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    • 专利摘要:
    The method for the preparation of esters of ib-aminnano-pennylline esters of formula (1) S 3, - 1 Ri-cH-coim- NOO NH2-phenyl, xyphenyl, fluorophenyl, where R, furyl or thienyl; . “2 is a group of the formula —CH — O — CO — E3 CH 3 or —CH — 0 COO-Y 3 CH j, where R j is C (—C 4 alkyl, or their acid addition salts, characterized in that the ester is 6-aminopenicillin Acid | TY of the formula (II) n tg CH3, where R, has the indicated values, is reacted with an acid derivative of the formula (III) Rt CH-COD A. Where R {has the indicated values; A is an amino group, an azido group or a group of the formula -Cn-ebc I and CH3 O or -NH-S and y is a halogen atom or a group of the formula: L © F-ONa or-O 1 2 2 (CCHH) 2: 90 in ethyl acetate, dimethyl forms of E d or chloroform as solventat temperatures from to room temperature, followed, if necessary, by removing the substituent of the cA-amino group, or in the case when A is an azido group, converting it into an amino group and isolating the target product in free form or as an acid additive salt.
    公开号:SU1153830A3
    申请号:SU731899287
    申请日:1973-03-27
    公开日:1985-04-30
    发明作者:Аке Экстрем Бертил；Олоф Харальд Сьеберг Берндт
    申请人:Астра Лекемедел Актиеболаг (Фирма)；
    IPC主号:
    专利说明:

    17.09.70. when R-J is methyl and L is an amino group or an azido group; 20,11.70,
    R, - Cj
    - SF - alkyl and L - amino group.
    I
    The invention relates to a method for the preparation of new antibiotics of the penicillin series, namely the complex of the i-aminopenicillin esters or their acid addition salts, which can be used in medicine as medicinal substances,
    A known method of obtaining biologically active (X.-aminopenicillins or their acid addition salts by acylation of 6-aminopenicillanic acid with a reactive derivative of its corresponding-amino-, oL-substituted amino or o-azidocarboxylic acid in an inert organic solvent at a temperature of -50 to 40 ° C, followed, if necessary, by the removal of the substituent of the coC-amino group, or in the case of using as the acylating agent o-azide derivative by transfer of the aa-d group to the amino group and dividing the desired product in the free form or as acid addition salts,
    Known with (.-Aminopeshchillins) have a broad spectrum of antibacterial action 2, however, it remains desirable to improve the absorbability of penicillin antibiotics by oral administration, distribution in body tissues, metabolic properties and removal rate.
    The purpose of the invention is to obtain new oi-aminopenicillins, which have improved properties,
    The objective is achieved based on the known reaction of N-acylation of 6-aminopenicillin acids in the preparation of esters of α-aminopenicillins of the general formula
    S .СНз
    t f C "h.
    CH-CONHN- - COOR "
    sh
    20
    R
    - phenyl, oxyphenyl, fluorofecene, furyl or thienyl;
     formula group
    -CH-O-CO-RZ SN,
    or "
    -СН-О-СОО-Кз
    f
    sns
    where RJ is C (-C f-alkyl, or their acid addition salts, which is that the 6-aminopenicillanic acid ester of the formula
    SNS
    HoN CHS

    -yr
    COOR
    0
    where RJ is indicated, reacted with an acid derivative of the formula
    RI-CH-COO -,
    BUT
    where R has the indicated meanings; A - amino group, azido group or a group of the formula
    -1U-C CH-CCH
    I
    SNS about
    whether
    -sh- $
    ko,
    35
    and y is a halogen atom or a group of the formula
    40 -ON6 -O lH2 (CgHn) 2
    in ethyl acetate, dimethylformamide or chloroform as a solvent at a temperature from to room, followed, if necessary, by removing the substituent from the amino group of the amino group or in the case when the A is an air group, by converting it into an amino group and isolating the desired product} free form or in the form of an acid additive salt. The compounds of general formula (I) are well absorbed by oral administration and give a higher concentration in the blood. The esters undergo hydrolysis in an aqueous medium, but such hydrolysis occurs more intensively when exposed to the influence of hydrolytic enzymes, for example, present in blood serum or other fluids of the human body. This property of esters is very important because it leads to the rapid release of antibacterial aminopenicillins from esters when absorbed from the intestinal tract or otherwise injected into the blood stream or into the tissue fluids. The compounds of formula (I) are well tolerated. The body is preferably administered orally either in free form or in the form of their salts, they can be mixed with solid carriers or auxiliary substances, or with both types of these substances. In such preparations, the ratio between the drug substance and carriers or excipients can vary from 1 to 95%. Preparations can be transformed, for example, into tablets, pills or dragees, they can be enclosed in containers, for example, capsules, and, if they are bold, they are poured into bottles. Pharmaceutically acceptable organic or inorganically solid or liquid carriers suitable for oral, parenteral or topical administration may be used in the preparation of preparations. The preparations for preparing the compounds according to the invention are gelatin, lactose, starch, magnesium staarate, talc, fats and vegetable or animal oils, natural rubber and polyethylene glycol. The preferred salt of the esters is hydrochloride, but salts with other inorganic or organic acids can also be used. In addition, preparations may contain other pharmacologically active ingredients suitable for use with specified esters in the treatment of infectious diseases, for example, other suitable antibiotics. For treating bacterial infectious diseases in humans, the compounds according to the invention are administered, for example, in an amount corresponding to 5-200 mg / kg / day, preferably in the range of 10-100 mg / kg, in the intervals of 10-100 mg / kg / day, in divided doses, for example, two, three or four times a day. They are prescribed in doses containing, for example, 175, 350, 500 and 1000 mg of the compound. Example 1. 1 -Acetoxyethyl- 6- (azidophenylacetamido) penicillanate, a) 1 -Acetoxyethyl-6- (B-06-azidophenylacetamido) penicillanate (58%, 2.8 g), dissolved in ethyl acetate (40 ml), treated with 0 , 2 M monosodium phosphate (40 ml), acidified to pH 2.2 with 2 M hydrochloric acid solution and hydrogenated over palladium on carbon (catalyst) at ambient conditions for 2 hours. The catalyst is removed by filtration and washed with ethyl acetate and buffer . The organic phase of the combined filtrates is separated and extracted with water at a pH of 2.1. The combined acidic aqueous phases are washed with ether, the ethyl acetate layer is separated and neutralized by adding 2N sodium hydroxide solutions with stirring. The aqueous phase is separated and extracted again with ethyl acetate. The combined ethyl acetate aqueous solutions are washed with brine and water and extracted twice with water at a pH of 2.5 by adding 2 M hydrochloric acid. The United acidic aqueous extracts are washed with ether and concentrated under vacuum at 25 ° C, which leads to the formation of an oily residue. dissolved in isopropanol and evaporated in vacuo. Get 1-acetoxyethyl-6- (P-oh aminophenylacetamido) penicillanate (1.1 g) hydrochloride (1.1 g) in the form of a slightly colored powder with a purity of 100% (hydroxylamine sample). The product inhibits the growth of microorganisms of the species Ktaphylococcus aureus, Oxford, at a concentration of 0.32 mg / ml, and Escherihia coli and Proteus mirabilis - at 50 mg / ml, b) The azido-derivative of ester In ethyl acetate (800 ml) is hydrogenated in
    environmental conditions over catalysts containing palladium (5%) on coal (25 g). The catalyst was removed by filtration and washed with ethyl acetate. The United filtrates were extracted with water at pH 2.5 in the presence of hydrochloric acid. After lyophilization of the aqueous phase, 1 acetoxyethyl-6- (P- (y; -aminophenylacetamido) penicillanate (110 g) is obtained. Mp. 160–164 ° С (c 1), + 1§4 ° С (С 1 CHCJ ,); +179.9 (C 1, 50% lzopropanol).
    Found,%: C 50, 78; H 5, .49; N 8.76; About 20.22; S 6.58; C1 7.39,
    .se
    Calculated,%:, 90; H 5.55; N 8.90; About 20.34; s6.79; C1 7.51.
    The product has a strong IR absorption at 1780-1744 cm, which indicates the presence of UZ-lactam and carbonyl ester groups. The product was found to inhibit the growth of Staphylococcus aureus, Oxford, at a concentration of 0.25 mg / ml.
    Example 2. 1 -Acetoxyethyl6- (B-e: -aminophenylacetamido) penicillanate.
    Suspension about - (o-nitrophenylsulfeyl) -aminophenylacetate dicyclohexyl ammonium (4.9 g 0.01 mol) and 1-acetoxyistil-6-aminopenicillanate hydrochloride (3.4 g, 0.01 mol) in chloroform. (60 ml) is stirred in overnight at room temperature. Dicyclohexylcarbodiimide (2.2 g, 0.01 mol) is added and stirring is continued for another 6 hours. The reaction mixture is filtered and washed with water, dilute sulfuric acid, 1N sodium bicarbonate and water, dried and evaporated to dryness under vacuum. The yellow residue is treated with ethyl acetate, filtered and again evaporated to form a residue, which is recrystallized from a mixture of ethyl acetate and petroleum ether. Get 1-acetoxyethyl-6- (P - ";- (about nitrophenylsulfonyl) aminophenylacetamide) penicillanate (1.5 g). M.p. 122 5 ° C.
    The product has a strong IR absorption at 1780-1750 cm, which indicates the presence of β-lactam and carbonyl groups of esters. o-Nitrophenylsulfenylaminopropyl ester (1.2 g, 0.02 mol is dissolved in 75% dioxane and brought
    pH up to 3 by adding 2N solution;) hydrochloric acid. Sodium iodide (1.2 g, 0.008 mol) is added, the mixture is stirred and the mixture is adjusted to pH 3 by the addition of acid. After 20 minutes, the resulting iodine is reduced by adding 2N of sodium thiosulfate solution and neutralizing mixture and extracting with ethyl acetate after adding water. The combined organic extracts are washed with water and extracted with water by adding 2N hydrochloric acid to pH 2. The aqueous phase is washed with ethyl acetate and lyophilized to obtain 1-acetoxyethyl-6- (B-64-aminophenylacetamido) penicillanate hydrochloride (0.15 d). The product is identified by the method of identifying the product obtained in Example 16 using the IR spectrum.
    I
    Example 3. 1-Ethoxycarbonyloxyethyl-6- (0-o. -Aminophenylacetamido) penicillanate 1.
    1-ethoxycarbonyloxyethyl ester of 6- (0-L-azidophenylacetamido) penicillanic acid (2.5 g) dissolved in ethyl acetate (40 ml), and 0.4 mol of monosodium phosphate are acidified to pH 2.2 with 2 M hydrochloric acid solution (40 ml), 10% palladium on carbon (4 g) used as a catalyst (4 g) is added and the mixture is heated at atmospheric pressure for 30 minutes. The catalyst is filtered off and washed with ethyl acetate and a buffer solution. The filtrate is separated and the organic phase is extracted with water at a pH of 2.1. The combined acidified aqueous the phases are washed with ether, ethyl acetate is added and neutralized with stirring using 2 mol of sodium hydroxide, the phases are separated and the aqueous solution is extracted again with ethyl acetate. The two ethyl acetate extracts are combined, washed with brine and water and extracted with water at a pH of 2.5 by adding 2 mol of hydrochloric acid. The combined acidified vodng 1e extracts are washed with ether and concentrated under vacuum at. The semi-solid residue is dissolved in isopropanol, concentrated again and this procedure is repeated once more. The residue is stirred with ether l G1pg: coal 1 1
    1 - :) toxicarg hydrochloride) 6- (D-Q (, - aminophenyl acetamido) penicillaiopic acid) (0.8 g) as a yellow-white powder with a content of 86, A% (hydroxy-5 amine sample).
    The product retards the growth of StaphyloOCCUS aureus, Oxford, at a concentration of 0.13 g / ml Escherihia coll at a concentration of 125 mg / ml (the solution was tested on agar) and gives a strong absorption of the IR spectrum at 1750 cm, it shows the presence of ft-lactam rings and functional groups of ester.5
    The azide derivative of ester (3.2 g) is obtained by treating 1-to-carboxycarbonyloxyethyl-6-aminopenicillanate hydrochloride (3.3 g, 0.01 mol) in dry dimethylformamide (50 ml) with 20-c-azidophenyl acetic acid chloride (2 g, 0.01 mol) the presence of triethylamine (2 g, 0.01 mol). After the reaction mixture was diluted with water, the ester was isolated by extraction with ethyl acetate.
    Example 4. 1 -Etoxycarbonyloxyethyl-6- (B-o - amine of NILE acetamido) penicillanate.
    a) To the suspension of hydrochloride chlorohydrin-30 rinoab-aminophenylacetic acid
    (2.6 g, 0.0125 mol), stirred in dry chloroform (50 ml) in a stream of dry nitrogen, while cooling with ice, sodium bicarbonate (1.1 g, 35.01225 mol) and hydrochloride 1-ethoxy- are added. carbonyloxyethyl-6-aminopvnicillanate (3.3 g, 0.01 mol). After stirring for 90 minutes, the mixture was filtered and isoprop-40 NOL (15 ml) was added to the filtrate. After evaporation under vacuum at room temperature, an oily residue is obtained, which upon dilution with petroleum ether forms a 45 1-ethoxycarbonyloxyethyl-6- (B-U, aminophenylacetamido) penicillanate hydrochloride residue (1.5 g). The product is purified by precipitation from a mixture of acetone and petroleum ether .50
    The identity of the product is determined by its IR spectrum.
    b) N- (1-Methoxycarbonylpropan-2il) - / -ami-11-phenylacetate sodium
    (2.5 I, 0.0092 mol) and K-methylmorpho-55 LIN (0.05 ml) in dry ethyl acetate (40 ml) is stirred and treated with isobutyl chloroformate
    (1.4 g, 0.01 mol). After 6 minutes, 1-ethoxycarbopyloxyethyl-6-aminopenylnatnat (0, .01 mol) in ethyl acetate (20 m.h.) is added dropwise with continuing overdamping at -15 ° (;; after 10 min after stopping the addition, the cooling bath is removed stirring is continued for a further 45 minutes, the reaction is CMCCI, washed with water, 0.5 mol of sodium bicarbonate and again with water, dried and concentrated under vacuum to an oily residue, which is treated with tetrahydrofuran (20 ml) and water (20 ml). acidified to pH 2.5 by adding 2N hydrochloric acid solution After 30 minutes, most of the tetrahydrofuran is removed under vacuum and the acidified aqueous phase is washed with ethyl acetate and evaporated. 1-ethoxycarbonyloxyethyl-6- (P-o6 aminophenylacetamido) penicillanate hydrochloride (0.35 g) is obtained as an amorphous solid identified by its IR spectrum.
    Example 5.1 -Lethoxyethyl6- (D-K -amino-m-fluorophenylacetamido) penicillanate.
    The 1-acetoxyethyl-6-aminopenicillanate hydrochloride (3.4 g, 0.01 mol) in dry dimethylformamide (50 ml) is stirred in an ice bath and treated with N, N-dimethyl-aniline (2.4 g, 0.002 mol), and then a solution of the acid chloride L-Azido-m-fluorophenylacetic acid (2.1 g, 0.01 mol in dry ether (5 ml). After stirring for 1 h, water (100 ml) is added, the pH is adjusted to 6.5 and extracted three times with ethyl acetate. The combined organic extracts are washed with water and the brine is dried and evaporated in vacuo to give 1-acetoxyethyl-6-D-and-azido-m-fluorophenylacetamido) nicillanate (1.5 g) as an oily residue. This product gives a strong IR absorption at 2110 and 1780-1750 cm, indicating the presence of the azido group, the / 3-lactam ring and the carbonyl groups of the esters.
    The azido ester (0.7 g) was dissolved in 60% ethanol (7 ml) and added to Rene's previously hydrogenated catalytic nickel (0.7 g) in 80% ethanol (5 ml). Hydrogenation occurs within 30 minutes at ambient conditions. The catalyst was removed by filtration and washed with ethanol. The combined filtrates were concentrated under vacuum at 35 ° C to an oily residue, which was dissolved in ethyl acetate. Water (20 ml) is added and the pH is adjusted to 1.6 by adding 2% hydrochloric acid to the stirred mixture. The aqueous phase is separated and evaporated under vacuum at 35 ° C. The l-acetoxyethyl-6- (B-cb-amino-mfluorophenylacetamido) hydrochloride penicillanate (0.4 g) is obtained as a crystalline residue.
    The product inhibits the growth of Staphylococcus aureus, Oxford, at a concentration of 0.25 g / ml and gives a strong IR-absorption at 1760, characteristic of / a) lactam. .
    Example 6. 1-Acetoxyethyl6- (D-amino-p-hydroxyphenylacetamido) penicillanate.
    (-) N- (1-Methoxycarbonylpropane 2-yl) -amino-p-hydroxyphenylacetate sodium (2.9 g, 0.01 mol) in dry ethyl acetate (40 ml) is stirred and treated at -15 to -20 ° With N-methylmorpholine (a few drops), and then isobutyl chloroformate (1.4 g, 0.01 mol). After 5 minutes, a solution of 1-acetoxyethyl-6-aminopenicillanate (3 g, 0.01 mol) in ethyl acetate (20 ml) cooled to -15 ° C was quickly added. After stirring for 1 hour without external cooling, the reaction mixture is washed with water, 0.5 M potassium bicarbonate solution, dried and evaporated under vacuum at room temperature to dryness. The residue is dissolved in a mixture (1: 1) of tetrahydrofuran and water (50 ml), stirred and incubated for 30 minutes at a pH of 2.5, by the addition of 2 M hydrochloric acid solution. The tetrahydrofuran is evaporated under vacuum, and the remaining aqueous phase is washed with ethyl acetate, diluted with isopropanol and evaporated under vacuum at room temperature. 1-acetoxyethyl 6- (D-o6 -amino-p-hydroxyphenylacetamido) penicillanate hydrochloride (2.3 g) is obtained in the form of white crystals. The product gives a strong IR absorption at 1760 cm, characteristic of β-lactam and carbonyl groups of esters. It was found to inhibit the growth of Staphylococcxis aureus, Oxford, at the end of tratra, 0.25 mg / ml.
    The solution used for 1-acetoxyethyl-6- (D-OG -aminofens / acetamido) penicillanate is obtained by neutralizing an aqueous solution of its hydrochloride and extracting with ethyl acetate.
    Example 7. 1 -Etoxycarbonyloxyethyl-6- (B- (and -amino-p-hydroxyphenylacetamido) penicillanate.
    According to the procedure of Example 6, 1-ethoxycarbonyloxyethyl-6- (B06 -amino-p-hydroxyphenyl-amido) pencyllanate is obtained, which is liberated as its hydrochloride (1.4 g) from (-) L- (1-methoxycarbonylpropen-2-yl) α-amino-l-oxyphenylacetate sodium (2.8 g, 0.01 mol, and 1-ethoxycarboxyloxyethyl-6-aminopenicillanate (0.01 mol).
    The product gives a strong IR absorption at 1760 cm, indicating the presence of β-lactam and carbonyl groups of esters. It was found that it retards the growth of microorganisms of the Staphylococcus aureus, Oxford species, at a concentration of 0.25 mg / ml.
    Example 8. 1 -Acetoxyethyl6- (bb-amino-3-furylacetamido) -penicillanate.
    N- (1 -Methoxycarbonylpropen-2-yl) -amino-e-furylacetate sodium (2.5 g, 0.0095 mol) and N-methylmorpholine (0.05 ml) in dry ethyl acetate (40 ml), stirred and treated at -15 ° C with isobutyl chloroformate (1.4 g, 0.01 mol). After 5 minutes, 1-acetoxyethyl-6-aminopeniclanate in ethyl acetate (20 ml) was added while stirring was continued at -15 ° C. After 10 minutes after stopping the addition, the cooling bath is removed and stirring is continued for another 45 minutes. The reaction mixture is washed with water, 0.5 mol of sodium bicarbonate and again with water, dried and concentrated under vacuum to an oily residue which is treated with tetrahydrofuranr (20 ml) and water (20 ml) and adjusted to pH 2.5 in 30 minutes by adding dilute hydrochloric acid. A large portion of the tetrahydrofuran is evaporated in vacuo and the aqueous phase is washed with ethyl acetate and lyophilized. The 1-acegoxy-6- (O4-amins-3-furylacetamido) penicillanate hydrochloride (1.9 g) is obtained in the form of a white vitreous mass.
    The product was found to inhibit the growth of a microorganism of the Staphylococcus aureus species, Oxford, at a concentration of 0.63 mg / ml and gives a strong IR absorption at 1760 cm, characteristic of the β-lactam ring and ester groups.
    Example 9. 1-ethoxycarbonyloxyethyl-6- ("; -amino-3-thienylacetamido) penicillanate.
    According to the procedure described in Example 8, 1-ethoxycarbonyloxyethyl-6- ((1b-amino-3-thienyl) hydrochloride is obtained.
    acetamido) penicillanate from 1-ethoxycarbonyloxyethyl-6-a-mnopenicillanate and H- (1-methoxycarbonyl-propen-2yl) -oL-amino-3-thienyl sodium tha.
    The product, as was found, gives a strong IR absorption at 1760 cm, which indicates the presence of the I-lactam ring and the remains of complex esters.
    I'll try it on. 1 -Acetoxyethyl6- (D-b6-amino-3-thieyipacetamido) penicillanate.
    The 1-acetoxyethyl-1-6-o, amino-3-thienylacetamido) penicillanag hydrochloride (1.2 g) is obtained by the procedure of Example 8 from K- (1-methoxycarbonylpropen-2-yl) -o (. -Amino-3-thienylacetate sodium (2.8 g. О, Оt mol) and 1-acetoxyethyl-6-aminopenicillanate (0.01 mol).
    The product gives a strong IR absorption characteristic of β-lactam and ester group (at 1760).
    Example P. Free based 1-ethoxycarbonyloxyethyl-6 (D-ot-aminophenylacetamido) penicillanate.
    1 -Etoxycarbonyloxyethyl-6- (B-v-α-aminophenylacetamido) penicillanate hydrochloride (5.4 g, 0, t1 mole is dissolved in portions in tOO ml of ice-cold water with stirring in an ice bath. With vigorous stirring, 200 ml of diethyl is added) ether, followed by the addition of 5 g of sodium bicarbonate. The mixture is maintained under vigorous stirring for 1 minute when all sodium bicarbonate is dissolved. The org phase is separated and washed with 125 ml of ice water and then dried by stirring for
    Fifteen minutes with an ice bath containing 2 g of magnesium sulphate supply and filtering. While stirring, 100 ml of petroleum ether are added dropwise until a solution is obtained. The latter is then stored at -25 ° C in a refrigerator overnight, giving a crystalline precipitate of plates and long needles (5-10 mm).
    The precipitate is decanted and immediately placed under high vacuum over phosphorus pentoxide to obtain a white product from microcrystalline plates and needles 1.5 g (30%) of the free base of 1-ethoxycarbonyl oxyethyl-6- (0-o6-aminophenylacetamido) penicillanate with a melting point 4849 ° C.
    Data from iodometric analysis showed a purity of 87% and 5.8% penicillanic acid.
    The IR spectrum curve has a strong band at 1780 cm for fi-lactam and at 1760 cm for the carboxylic ester group,
    H-NMR DMCO d6, fi ppm, TMS as internal standard): 1.22 (t., ZN, J 7 Hz); 1.44 (d., MN); 4.15 (q, 2H, J = 7 Hz); 6.62 (q, 1H, J 5 Hz) for the carboxylic ester group and 5.41 (d, 1H, J 5 Hz) and 5.51 (d, 1H, J 5 Hz) for p - lactam protons. The NMR curve showed a resonance for an ester in a mixture of epimers of the ester group at a ratio of 65:35 with S 4.34 and 4.37 (s, 1I) a Cj proton.
    An additional 50 ml of cold (-20 ° C) petroleum ether is added to the mother liquor. The solution is incubated for -25 ° C to obtain a crystalline product from long needles, which are filtered on a cold glass filter C, and washed with 5 ml of cold petroleum ether. The filter with the crystalline product is immediately dried in a cold desiccator, obtaining a crystalline product from long needles (10-15 mm) weighing 0.5 g (10%) with a melting point of 48-5tC.
    Data from iodometric analysis showed a purity of 87%.
    Example 12. The free base of 1-ethoxycarbonyloxyethyl-6- (B-in-aminophenylacetamide) penicillanate.
    3.2 g (0.006 mol) of hydroxdoride
    1-ethoxycarbonyloxyethyl-6- {B- "th aminophenyl acetamido) penicoplanate is dissolved in 150 ml portions of cold water at +1 s and drunk three times with diethylether. The aqueous phase is freed from ether by evaporation.
    under vacuum and added dropwise to 150 ml of cold water while cooling with ice, while at the same time 2.0% sodium hydroxide (0.0066 mol) is added at a rate that the pH is kept constant. nnm 9-9.5, which during the reaction is up to 10 minutes
    2n sodium hydroxide solution is started when 10% hydrochloride solution is added to the reaction solution.
    The precipitated product is spun on a cold (-US) Buchner funnel, washed with 2x5 ml of cold water (+ 0 ° C) and quickly transferred to a desiccator for drying in a vacuum at 1 mm Hg, yielding 2.10 g (75.3 %) of the free base of 1-ethoxycarbo-NSh10KSIETIL-6- (D- "aminophenylacetamido) penicillanate.
    Purity according to mercurimetric analysis (mercury analysis) is 96.4%.
    H-NMR (DMCO d6, S ppm, TMS As an internal standard): 1.22 (t., ZN, J 7 Hz), 1.44 (d, ZN); 4.15 (q, 2H, J 7 Hz), 6.62 (q, 1H, J 5) for the carbonate complex group and 5.41 (d, 1H, J 5 Hz) and 5.51 (d ., 1H, J 5 Hz) for d-lactam protons.
    Example 13. Oral absorption of 1-acetoxyethyl- (compound I) and 1-acetoxycarbonyl oxneth1- (compound II) -6- (D-oi-aminophenylacetamido) penicillanate in humans.
    Oral absorption of 1-ethoxycarbonyloxyethyl-b-O-o-aminophenylacetamido) penicillanate (I) and l-acetoxyethyl-6- (1) - ci-aminophenylacetamido) peniclanate (II) is studied on experiments with 9 healthy male volunteers using 6- ( Do (, -aminofensh1 acetamido) penicillanic acid - ampicillin 2 as a control. Compounds are administered in the form of tablets of the following composition, mg: I II
    Ester
    penicillin 359 338
    101 10
    102 10
    The number of esters corresponds to 250 mg of free ampicillin. As a control, commercially available tablets (doctacillin 0.25 g) containing 250 mg of free ampicillin are used. Tablets are taken by nat (shak. Blood samples are taken at specific time intervals and 1K is taken to their analysis to determine the content of ampicillin with microbiological tests. Table t shows the concentrations of tibiotic in the short-run with mean standard error.
    The average cumulative urine output after 8 hours is as follows,% to the dose:
    Compound I 53,, 5 Compound II 53,7-t-4.9 Ampicillin 34.5 + 2.8 Example 14. Hydrolysis of the complex effects of aminopenicillin into the corresponding aminopenicles in the buffer and in the presence of human serum,
    The total pQJm3 of aminopenicillin esters prepared according to the invention is determined in a buffer solution in the presence and absence of human serum. The esters are incubated for 30 min at 37 ° C at a concentration of 10 g / ml in Sorensen phosphate buffer (pH 7.4), and in another experiment in the same buffer containing 10% human blood serum. Test solutions were extracted with ethyl acetate to remove non-hydrolyzed esters and subjected to microbiological analysis for aminopenicillins, control values were obtained by dissolving the esters in phosphate buffer at the same concentrations and immediately before extraction. The values in table 2 are adjusted.
    As can be seen from the above data, the new compounds exhibit a high rate of their absorption and hydrolysis with an increased maximum serum level and a shorter time to reach it.
    Example 15. Toxicity of aminopenicillin elephant esters when administered intravenously to mice.
    The acute toxicity of the compounds according to the invention upon intravenous administration to mice was investigated. Each dose was tested on a group of 10 animals, and compounds such as hydrochlorides were dissolved in physiological saline and injected into the side of the cyst of the veins to mice that were monitored for 7 days after administration. In all cases, death occurred 2 hours after administration. The results are given in table. 3
    PRI me R 16. Drugs.
    In order to obtain tablets, the following preparations were made:
    a) Hydrochloride 1-acetoxyethyl-b-CTN-aminophenylacetamido) -penncilanata338 mg
    . Starch too ml
    Magnesium Stearate 10 mg
    b) Hydrochloride 1-ethoxycarbryloxyethyl-6-C1 aminofeiacetamino) peishishanshata359 mg Starch 100 mg Magnesium stearate 10 mg
    c) Ethoxycarbonyl6-methylmethyl-6 hydrochloride (pb4 - acnophenylacetamido) penicillinate 350 mg, calcium carbonate 100 MJi Magnesium stearate 10 mg
    d) Hydrochloride-β-ethoxycarbonyloxymethyl-6- (Bod-aminophenylacetylene) penicillinate 359 mg Lactose 100 mg Magnesium stearate 10 mg
    d) Hydrochloride I-ethoxy carbonyloxymethyl 6- (
    -amino-m-fluorophenyl-acetamido) penicillinate 370 mg Microcrystalline cellulose Avicel 100 mg Magnesium stearate 10 mg
    e) 1-acetoxyethyl-6- (B-ob-aminophenylacetamido) penicillinate hydrochloride338 mg
    Calcium carbonate 100 mg Lactose 100 mg
    Magnesium Stearate 10 mg
    The following formulations were prepared for capsule filling: g) 1-acetoxyethyl-6- (1) -ct-aminophenylacetamido) penicillinate hydrochloride 350 mg
    5 mg
    Magnesium stearate
    h) 1-ethoxycarbonshloxyethyl-6- (B-aminophenylacetamido) penicillinate hydrochloride 350 mg
    Lactose 40 mg
    Magnesium Stearate 5 mg
    Preparations were prepared for oral suspensions according to the following formulation:
    i) 1-acetoxyethyl-6- (B-o (, - aminophenylacetamido) penicillinate hydrochloride 34 mg Aluminum monostearate 50 mg Taiin-80 1.2 mg
    Peanut oil Up to 1000 mg k) 1-ethoxycarbonyloxyethyl-6- (D-L-aminophenylacetamido) hydrochloride penitsinlinata36 g.
    Sodium Benzonate 0.48g Sodium Chloride 0.75 g Odorant 4.7 g
    Aerosi 0.3 g
    Antifoam 0.0375 g
    Soap alkali metal sulfate polysaccharides 4.0 g sodium saccharinate. Oh, 1 g Sorbitol °
    Table 1
    权利要求:
    Claims (1)
    [1]
    The method of obtaining complex esters of et-aminopeiicillins of General formula (I)
    S w s
    Rt-CH-CONH-τ — J ′ T ^ CH3 NH 2 0 J — N — k coORy where R ( is phenyl, hydroxyphenyl, fluorophenyl, furyl or thienyl;
    R 2 ~ group of the formula
    -CH-0-C0-R 3
    CH 3 or **
    -CH-0-C00-R,
    I sn 3 >
    where Rj is C | -C 4 -alkyl.
    or their acid addition salts, with the exception that the 6-aminopenicillino ester is sour / g of the formula (II) /
    where R has the indicated meanings, is reacted with an acid derivative of the formula (III)
    Rf-CH-COT A <R {has the indicated meanings; A is an amino group, an azido group or a group of the formula —NH — C═CH — C — 0CH 3 I II
    CH 3 0 where or
    -NH-S
    NOj>
    - a halogen atom or a group of the formula
    Θ®. .
    -ΟΚα or “0 ΝΗ 2 (С $ Нц) 2 in an environment of ethyl acetate, dimethylformamide or chloroform as a solvent at a temperature of from -15 ° C to room temperature, followed by, if necessary, removal of the substituent from the ob-amino group or in the case when A is an azido group, converting it to an amino group and isolating the desired product in free form or in the form of an acid addition salt.
    Priority but featured:
    09/17/70. when Rj is methyl and A is amine at R - C 2 - C-alkyl and A is an amino group or an azido group; 11/20/70. Group.
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    SE7012688A|SE374747B|1970-09-17|1970-09-17|
    SE1572070A|SE380806B|1970-11-20|1970-11-20|PROCEDURE FOR MAKING NEW ESTRAS OF ALFA-AMINOPENICILLINS|
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