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  • 专利说明
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    • 专利摘要:
    The present invention relates to hitherto unknown compounds of the general formula I: <IMAGE> I in which R1 stands for a five- to ten-membered azacycloalkyl or azabicycloalkyl residue attached via the nitrogen atom and optionally being substituted by one or two, the same or different, lower alkyl groups; R2 represents a hydrogen atom or a lower alkyl, aryl, or aralkyl radical; and A represents a radical of a beta -lactamase inhibitor containing a beta -lactam ring as well as a carboxy group, A being connected via the carboxy group.
    公开号:SU1015830A3
    申请号:SU802882798
    申请日:1980-02-12
    公开日:1983-04-30
    发明作者:Оле Годтфредсен Вагн；Фон Даене Велф
    申请人:Лео Фармасьютикал Продактс Лтд А/С (Левенс Кемиске Фабрик Продукционсактиесельскаб) (Фирма)；
    IPC主号:
    专利说明:

    4. A method for preparing 9-fat complexes of 6-amidinopenicillanic acids of general formula
    . n ench
    ) - .to.
    (fH-A:
    o and i
    de p 6 or 7;
    R is hydrogen or methyl; A is a radical (11), (111) or (IV)
     4lHVx i
    tO ""
    about-rNf n
    n
    14) about
    where R is hydrogen or. chlorine;
    R is hydrogen or 2, b-dimethoxy benzamide group, at least one of the radicals q, and R is hydrogen.
    ciHj
    n ..
    -eNe
    -IT C
    (one)
    Ogde R- - bromine or iodine
     HE
    L .CJH. ixOv CjH
    .0 0Н
    or their acid addition salts with, and characterized in that the compound of formula U11
    A-CH-X (Y11)
    R where A and R have the indicated meanings;
    X is a leaving group, is reacted with a compound of the formula
    -. H N
    (ClHzllf-rf.
    - TT RSNZ
    About N {-0o
    where n has the indicated values;
    M is a cation,
    and select the desired product in free form or as an acid addition salt.
    5. The method according to p. 4, I distinguish. u and with the fact that they use a compound of formula (Y11), where X is a halogen.
    6. Method pop. 4, which differs from the fact that a compound of formula (1) is obtained, where p b, R is hydrogen and A is a radical of formula (11), where R and RZ. - hydrogen.

    Priority signs: 13.02.79 while A is a radical of formula 11,
    where H and H 2, is hydrogen;
    P 6 or 7;
    R is hydrogen or methyl. 06.19.79. pri.A - radical of formula 11
    where R is hydrogen and R is a 2,6-dimethoxybenzamide group or R is chlorine and Rg is hydrogen, or A is a radical of formula 111 or IV; n 6 or 7; ,
    R is a hydrogen atom or methyl.
    The invention relates to a method. obtaining new penicillin antibiotics that can be used as medicinal substances in medicine and in veterinary practice, as well as to its variant. .
    A known method of producing bisesters of 6-amidino-penicillan acids and 1,1-diols, namely l, l-6HCi j 6- (polymethyleneimino) methylenamino} -penicillanoyl oxy 5 alkanes or their addition salts with acids, by the interaction of 1-halogen- (or 1-h -toluolsulfoniloksi-) -alkyl ester b- C (polimetilenimino) metilensu "shn7-penicillanic acid with an alkali salt of the 6-C (-polimetilenimino) methylene Mino -penitsillanovoy acid in a solvent followed by isolation of the desired product in the free form or in acid -addition salt Cl.
    These compounds have an effect on many .gram-negative bacteria and can be used both parenterally and orally.
    In the clinical practice of treating bacterial infections, a serious problem, however, is the growing occurrence of bacteria that secrete r-lactamaeu, which inactivate most (5-lactic antibiotics. Therefore, the detection of compounds with both antibacterial activity and the ability to inhibit β-lactamase. The purpose of the invention is to expand the arsenal of penicillin antibiotics of a number that simultaneously possess inhibitory properties of β-lactamase. This is known to the reaction of the preparation of esters to the method for the preparation of esters of b-amidinopenicillanic acids, the formula (6C -HNCZe-O-CH b or 7; hydrogen or methyl; a radical of formula (11), (1 or (IV) ) -i V. (JH. t j4 RZ ciH3 about JN- / V where R is hydrogen or chlorine; R is hydrogen or 2, b-dimethoxy is benzamide,. and at least one of the radical R and H is hydrogen. H H dHj 3 (iH5 1 -N where R a is bromine or iodine; I "ij-y--" or their additive salts with an acid, which consists in the combination of the formula (Y) AND H, J ,,. No) „n- ° / -“ - 0 - o to i where n and R have the indicated values X is a leaving group, interact with the compound of the formula A - M (U1) where A has the indicated values M - cation f. and isolate the desired product in free form or as an acid addition salt. In addition, a compound of formula A-CH-X where A, R and X have the indicated meanings. is reacted with a compound of the formula (Y111 H H, -. c, Hz (dH4ii-eH-Nsr, K, where n and M have the indicated values), and the desired product is isolated in free form or as an acid addition salt. According to The proposed method preferably uses a compound of formula (Y) or a compound of formula (Y11), respectively, (where X. is halogen.) According to the proposed method, the compound of formula (1) is mainly prepared, where pb, R is hydrogen, and A is a radical of formula (11) where R and R 4 are hydrogen. In compounds of formula (A1) and (Y111), M may mean sodium cation potassium, ammonium or tetraalkylammonium, for example tetrabutyl ammonium. The reaction between compounds of formulas (y) and (U1) or formulas (UH) and (U111) is carried out in a suitable solvent, for example dimethylformamide, ethyl acetate, dichloromethane, acetone or triamide hexamethylphosphorus , for a sufficient time and at suitable temperatures, the values of which are determined by the required degree of conversion, and are in the range from 0 to. The compounds of formula (1) are intended for enteral use and have strong antibacterial activity in vivo. These compounds have a positive effect against bacteria secreting beta β-lactamase, because the same molecule contains both the 6-amidinopenimillanic acid group, which has a high antibacterial activity, and the group of a strong beta-lactamase inhibitor.
    However, to realize these properties of new compounds, the following two conditions are required. They must be absorbed in the gastrointestinal tract and, during or after absorption, must undergo hydrolysis to release amidinopenicillanic acid and a beta-lactamase inhibitor. It turns out that both of these conditions are fulfilled / and / therefore / the present compound is a valuable drug that
    . inherent properties as amidinopeni; cyllic acids and inhibitors
    beta lactamay.
    Studies conducted on animals and human volunteers have shown that animal compounds are easily absorbed in the gastrointestinal tract. When or after absorption, these compounds are hydrolyzed with the use of equimolar amounts of these two compounds, such as (6-amidinopenicillanic acid and inhibitor beta-lactamase), which leads to a simultaneous increase in the content of both components both in blood and in blood.
    fabric x Because of this, b-amidinopenicillanic acids are most effectively protected from inactivation by beta-lactamases.
    The effective in vivo uptake and hydrolysis of the proposed compounds is illustrated by experiments conducted on volunteers who were orally given one of the new compounds, namely 1/1-dioxopenicillanoyl oxymethyl b- (hexahydro-1H-azepin-1-yl) methylene-amino-penicillanoic acid hydrochloride, hereinafter referred to as VD-1825.
    For comparison, the same group of volunteers were also given equimolar amounts of the orally active pivaloyloxymethyl ester of the mecillinam (mecillinam — the traditional name of 6-G (hexahydro-1H-aepin-1-yl) methylenamino-penicillanic acid) / hydrochloride, m. , 1-dioxide, respectively.
    The data of these experiments are given in table. 1 and 2,
    (b
    I
    F
    Table 2. Excretion with urine for 0-6 penicillanic acid 1,1-dioxide in a healthy patient with oral administration of 60 mg of potassium penicillanate-1, 1-dioxide (corresponding to 52 mg of penicillanic acid dioxide 1.1 in aqueous solutions ( A) and 128 mg of VD-1825 gyrochloride (corresponding to 49.0 mg of penicillanic acid 1,1-dioxide) in aqueous solutions (B) 2.9 83 average 4.3 77 From Table.  1, it follows that oral administration of VD-1825 leads to an increase in serum levels of mecilliname in the serum to the same level as with the introduction of an equimolar dose of pivmecinelinam.  From the data of the same table, it follows that the release of mecillinam with urine upon administration of VD-1825 is comparable to that achieved with the administration of pivmecillinam.  As follows from the table. 2, only 4.3,3 of penicillanic acid 1,1-dioxide is excreted in the urine after oral administration of the corresponding potassium salt.  In contrast, the administration of an equimolar amount of VD-1825 is accompanied by a 77% urinary excretion of penicillanic acid 1,1-dioxide.  This illustrates the suction efficiency of either the VD-1825.  The compounds can be used in pharmaceutical compositions that are suitable for treating infectious diseases in humans and in animals, and allow enteral, parenteral or topical treatment. Such compositions include at least one active compound from the group containing compounds of the formula (1) or salts thereof with solid or liquid pharmaceutical carriers and / or diluents.  In these compositions, the ratio of therapeutically active substance to carrier can vary from 1 to 95% by weight. %  The compositions can be formulated in various pharmaceutical forms, for example, in the form of tablets, pills, dragees, suppositories, capsules, long-release tablets, suspensions, and in similar forms containing the compounds of formula (1) or their non-toxic salts, in a mixture with a carrier. mi and / or diluents.  Pharmaceutically acceptable, non-toxic, organic or inorganic, solid or liquid carriers and / or diluents can be used to make the compositions.  Gelatin, milk sugar, starch, magnesium stearate, talc, vegetable or animal fats and oils, gum, polyalkylene glycol, buffers or other known carriers, auxiliary components and / or diluents for medical products are suitable for this purpose.  In addition, the compositions may contain other therapeutically active components, which are expediently administered with the proposed compounds in the treatment of infectious diseases.  diseases, such as antimicrobials, antitussives, pain medications, probenecid, and similar drugs.  In particular, it is desirable to use antimicrobial agents, such as penicillins or cephalosporins, which have a synergistic effect in a mixture with one or both of the active components that are formed during in vivo hydrolysis of the proposed compounds.  The compounds of formula (1) may be used either as such or as salts.  As such, the compounds are only slightly soluble in iodine, while many salts, for example hydrochlorides (chlorohydrates), are readily soluble in water.  Pharmaceutical compositions suitable for oral administration may be a suspension of one of the compounds according to the invention, the compositions containing 10-100 mg of the active ingredient per 1 ml of carrier.  The compounds described are administered in two doses / that the required activity is achieved without concomitant secondary reactions.  In therapeutic practice, the proposed compounds are used in the form of dosage forms containing 50 to 2500 mg, preferably 100 to 1000 mg of the compound of formula (1) or its salt, the amount of the latter being calculated as equivalent compound to compound (1).  By expression, the dosage form is meant as a single dose that can be administered to a patient and is easily molded and packaged, a dow physically stable single dose that contains either active materials as such, or their mixture with solid or liquid pharmaceutical solvents, carriers, solvents mi and / or excipients.  The compounds in dosage forms can be administered to the patient once or several times a day through appropriate intervals, which depend on the condition of the patient and comply with the doctor's prescription.  Thus, the daily dose will preferably include from 0.25 to 15 g of the compound. Formula (1) or sKBtiaal is the amount of its salt, as defined above, and it is advisable to divide this daily dose into several single doses.  With long-term treatment of patients suffering from infectious diseases, convenient pharmaceutical forms are tablets or capsules, and if necessary, slowly dissolving compounds. In veterinary practice, it is also possible to use the above pharmaceutical compositions, preferably in dosage forms, which contain 50 - 25 g of a compound of formula (IV or an appropriate amount of a salt thereof.  In the treatment of diseases of the mammary glands, especially mastitis, antimicrobial agents can be administered into the gland as a liquid or in a semi-liquid form, such as an ointment, or together with substantially non-soluble or HepacTBOpHKOJM in an oil-binding agent in the form of granules.  The compounds of formula (1) are usually administered in amounts of 3-200 mg / kg patient weight per day, which for an adult patient corresponds to 0.25 15 g per day, or an equivalent amount of the compound of formula (1), which corresponds to the definition given above.  Example 1  1,1-Dioxane pephenicillanoyl oxymethyl b- (hexahydro-1H-azepin-1-yl-methylene hydrochloride) M-penicillanic acid.  To a solution of 1.87 g (5 mmol) of chlorine methyl ester of 6- (hexahydro-1H-azepin-1-yl) methylenamin-J-penicillanic acid in 25 ml of dimethylformamide was added 1.36 g (5 mmol) of 1,1-dioxopenicillanate.  potassium and mixture Stir at room temperature for 48 h.  75 ml of ethyl acetate is added and the mixture is washed with water (4-25 ml) to remove dimethylformamide.  The remaining organic phase is dried and discolored by mixing with coal.  After the carbon is filtered off and the filtrate is concentrated to approximately 30 ml, 25 ml of water are added and the pH of the mixture is adjusted to 2.6 by adding 4 n.  hydrochloric acid with stirring.  The aqueous phase is separated and freeze dried.  The result is the target compound in the form of an amorphous powder.  NMR spectrum () with (, 48 and 1.55 (2S, bN; C (CH3) 1); 1.60 and 1.72 (25, 6H; C (CH5) a) g 1.68 {b, 8H; CH2. CH / s, CH, 2) s, 65 (w, 6H; CHoNCH ,, 6oL-H and 6p-H), 4.68 (5, 1H; 3-H), 4.75 (S, 1H; 3 -H), 5.08.  (d-Sil 4HZ, 1H; 5-H), 5.56 (d ,, HZ, IH; 6-H), 5.68 (d, IH; 5-H), 6.02 (S, 2H,) and 8.03 (S, IH; M-CH-N) ppm.  million  share.  Tetramethylsilane is used as an external standard.   .  Isopropanol is added to a solution of 0.5 g of the resulting product in 1.5 ml of methanol until the solution is cloudy, and crystallization is induced by seeding.  After soaking in the refrigerator for 24 hours, the crystals are filtered, washed with isopropyl alcohol and dried in vacuo.  The result is the target compound as a colorless crisstaclic product that does not have a specific melting point (slow decomposition at temperatures above 120 s).  IR-crteKTp (KBG) indicates the presence of bands V1690 and 1790 cm (wide).   Example 2  1,1-dioxopenicillanoyloxymethyl ester of 6 -Phexahydro-1H-azepin-1-yl) methylamino-penicillanic acid.  To solution 1 ,. 63 g (5 mmol) (hexahydro-1-azepin-1-yl) -methylamino-penicillanic acid and 0.7 ml (5 mmol) of triethylamine in 25 ml of dimethylformamide were added 1.41 g (5 mmol) of chloromethyl ester 1, 1-dioxopenicillanic acid and the mixture is stirred at room temperature for 16 hours  After dilution with 75 ml of ethyl acetate, the mixture is washed with water (ml), and the remaining organic phase is dried and decolorized with charcoal.  The carbon is filtered off and 35 ml of water are added to the filtrate, the pH of the mixture is adjusted to 2.8 by the addition of 2N.  hydrochloric acid when mixed.  The aqueous phase is separated and freeze dried.  In The result is amorphous. compound identical to that obtained in example 1.  Example 3  Analogously to example 1, 1,1-dioxopenicillanoyloxymethyl-6-C (hexahydro-1 (2H) -azocin-1-yl) methyleneamino-penicillanate hydrochloride is obtained.  NMR spectrum (Szue, tetramethylsilane as an internal standard) showed peaks at; cG 1.46 (S, 3N 2-CHj), 1.57 (S, 6H; 2-СНз), 1.74 (S, 3N; 2-СН), 1.5-2.0 (ki, YUN ; (SNZ. )) g 3.2-3.8 (t, bN; (CH,) ,. M, bsb-H and br-H), 4.48 (5, 1H; 3-H); , 4.63 (5, 1H; 3-H), 4.93 (t, 1H; 5-H 5.53 (Sr:) 4 Hz, 1H 6-H), 5.63 (d, 1H, 5-H), 5.97 (, 2H, OCH O) and / 8.18 (S, 1H; N-CH N) ppm.  Example 4  In a similar manner to Example 1, clavulino yloxymethyl-b- (hexahydro-1H-azepin-1-yl) methylamino-penicillanate hydrochloride (NMR spectrum; SASR / tetramethylsilane) was shown as an internal standard; CH,), 1.65 (S, 3N; 2-СНз), i, 4-2.0 (m ,.  8H; (CH), 3.11 (d, Hz, 1H; 6P-H), 3.48 (dd, j 17 G -J-3 Hz, 1H; 6a, -H), 3.3-3.6 ( l, 4H; (CH) aM), 4.22 (d ,. 7 Hz, 2H; 6H OH), 4.41 (5, 1H; 3-H), 4.91 (b, J-7 Hz, 1H; C -CH), 5.08 (S, 1H; 3-H), 5, 18 (d, J - 4 Hz, 1H; 6-H), 5.51 (c, Hz, 1H; 5-H), 5.68 (d, d-3 Hz, 1H; 5-H), 5.87 (t, 2H;) and 7.60 (S, 1H;) h / m. Example 5.  Analogously to Example 1, 6 (-Bro-penicillanoyloxymethyl-6- {(hexahyl-1H-azepin-1-yl) -methylenamino-penicillanate hydrochloride is obtained.  NMR (D) showed signals at (, 48 (5, 3N; 2-СН ,,), 1.51 (S 3N; 2-СНз), 1.62 (S, 3N; 2-СНз), 1 , 68 (S, ЗН; 2-СНз), 1.4-2.0 (g, 8В; (СН2) 4, 3.47-3.75.  (“4H; 4.71 (S, 1H, 3-H), 4.76 (S, 1H; 3-H 5.46, 5.69, 5.62, and 5.66 (4d, Hz 8H; 5-H and 6-H), 5.93 (S, 2H;) And 7.97 (5, 1H;) ppm.  S is a singlet, d is a doublet, t is a three plet, W is a multiplet, Example 6.  Hydrochloride of 1,1-dioxopenicillanoyloxymethyl ester of 6- (hexahydro-1H-azepin-1-yl-methylene-amino-penicillan acid).  To a cooled mixture of 5.85 g (18 mmol) of 6-C (hexahydro-1H-azepin-1-yl) methylenamine -bags. -. Llanoic acid and 6.12 g (18 mol) of tetrabutylammonium hydrogen sulphate in 35 ml of dichloromethane and 35 ml of water are added 18 ml of 2N.  sodium hydroxide with stirring.  The organic layer is separated, the aqueous phase is re-extracted with 15 ml of dichloromethane, and the combined dichloromethane extracts are dried over magnesium sulfate and evaporated in vacuo.  The resulting colorless oil is dissolved in 100 ml of ethyl acetate and the resulting solution is concentrated to about half under reduced pressure, to the concentrate is added one portion of a solution of 1,1-dioxopenicillanic acid iodomethyl ester (5.6 g, 15 mmol) and (The mixture is stirred at room temperature temperature for 10 min.  The tetrabutylammonium iodide precipitated out is filtered off, 75 ml of water is added to the filtrate and the pH of the stirred mixture is adjusted to 3.0 by adding 1N.  hydrochloric acid at 5C.  The aqueous phase is separated and under a layer of ethyl acetate (50 ml) the pH is adjusted to 7.2 by adding 0.5 M aqueous sodium bicarbonate with stirring.  After separating the organic layer, 50 ml of water are added and the pH of the stirred mixture is adjusted to 3.0 with 1 n.  hydrochloric acid.  The aqueous phase is separated and freeze dried.  The result is the target compound in the form of a colorless amorphous powder.  A solution of 5 g of this product in 15 ml of ethyl alcohol is diluted with about 20 ml of isopropyl alcohol until the solution becomes cloudy, and the mixture is seeded.  After stirring at room temperature for about 1 hour, a dense crystalline precipitate is formed.  A mixture. 40 ml of isopropyl alcohol are gradually diluted and kept for 3 hours.  The precipitate is filtered off, washed with isopropanol, and then with ethyl ether and dried in vacuum.  As a result, the desired product is obtained in the form of colorless crystals with an indefinite melting point (slow decomposition above 120 s) identical to the product described in Example 1.  Example 7  1,1-Dioxopenicillanoyloxymethyl b-, (hexahydro-1 (2H) -azotsin-1-yl) methyleneamino-penicillanic acid hydrochloride.  Following the procedure of Example 6 and using instead of 6- (hexahydro-1H-azepin-1-yl) methylamino-penicillanic acid 6- (hexahydro- (2H) -azocin-1-yl) methylamino-penicillanic acid, the desired compound is obtained as colorless freeze dried powder.  NMR spectrum (, TMS as an internal standard): at (f-1.46 (S, 3N; 2-СНз), 1.57 (B, 6H; 2-СНз), 1.74 (S, 3N; 2-SS) 1.5-2.0 (t, YUN; (CH2) j. ), 3.2-3.8 (m, 6H; (CHa), 2N, 6oL-H and 6p-H), 4.48 (S, IH; 3-H), 4.63 (S, DN; 3-H), 4.93 (m, IH, 5-H) 5.53 (d, J-4 Hz, IH; 6-H), 5.63 (d, j-4 Hz, IH, 5- H), 5.97 (5, 2H, OCHjO) and 8.18 (S, IH;) mln.  share.  Example 8  1- (1,1-Dioxopenicillanoyloxy) ethyl ester of b- (hexahydro-1H-azepin-1-yl) methylamino-penicillanic acid hydrochloride.  To a solution of 4.53 g (8 mmol) of 6-C (hexahydro-1H-azepine 1-yl) methyl and amino3-penicillanate tetrabutyl ammonium in 40 ml of ethyl acetate was added a solution of 1,1-dioxopenicillanic acid 1-iodo-ethyl ester (8,13 g, 38% purity, which corresponds to 3.09 g or 8 mmol) in 25 ml of ethyl acetate.  After stirring for 5 minutes at room temperature, the separated tetrabutylammonium iodide is filtered off and washed with ethyl acetate.  From the filtrate, the target compound is transferred to the aqueous phase (40 ml) with hydrochloric acid (pH 3.0) and from the aqueous phase to the organic phase (ethyl acetate, 40 ml) with aqueous sodium bicarbonate (pH 7.0).  The organic phase is washed with water, and the target compound is again extracted into the aqueous phase, as described in. higher.  By freezing the aqueous phase, the desired compound is obtained as a colorless solid.  The following peaks were found in the NMR spectrum (D, O): at, 50 (5); 1.56 (5); 1.61 (s); 1.66 (c1) 1.73 (s); 1.5-2.0 (t), 3.20-3.85 (t); 4.61 (;), 4.75 (S); 5.10 (t).  5.53 {d,); 5.68 (d,: J-4); 7.05 (CV, J 7) 8.03 (5).  Example 9  1,1-Dyoxo-6- (2,6-dimethoxybenzamido) penicillanoyloxymethyl 6- (hexahydro-1H-azepin-1-yl) hydrochloride 6-penicillanic acid ester To ice-cooled solution 1.11 g X2 mmol) iodomethyl ether 1,1-DIOXO-6- {2,6-dimethoxybenzamido) -penicillanic acid in 10 ml of dimethylformamide 0.7 g (2 mmol) of 6- (hexahydro-1H-azepin-1-yl) methylamino-3-penicyl sodium sodium .  After stirring for half an hour at room temperature, the mixture is diluted with 4 O ml of ethyl acetate and washed with water (4 x 10 ml).  The organic phase is stirred with water and hydrochloric acid is added at the same time to pH 3.  The aqueous phase is freeze-dried, whereby the target compound is obtained as a colorless powder.  The NMR spectrum (SVZOK) has the following signals: at, 47 (S, ZN; 2-CHE), 1.58 (5, bN; 2-CH3), 1.76 (5, ZN; 2-CH3), 1.25-2.25 (t, 8H; (CH2) 4) 3.5-4.0 (t, 4H; (Srg)), 3.83 (5, 6H; OCH,), 4.67 ( 5, 1H; 3-H), 4.70 (S, 1H; 3-H), 5.29 (d, i4 Hz, 1H; 5-H), 5.5–5.8 (t, 2H; 5-H, 6-H). , 6.03 {t, 2H; ), 6.26 (d, :) 4 Hz, 1H; 6-H), 6.71 (, 2H; aromatic 3-H and 5-H), 7.41 (-t, 1H; aromatic 4-H) and 8.21 (5f 1H, N-CH-N) million  share.  Tetramethylsilane is used as an internal standard.  Example 10  Clavulanoyloxymethyl ester of 6-E (hexahydro-1H-azepin-1-yl) methylenamino-penicillanic acid.  To a solution of 0.23 g {0.5) β-methyl hexahydro-1H-azepin-1-yl-methylamino-3-pencyllanic acid ester methyl ester in 3 ml of hexamethylene phosphoric acid triamide, 0.1 g (0.5 mmol) of clavulanate is added lithi.  After stirring for 90 minutes at room temperature, the mixture was diluted with 20 ml of ethyl acetate and washed with water (410 ml).  The organic phase is stirred with water (20 ml) while adding hydrochloric acid to pH 3.  The aqueous phase is separated and stirred with 10 ml of ethyl acetate, while aqueous sodium bicarbonate is added to pH 7.  The organic phase was dried and evaporated to give an oil, which was purified by chromatography on Sephadex / H-20 (8 g).  The desired product is isolated in the form of a colorless oil.  The following signals were found in the NMR spectrum (CDCE, tetramethylsilane as an internal standard): at (1.49 (S, 3N; 2-СН,), 1.65 (S, 3N, 2-СН ,,), 1, 4-2.0 (t, 8H; (CHa) 4) 3.11 (d, -J-l7 Hz, 1H; brg-H); 3.48 (d, dr Hz, 3-3 Hz, 1H, bo -H), 3.3-3.6 (UE, 4H; (CH2) zN), 4.22 (d, Hz, 2H;), 4.41 (5, 1H; 3-H), 4.91 (-fc, 3-7 Hz, 1H, CgCH), 5.08 (5, 1H, 3-H), 5.18. (C1, J-4 Hz, 1H; b-H) ,. 5.51 (d, J-4 Hz, 1H, 5-H), 5.68 (d, HZ, 1H; 5-H), 5.87 (gp, 2H;. ) and 7.60 (s, 1H; V1-CH-W) ppm.  share.  Example 11  6p-Bromopenicillanioxymethyl 6-C (hexahydro-1H-azepin-1-yl) -methyleneamino-penicillan O hydrochloride hydrochloride Acid.  To a solution of 6.52 mg (1.40 mmol) of 6- (hexahydro-1H-azepin-1-yl) methylamino-penicycillanic acid iodomethyl ester in 15 ml of dimethylformamide was added 535 mg (1.68 mmol) of potassium-bromopenicillanate potassium.  After stirring for 30 minutes at room temperature, the mixture is diluted with 60 ml of ethyl acetate and is wiped off with water (4-15 ml).  The organic phase is separated and concentrated in vacuo to approximately 20 ml.  15 ml of water are added to the concentrate and the pH of the stirred mixture is adjusted to 3 by the addition of 0.5N.  hydrochloric acid.  The aqueous phase is separated and freeze dried.  As a result, the target compound is obtained as a colorless foam. In the NMR spectrum () the presence of the following signals was established at, 48 (5, 3N, 2-СН), 1.51 (5, З 2-СНз), 1.62 ( 5, ZN; 2-С%), 1.68 (S, ZN; 2-СНз), 1.4-2.0 (hi, 8Н; {СНа. ) 4), 3.47-3.75 (t, 4H; (.  4.71 (5, 1H; 3-H), 4.76 (S, 1H; 35, 46, 5.59, 5, C2, and 5.66 (4d, Hz, 8H; 5-H, and -H ), 5.93 (, 2If; OCH2. O and 7.97 (5, 1H; V1-CH N) ppm.  share.  Example 12  Hydrochloride 6 | • iodopenicillanoyl oxymethyl ester of 6- (hexahydro-1H-azepin-1-yl) methylenamino D-penicillanic acid.  Following the method described in example 11, but replacing the corresponding 6 (-6 ppm 6p-potassium iodopenicillanate), the target compound is obtained as a colorless powder. The IR spectrum (KBr) shows the presence of strong bands at 1780 and 1680 cm.  Example 13  Hydrochloride of 1, -dioxopenicillanoyloxymethyl ester of 6- (hexahydro-1H-azepin-1-yl) methylamino3-penicillanic acid.  BUT.  6p) -aminopenicillanate tetrabu tylammonium.  To a stirred, cooled mixture of 6p-amino-penicillanic acid (4.32 g, 20 mmol), tetrabutylammonium sulphate (6.8 g, 20 mmol), dichloromethane (50 ml) and water (20 ml) are slowly added 60 g (40 mmol) of sodium hydroxide in 3.5 ml of water.  The organic layer is separated and the aqueous layer is extracted with dichloromethane (2-25 ml. The combined organic layers are dried and evaporated in vacuo to give the title compound as a viscous oil.  In the IR spectrum (CHCP-j,), the presence of strong bands at 1760 and 1610 cm is detected.  B.  Br-aminopenicillanic acid 1,1-dioxopenicillanoyloxymethyl ester hydrochloride.  A solution of 3.73 g (10 mmol) of 1,1-dioxopenicillanic acid iodomethyl ester in 25 ml of ethyl acetate was added to a solution of 5.1 g (11 mmol) of tetrabutylammonium 6p-aminopenicillate in 25 ml of ethyl acetate.  After stirring for 15 minutes at room temperature, the precipitate is filtered off and the filtrate is evaporated in vacuo.  The residue is purified on a Sephadex (trade mark) UH 20 chromatography column using a mixture of chloroform and hexane (65:35) as an eluting solvent.  The purified product is dissolved in 25 ml of ethyl acetate, 25 ml of water are added and the pH of the mixture is adjusted to 2.0 by adding normal hydrochloric acid.  The aqueous phase is separated and freeze dried.  The result is the target compound in the form of a colorless powder.  The following signals were detected in the NMR spectrum: at, 52 (5, 3N; 2-С%), 1.60 (5, 3N; 2-СНз), 1.65 (5, 3N; 2-СНэ), 1 , 76 (s, 3N; 2-CH ,,), 3.52-3.8 (5, 2H; 6-H), 4.78 (5, 1H; 3-H), 4.90 (5, 1H; 3-H), 5.05-5.25 (№, 1H; 5-H), 5.20 (d, j4 Hz, IB; 6-H), 5.78 (d, j - 4 Hz , IH, 5-H) and 6.08 (, 2H; OCH / jG) ppm, fractions, tetramethylsilane is used as the external standard.  AT .  1,1-dioxpenicillanoyl oxymethyl ester of 6ji-aminopenicillanic acid.  The hydrochloride obtained in (B) is dissolved in water and cooled in an ice bath.  Ethyl acetate is added and a saturated sodium bicarbonate aqueous solution is added with stirring until the pH of the aqueous phase is about 7.  The organic phase is separated, dried and evaporated in vacuo to give the title compound as a yellow oil.
    权利要求:
    Claims (6)
    [1]
    1. A method for producing esters of b-amidinopenicillanic acids of the general formula or their additive distinguishing uv) salts with acids, where I where
    6 or 7; hydrogen or methyl; a radical of formula (11) or (1U). compound of the formula
    W) where
    Kg
    R 3 is hydrogen or R is hydrogen or benzamide
    Sn e 'CH3 4 C-011 0 chlorine;
    [2]
    2,6-dimethoxy group, wherein (i) at least one of the radicals R ^ hr is hydrogen;
    where η and R have the indicated meanings;
    X is a leaving group, is reacted with a compound of the formula
    A - M (U1) where A has the indicated meanings:
    M is a cation, and the target product is isolated in free form or in the form of an addition salt with an acid.
    2. The method according to π. 1, characterized in that the use of a compound of formula Y, where X is halogen.
    [3]
    3. The method of pop. 1, characterized in that a compound of formula (1) is obtained, where η = 6, R is hydrogen, A is a radical of formula (11), where R 4 and R 2 are hydrogen.
    SU „„ 1015830
    [4]
    4. The method of obtaining esters of 6-amidinopenicillanic acids of the General formula or their additive salts with acids, characterized in that the compound of formula U11
    A — CH — X (Y11),
    R where A and R have the indicated meanings; X is a leaving group, is reacted with a compound of the formula ^ !!!
    where η i 6 or 7;
    R is hydrogen or methyl;
    A is a radical of the formula (11), (111) or (1U) (VIII) where R is hydrogen or. chlorine;
    R 4 is hydrogen or 2, b-dimethoxy 1 benzamide group, with at least one of the radicals R, and r 2 is hydrogen, bromine or iodine where R, o (IV) where η has the indicated meanings;
    M is a cation, and the target product is isolated in free form or in the form of an addition salt with an acid.
    [5]
    5. The method of pop. 4, distinguish. and the fact that they use the compound of the formula (Y11), where X is halogen.
    [6]
    6. The method of pop. 4, characterized in that a compound of formula (1) is obtained, where η = b, R is hydrogen and A is a radical of formula (11), where R 4 and R z are hydrogen.
    Priority by signs: 02/13/79 at A - radical of the formula 11, where R 4 and R 2 - hydrogen;
    η = 6 or '7;
    R is hydrogen or methyl.
    06/19/79. at.A is a radical of formula 11, where R is hydrogen and R is a 2,6-dimethoxybenzamide group or R ^ is chloro and R a is hydrogen, or A is a radical of formula 111 or 1U;
    η at 6 or 7;
    R is a hydrogen atom or methyl.
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    同族专利:
    公开号 | 公开日
    SE8001100L|1980-08-14|
    SG43683G|1984-08-03|
    PT70806A|1980-03-01|
    DK59380A|1980-08-14|
    LU82163A1|1980-09-24|
    YU35980A|1983-04-30|
    YU42098B|1988-04-30|
    CU35227A|1982-03-28|
    IE800170L|1980-08-13|
    CA1144540A|1983-04-12|
    CH646176A5|1984-11-15|
    DD149528A5|1981-07-15|
    AT370106B|1983-03-10|
    AU532244B2|1983-09-22|
    GB2045746B|1983-05-11|
    PL221963A1|1980-12-01|
    FI71741C|1987-02-09|
    US4325960A|1982-04-20|
    AU5540080A|1980-08-21|
    FI71741B|1986-10-31|
    GB2045746A|1980-11-05|
    CS236766B2|1985-05-15|
    DE3005220A1|1980-08-21|
    AR230640A1|1984-05-31|
    GR73697B|1984-04-03|
    CY1206A|1983-12-31|
    HK5784A|1984-01-20|
    FR2449090A1|1980-09-12|
    NL8000881A|1980-08-15|
    HU182663B|1984-02-28|
    FR2449090B1|1983-07-29|
    PL127413B1|1983-10-31|
    MA18732A1|1980-10-01|
    ES488493A0|1980-12-16|
    KE3308A|1983-08-19|
    IL59257D0|1980-05-30|
    IT1128361B|1986-05-28|
    FI800412A|1980-08-14|
    IE49371B1|1985-09-18|
    IT8067207D0|1980-02-12|
    IL59257A|1983-09-30|
    MY8500007A|1985-12-31|
    ATA61680A|1982-07-15|
    ES8101595A1|1980-12-16|
    NZ192776A|1984-09-28|
    PH16933A|1984-04-17|
    SE446187B|1986-08-18|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3957764A|1969-11-11|1976-05-18|Lovens Kemiske Fabrik Produktionsaktieselskab|6-aminopenicillanic acid derivatives|
    GB1335718A|1971-05-05|1973-10-31|Leo Pharm Prod Ltd|Penicillin esters salts thereof and methods for their preparation|
    US4089963A|1972-03-13|1978-05-16|Astra Pharmaceutical Products, Inc.|Esters of amidinopenicillanic acids, pharmaceutical preparations and method for treating infectious diseases|
    GB1578128A|1976-03-30|1980-11-05|Leo Pharm Prod Ltd|Amidinopenicillanoyloxyalkyl amoxycillinates|LU77362A1|1977-05-17|1979-01-19|
    US4364957A|1979-09-26|1982-12-21|Pfizer Inc.|Bis-esters of alkanediols as antibacterial agents|
    US4393001A|1981-03-23|1983-07-12|Pfizer Inc.|Intermediates for production of 1,1-dioxopenicillanoyloxymethyl 6-penicillanates|
    FR2520362B1|1982-01-26|1986-04-11|Leo Pharm Prod Ltd|NOVEL B-LACTAM TYPE COMPOUNDS, INCLUDING THEIR SALTS FORMED WITH ACIDS OR BASES ACCEPTABLE IN PHARMACY, METHODS FOR PRODUCING THE SAME, DRUGS CONTAINING THEM AND THEIR USE FOR COMBATING INFECTIOUS DISEASES|
    EP1330250B1|2000-10-30|2004-05-12|Lupin Limited|Rapidly disintegrating sustained release cefuroxime axetil composition|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB7905021|1979-02-13|
    GB7921342|1979-06-19|
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