Method of preparing derivatives of 4-aminooleandomycin or their pharmacetically adopted acid-additiv

专利摘要:
A series of 4''-deoxy-4''-amino-oleandomycin antibacterial agents and their preparation from semi-synthetic 4''-deoxy-4''-oxo-oleandomycin intermediates.
公开号:SU888824A3
申请号:SU792739695
申请日:1979-03-15
公开日:1981-12-07
发明作者:Кристиан Сциаволино Фрэнк
申请人:Пфайзер Инк (Инофирма)；
IPC主号:

专利说明:

ki acceptable acid addition salt.
The reduction is usually carried out by catalytic hydrogenation, with a rtorine solution of a compound of formula I. in isopropyl alcohol containing Raney nickel as a catalyst, is left overnight with shaking under a hydrogen atmosphere at an initial pressure of 3.515 kg / cm at room temperature. Filtration of the spent catalyst, followed by removal of the solvent from the filtrate, results in the isolation of the desired 4-deoxy-4-amino-substituted antimicrobial agent of Formula 1. The separation of the desired product from the impurities is carried out as follows.
The aqueous solution of the product is extracted with a gradual increase in the pH value, so that neutral or minor materials are extracted at lower pH, and the target product is extracted at pH 9.0. Extraction solvents, which are either ethyl acetate or diethyl ether, are washed with brine or water, dried over sodium sulfate, and the target product is obtained by removing the solvent.
Additional purification, if necessary, is performed by chromatography on a column of silica gel using known methods.
Acids giving pharmaceutically acceptable anions can be hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric or sulfurous, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic, gluconic and aspartic acid.
The stereochemistry of the starting materials resulting in the preparation of antibacterial agents according to the invention does not differ from the natural material.
New derivatives of 4-deoxy-4-amino oleandomycin have activity in vitro against various gram-positive microorganisms, such as Staphy ococcus aureus and Streptococcus pyogenes, and against some literate microorganisms that have a spherical and ellipsoid form (cocci). Their activity is easy to demonstrate on
in vitro tests against various microbes in the environment of cardiovascular stretching by the usual method of a two-fold dilution series. In vitro activity makes them useful for local application in the form of ointments, creams, etc., for the purpose of sterilizing, for example, household items in the patient's room and as industrial antimicrobial preparations, for example, for water treatment, sludge control and for the protection of paintings and wood.
For use in vitro, i.e.
5 when applied locally, it is often advisable to combine the selected product with a pharmaceutically acceptable carrier, such as vegetable or animal oil or emollient cream. Similarly, they
may be dissolved or dispersed in liquid carriers or solvents. Such as water, alcohol, polyhydric alcohols or their mixtures or in
5 other pharmaceutically acceptable inert media, i.e. in an environment that does not adversely affect the active ingredient. For these purposes, concentrations of the active ingredient from about 0.01 to 10% by weight can usually be used.
When used in vitro, these new compounds can be administered orally or parenterally, i.e. subcutaneous or intramuscular injection in a dose of 1 mg / kg to 200 mg per 1 kg of body weight per day. The dose range is 5 mg / kg to 1000 mg / kg body weight per day. Carriers suitable for parenteral injection can be either liquids, such as water, isotonic solution, isotonic dextrose, Rings solution, or anhydrous, such as fatty oils of vegetable origin (cottonseed oil, peanut oil, corn oil, sesame oil), dimethyl sulfoxide and other carrier carriers that are not affected by the therapeutic efficacy of the drug
0 and non-toxic in applicable volume

权利要求:
Claims (2)
[1]
or ratio (glycerin, propylene glycol, sorbitol). Improvised preparations may be prepared in solutions before administration. Such useful mixtures include liquid diluents, for example, propylene glycol, diethyl carbonate, glycerin, sorbitol, etc., buffering agents, hyaluronidase, local anesthetics and mineral salts to impart desired pharmacological properties. These compounds may also be combined with various pharmaceutically acceptable Inert carriers, including solid diluents, liquid carriers, non-toxic organic solvents in the form of capsules, lozenges, dry mix, suspension, solution, elixir, and parenteral solution or suspension. The compounds are used in various dosage forms in concentrations from 0.5 to 90% by weight. Example 1.a) 11,2-diacetyl-4-deoxy-4-amino oleoandomycin. A suspension of 1 g of Rene nickel, washed in 25 kn of isopropanol, containing 250 MP of 0-acetoxime P, 2-diacetyl-4-deoxy-4-oxroleandomycin, is stirred in an atmosphere of hydrogen at an initial pressure of 3.515 kg / cm at room temperature during the day. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and 201 mg of the desired 11.2-diacetyl-4-deoxy-4-amino oleandomycin was obtained. mp ((f, CDCf3) 3.43 (symbol) s; 2.70 (2H) m; 2.30 (6H) S and 2.10 (6H) 6) The resulting 201 mg of product are heated at reflux temperature a refrigerator in methanol {10 ml) for 1 h and get 1,1-acetyl-4-deoxy-4-aminooleandomycin, so pl. 157-160 C. PRI mme R 2. -1-acetyl-4-deoxy-4-amino oleandomycin dichloride. To 7.26 g of 11-acetyl-4-deoxy-4-amino oleandomycin in 50 ml of dry ethyl acetate, 20 ml of 1N hydrogen chloride in ethyl acetate are added and the resulting solution is concentrated to dryness under reduced pressure. The residue is dissolved in powder with ether , filtered and get the desired product as a salt. Similarly, the amino compounds of the present invention are converted into their double acid addition salts. Example 3. P, 2-diacetyl-4-deoxy-4-amino oleandomycin hydrochloric. The process described in the example is repeated.
[2]
2. In addition, 24 "10 ml of 1N solution of hydrogen chloride in ethyl acetate is added. The solution is concentrated in vacuo to dryness, the remaining acidic hydrochloride salt is triturated with ether and filtered. Similarly, the proposed amino compounds are converted to their acid addition salts. Example 4. To 96 ° C mg of 11-acetyl-4-deoxy-4-amino oleandomycin in 6 ml of acetone was added 18 ml of water, followed by the administration of 175 mg of aspartic acid. The mixture is heated in countercurrent to obtain a cloudy solution. The mixture is filtered, the hot and clean filtrate is concentrated to remove acetone. The remaining solution is freeze dried and the desired product is obtained as a residue — 11-acetyl-4-deoxy-4 -amino oleandomycin asparginate. The invention of the method of obtaining 4-amino oleandomycin derivatives of general formula I to 5G). ft О HjC-jj-O, V, 8 V HH where R is hydrogen or acetyl, or their pharmaceutically acceptable acid addition salts, characterized in that the compound of formula I. СНз-0 lf ((JHs) 2 CHfO Г о V rS fl "5 5-5-0, 1 (.. I I VO //, ON .11 I
 888624. 8
subjected to catalytic gidrirova-in the form of pharmaceutically acceptable
in the presence of Nickel Renen, acid addition salts,
environment isopropanol at room temperature-Sources of information
perature and, if necessary, carried out into consideration during the examination
hydrolysis in methanol at reflux cj f. Carrer P. The Course of Organic
the subsequent selection of target chemistry. Ed. M.N.Kolosova, L.,
product in free state or 1960, p. 162.

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引用文献:

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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US05/765,486|US4125705A|1977-02-04|1977-02-04|Semi-synthetic 4-amino-oleandomycin derivatives|

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