective preventive measure. When treating an established infection, higher doses may be needed. The posture used in the feed is usually in the range of 15-120 ppm. When used in drinking water, poses should be such as to provide
the same daily dose, i.e. 15-120 ppm, given a ratio equal to the ratio of the average daily food intake to the average daily water consumption.
9 pgn Q
BUT d.
soon
or its pharmaceutically acceptable cationic salt, distinguishing s o OCHj
 OSSN
soon CHj
subjected to controlled acid-, containing 95 wt.% acetonitrile and mu hydrolysis by the action of 1.1 mol. equiv. of 5 wt.% of water, and, if necessary, valenta p-toluenesulfonic acid translate the free acid into its farmate 1 mol. equivalent of a compound formically acceptable cationic. Mools II in a solvent mixture medium, salt.
..OSNZ
About SNS: S C
r xj / ,, CHl
) H CH, CH3
3
u and with the fact that the compound of formula II
..OSNZ
H-iC
ii-CH-i
ABOUT
I j and g g LT - l ,,
nn nn nn n he
3
.Table 2

权利要求:
Claims (1)
[1]
The claims of the identity of each component.
These LDy ^ values show that
IR-61 "689 approx. 10. times less
A method of obtaining a polycyclic essential antibiotic'formula I:
or a pharmaceutically acceptable cationic salt thereof, characterized in that the compound of formula II is subjected to controlled acid hydrolysis by the action of 1.1 molar equivalent of p-toluenesulfonic acid per 1 molar equivalent of the compound of formula II in a medium of a solvent mixture containing 95 wt.% acetonitrile and
5 wt.% Water, and, if necessary, convert the free acid into its pharmaceutically acceptable cationic salt.
Table 1
Organism | Strain No. | MIC, μg / ml Clostridium perfringens 10A006 25 10A009 3.12 Actinomycu pyogenes 14 002 0.39 14 008 0.39 14 011 0.39 Tuponema hyodysenterial 94A001 6.25 94A002 6.25 94A007 3.12 ’94A008 3.12
Il
. T a blitz 2 Rodents | Method of administration I mgG ”YK-587852 ~ / kgNut = b17b89 Male mouse Orally 2-5 25 - 50 Male mouse Intraperitoneally 2-5 15 - 30 Male rats Orally 12 50 - 100 Male rats Intraperitoneally 0.2 - 1 > 10
Compiled by And, Dyachenko

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法律状态:
2007-09-20| REG| Reference to a code of a succession state|Ref country code: RU Ref legal event code: MM4A Effective date: 20040801 |

优先权:

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申请号 | 申请日 | 专利标题

---

GB868618844A|GB8618844D0|1986-08-01|1986-08-01|Polycyclic ether antibiotics|LV931086A| LV5623A3|1986-08-01|1993-09-22|Attenuation of polycyclic ether antibiotics and its pharmaceutically acceptable cationic acid|