Method of obtaining bis-esters of methadiol with penecillin and 1,1-dioxide of penicillanic acid

专利摘要:
METHOD OF OBTAINING METHANDIOL BIS-ETHERS WITH PENICILLIN AND 1,1-DIOXIDE OF PENICILLANIC ACID of the formula N N n-sn, -so n-4 W:. O o Cn, Y cn, 5x5-0 Cl R o where R is a phenyl or phenoxy group, characterized in that the compound of the formula HH is ,, VT T. V. H, N cps Q - 14-- / s-o p о о 0 ri V f «W i vS-s4- 3 tons of pH of S c-J. ,, f.- с-о 0 в о is subjected to acylation with a reactive carboxylic acid derivative of the formula: N9 GO R-CH, j-COOH where R has the indicated values 00 when cooled in an inert solvent.
公开号:SU1122228A3
申请号:SU813274747
申请日:1981-04-27
公开日:1984-10-30
发明作者:Кливлэнд Бигхэм Эрик
申请人:Пфайзер Инк.(Фирма)；
IPC主号:

专利说明:

This invention relates to a process for the preparation of new penicillin derivatives, namely bis-esters of methanediol with penicillin and penicillanic acid 1,1-dioxide, possessing antibacterial activity.
A known method of producing antibacterial activity of bis-esters of methanedol with penicillin and penicillanic acid 1,1-dioxide of the formula
H -S v.jv
.chSNz
sns
1 C-0 II O o O ng /, where RJ is phenyl or p-hydroxyphenyl; R P-amino group or DjL-to boxy group, concluded that the compound-formulas; nn RrCH-cora-f - fJ CH3: .L-i1 0 - s.cH3-phenyl or n-hydroxyphenyl; An α-D-azido group protected by a D-amino group or protected on the D L-carboxy group is subjected to catalytic hydrogolysis or hydrolysis Q. The purpose of the invention is to prepare new bis-esters of methanediol with penicillins that expand the arsenal of means of action on a living organism. The goal is achieved on a well-known reaction
method of producing 6-aminopenicillins 21 by the method of preparing methandiol bis-esters with penicillin and penicillanic acid 1,1-dioxide of the formula
R-CHj-CONH About
ten
15 where R is phenyl or phenoxy; which implies that the compound of the formula 11 HH - r-S.o CH “Wa. i№ - j .., ..: n-g ch 3 is subjected to acylation of a reactive carboxylic acid derivative of formula (III) with R-CH-COOH, where R has the indicated values, when cooled in an inert solvent. The compounds of formula (I) possess anti-bacterial activity in vivo in the mammalian case. In order to evaluate the activity, the compound of formula (1) is administered, for example, to mice infected with a previously acute infectious disease, via an intrabiotamine standard culture injection, pathogenic bacteria. The magnitude of the dose of bacterial culture during infection was chosen so that mice received 1-10. At the end of the test, the activity of the compound was evaluated by the number of survivors who were infected with bacteria and who also obtained a compound of formula (I). The compounds of formula (I) can be administered orally (P.O.) and subcutaneously (S.c). The in vivo activity of the proposed antibacterial compounds is suitable for controlling bacterial infection of mammals, including humans. These compounds can be used to control infections caused by bacteria to which the human body is sensitive. After the compound of formula (I) has been introduced into the body of a mammal, it decomposes into the corresponding penicillin and penitsshanic acid 1,1-dioxide. In this case, penicillanic acid 1,1-dioxide plays the role of a beta-lactamase inhibitor and increases the antibacterial activity of the corresponding penicillin. The compounds of formula (I) can be used in particular to control infections caused by bacteria of the strain Staph lococcus aureus. To determine the sensitivity of the Staphyloc.aureus strains with respect to the individual compounds of formula (I), an in vivo test can be used. Another method for this purpose is to determine the minimum Hyo concentration (MKI) at which inhibition occurs. For determination, heart-brain stretch (SMV) on agar and a device for re-infection are used. To obtain a standard graft, culture grown in tubes overnight was diluted 100-fold (10,000 to 20,000 cells in about 0.002 ml were placed on the surface of the agar; 20 ml of CMV agar per dish). For the determination, 12 2-fold dilutions of the test compounds with an initial drug concentration of 200 µg / ml were used. Separate colonies in the control of Petri dishes after holding them for 18 hours at 37 ° C were not taken into account. As a criterion of susceptibility (MKI), the test of my organism was taken of the minimum concentration of the compound at which the full growth pressure was observed (when evaluated with a non-military eye). 8 When using the proposed antibacterial compounds in the case of mammals, in particular humans, they can be administered into the body either alone or in mixture with other antibiotics and / or pharmaceutically acceptable carriers or diluents. The choice of carrier or diluent depends on the method of administration of the drug in the body. For example, when administered orally with antibacterial preparations, the latter can be used in the form of tablets, capsules, lozenges, powders, syrups, elixirs, aqueous solutions and suspensions, and other forms accepted in pharmaceutical practice. The ratio between the active substance and the carrier in the preparation depends naturally on the chemical nature, solubility and stability of the active substance, as well as the proposed dosage. In tablets as a carrier is usually used. lactose, sodium citrate and phosphoric acid salts. In addition, dispersants, for example starch, and lubricants such as magnesium stearate, sodium lauryl sulfate and talc are commonly used in the manufacture of tablets. In capsules for oral administration, lactose and high molecular weight polyethylene glycols, for example polyethylene glycols with a molecular weight of 2000-4000, can be used as a diluent. When used for oral administration of aqueous suspensions, the active ingredient is mixed with emulsifiers and dispersing agents. If desired, flavoring and flavoring agents can be added to the preparations. For parenteral administration, sterile solutions of the active substance are usually prepared, buffering them accordingly and setting the desired pH. In the case of intravenous administration, it is necessary to control the total concentration of solutes in order to obtain an isotonic solution. The required daily dose for administration is not significantly different from other penicillin antibiotics used in practice. Its value may vary depending on the age, weight and reaction of I 1 to the drug, as well as on the nature and severity of the disease. With oral administration of the proposed compounds, the daily dose is 20,100 mg / kg patient weight, and with a couple of oral doses. -1 changes - 10-100 mg / kg. Usually, the daily dose is administered in several doses. In some cases, the dose may exceed the specified limits. The test results showed that the MKI for the compounds of formula (I) is µg / ml against Staphylococcus aureus 01A005 and 12.5 µg / ml against EreaiviMa Staphylococcus aureus 01A400j, and the strain 01A400 is not affected by penicillin G and penicillin V. Example 1. 151- DIOXID-6 (2-phenylacetamido) penicillanoyloxy meth, l penicillanate. To a stirred solution of 4.62 1S1-b-aminopenicillanoyloxymethyl penicillayate dioxide in 25 ml of chloroform was added 1.50 mol of triethylamine. The mixture is cooled to O C and a solution of 1.55 g of 2-phenylacetate 1chloride in 10 ml of chloroform at O C is added dropwise to it. The resulting mixture is stirred for 5 minutes at then 30 minutes at 25 ° C. The solvent is then distilled off. in vacuo, and the residue is partitioned between ethyl86 acetate and water of pH 8. The ethyl acetate layer is separated, washed with water, dried with Na «sdij and evaporated in vacuo to give the desired product. 1 In the IR spectrum (tablet KBr), there is absorption at 1783 cm. The NMR spectrum (CDCI) has the following absorption maxima: 7.4 (singlet), 6.3 (doublet), 5.9 (singlet), 5.8 -5.3 (multiplet) ,, 4.65 (triplet), 4545 (singlet), 3.65 (singlet), 3.45 (doublet), 1.62 (singlet) and 1.481.4, 4 (multiplet). Example 2. 1,1- dioxide 6- (2-phenoxyacetamido) pentionylanoyloxymethyl penicillanate. This product is obtained by acylation of 1,1-dioxide with 6-aminopenicillanoyloxymethyl penicillanate with 2-phenoxyacetyl chloride, analogously to Example 1. In the IR spectrum (KBr tablet), there is an absorption maximum at 1786 cm. The NMR spectrum has the following absorption maxima (CDCIj): 7.4 (singlet), 5.85 (singlet), 5.45 (snnglet) w 5505 (singlet ), 4.6 (triplet) 5 4.43 (singlet) J 454 (singlet), 3.45 (doublet), 1.62 (singlet), 1.48 (singlet), 1.44 (singlet) and 154 ()

权利要求:
Claims (1)
[1]
METHOD FOR PRODUCING METHANEDIOL BIS-ETHERS WITH PENICILLINE AND 1,1-DI- 'OXIDE OF PENICYLANIC ACID of formula НН where R is phenyl or phenoxy group, characterized in that the compound of the formula is acylated with a reactive carboxylic acid derivative of the formula r-ch ₂ where has the specified values; when cooled in an inert solvent.
>
1 1122228

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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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US06/039,539|US4244951A|1979-05-16|1979-05-16|Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide|

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