• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    1. METHOD FOR OBTAINING AN ADDITIVE SAPI OF BENZENESULPHY1SLOTS SULTAMIZSH1LIN of the formula 4-XSbN4503NS-8HGO where X is a hydrogen or chlorine atom; In the compound of formula S. СНз ГСНз со-о
    公开号:SU1138030A3
    申请号:SU833578255
    申请日:1983-04-19
    公开日:1985-01-30
    发明作者:Эрнест Барт Вейн；Джон Джэсис Витаутас
    申请人:Пфайзер Инк.(Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the delivery of new salts of benzenesulfonic acid 1,1-dioxopenicillanos 1 x 1 -6-0 g (2-amino-2-phenylacetamide of ganygesillanate (sultamipillin), which have advantages when used in antibacterial compositions; 1.1-dioxides are known; (sulbactam) and its esters, which readily hydrolyze in a living organism and are useful as antibacterial agents, as well as to increase the effectiveness of beta-lactam antibiotics such as ampicillin, whose action is It is found against many bacteria that produce beta-lactamase ij.  Conjugated penicillanic acid 1,1-dioxide compounds with known penicillin antibiotics are known, which are connected using methylenedioxy groups.  These conjugated compounds have the general formula A.  in which R represents an acyl group of natural or semi-artificial penicillin 2.  A compound having the formula in which it is represented by 1) - (2-amino-2-phenylacetyl) is sultamycylline.  This compound is a conjugated penicillanic acid 1,1-dioxide compound and ampicillin, a methylenedioxygrugsp compound.  Sultamicillin free base has poor processing characteristics and inadequate resistance.  The only known salt of sulfamicillin is the hydrochloride salt.  Although it is suitable for the preparation of certain antibacterial compositions, it is also characterized by poor stability in the solid state, which is reflected in the difficulties associated with its processing and is very soluble in water in which it undergoes hydrolytic decomposition.  Thus, it is not suitable for aqueous dosage formulations, including aqueous suspensions, which are preferred in pediatrics.  Generally, preference is given to crystalline forms over noncrystalline forms.  Crystalline substances are more stable, have a better appearance and are easier to handle than their amorphous counterparts.  In the case of pharmaceutical use, crystalline compounds are particularly preferred. MIs with regard to the methods of making, shaping and using acceptable dosage forms, such as solutions, suspensions, elixirs, tablets, capsules and various other (home medicine preparations.  It is known that in the treatment of children, the preferred dosage forms are solutions or liquid suspensions.  It is difficult for children to swallow tablets and capsules, and the amount of medication a child receives in this form does not lend itself to such flexible variation as is often required for children's medications.  In contrast, when using liquid dosage forms, the amount of medication given to a patient can be varied over a wide range by changing the volume of the dose having a known concentration.  Thus, the conjugated antibiotic sultamicillin undergoes frequency hydrolysis to the components: ampicillin and sulbactam when stored in aqueous media, and its hydrochloride salt has a high solubility and instability.  The purpose of the invention is the consciousness of new acid additive salts of sultamicillin, which have low solubility and high stability in aqueous suspensions.  The delivered chain is achieved in that according to the method for producing the benzenesulfonic acid additive salt of sultamicillin of the formula 1 4 - XC (-; i50jI-B2n20 CgHs-CH-COW, the compound of the formula B or its hydrohalide is reacted with the benzenesulfonic acid of the formula 4 - where X has the indicated values, in aqueous form , an organic or aqueous organic medium at room temperature or a hydrohalide of a compound of formula B is reacted with an alkaline salt of the benzenesulfonic acid of formula 4 - where X has the indicated values, in an aqueous medium with rooms As a hydrohalide of a compound of the formula B, its hydrochloride is used and reacted with the sodium salt of the benzenesulfonic acid of the formula where X has the indicated values.  Ethyl acetate, methanol, butanol, acetone, methyl ethyl ketone or tetrahydrofuran can be used as the organic medium.  .  A mixture of water with the above solvents can be used as the aqueous organic solution.  The proposed crystalline dihydrates are characterized by high pharmacokinetic properties, almost optimal solubility in aqueous systems, and improved stability in bulk and in suspensions.  As a result, the proposed crystalline salts have valuable advantages in the manufacture of various dosage forms.  S CH goose; -N-J- CO -o Ooh sn -fcnz -N-k p co-o Crystalline dihydrate salts have useful properties that make them particularly suitable as oral antimicrobial agents.  They are characterized by rapid absorption from the gastrointestinal tract.  During or after absorption in vivo, ether hydrolysis occurs with the release of ampicillin and beta-lactamase inhibitor, penicillanic acid 1,1-dioxide (sulbactam).  These salts are characterized by relatively low, but quite sufficient solubility in aqueous systems, which leads to an improvement in the sustainability of aqueous dosage forms for oral administration, which is preferred in pediatrics.  It was established that when administered to the laboratory animals through the mouth of the proposed crystalline compounds and the hydrochloride salt, both of these substances showed excellent pharmacokinetic properties.  In that. bl.  Figure 1 shows the forma-kinetic data after administration to the rats through the mouth of a 2D mg / kg saltymitsillin salt.  The data table.  1 show that each of the three salts is rapidly absorbed and hydrolyzed at.  by mouth. with the achievement of high serum levels of both ampicillin and beta-lactamase inhibitor, sulbactam.  It was found that the differences between the three salts presented in table.  1 are statistically insignificant.  Given in Table.  1 data was obtained using Sprague-Dawley outbreed rats.  These compounds were administered through the mouth (5 rats per | one compound) in the form of an aqueous sus-.  0.5 ml of penny containing 20 mg / kg of the drug.  Blood samples were taken after specified periods of time and subjected to their differential bioassay to determine the levels of ampicillin and sulbactam.  Ampicillin bioassay uses Sarcina lutea (ATCCC 93ii1), which is ampicillin sensitive,.  but insensitive to sulbactam at concentrations up to 100 µg / ml, since this species does not contain beta-lactamase.  Thus, this organism does not exhibit synergies for combinations of ampicillin and sulbactam.  The standard curve was obtained in normal serum at ampicillin levels of 4, 2.1, 0.5, 0.25, and 0.125 µg / ml.  Sterile discs from filter paper were loaded with 25 lambda volumes.  Analytical plates were prepared using seed agar (Difco), Overnight, a cult of Sarcina lutea was diluted to a ratio of 1: 100, and 1 MP of this solution was added to 100 ml of agar in 12/12 inch plastic plates.  The cultures in these plates were flashed at 37 ° C for 18 hours, after which the resulting zones were measured.  The determination of trial trial is based on the insensitivity of Pasteurella histolytica (59B010) to high concentrations of ampicillin or sulbactam alone.  However, because its stability is mediated by beta-lactamase, this culture responds synergistically to combinations of ampicillin and sulbactam.  A standard curve was obtained by a method similar to that described for ampicertlin. Analytical plates were prepared by adding 1 ml of Pasteurella histolytica culture overnight to 100 ml of Muller-Hinton agar, to which 50 µg / m ampicillin and 5% sterile plant were added. Blood cultures in these cups were grown at 37 ° C for 18 hours, after which the resulting zones were measured.  Solubility. A comparison was made between the solubility of these salts in water and in artificial gastric juice without pepsin (pH 1.2). Equilibrium solubility was not determined, since these compounds are not completely stable in aqueous systems for long periods of time. achieve balance.  Therefore, apparent solubility was determined by vigorous stirring with the solvent for 30 minutes, the crumbled mixture was filtered by%, and the amount of compound in solution was determined by high pressure liquid chromatography (HPLC),.  The apparent solubility of sultamicillin salts in water and in artificial gastric juice (without pepsin, pH 1.2) is shown in Table 2, Crystallinity, a Siemens X-ray diffractometer equipped with a device for emitting copper and a scintillation counter detector, and powder X-ray diffraction data were obtained.  The beam intensity as a function of angle 2 theta was recorded with a scan rate of 2 / min.  The crystallinity of sultamicillin benzenesulphonate dihydrate and sultamicillin 4-chlorobenzenesulphonate dihydrate was tested on the basis of the multiplicity of peaks on x-ray powder diffraction patterns for these salts.  Resistance When storing samples of these three salts at 50 ° C for three weeks, it was found that crystalline benzenesulfonate / 2H2O and A-chlorobenzenesulfonate-2H20 retained respectively 97 and 100% of their strength.  The hydrochloride salt retained only 67% of its original strength under the same conditions. High pressure liquid chromatography (HPLC). In the solubility and stability studies, the above samples of substances were analyzed using high pressure liquid chromatography using a C-column. 8 (trademark of ES Industries), internal diameter 4.6 mm x 30 cm.  The mobile phase consisted of 30 wt.% Acetonitrile in phosphate buffer with pH 3 (0.1 M solution).  The flow rate was 1.6 mp / min.  The determination was carried out in ultraviolet light at 230 nm.  7 When using the proposed antibacterial salt for treating mammals, in particular humans, this compound can be used alone or it can be mixed with other antibiotic substances and / or pharmaceutically acceptable carriers or diluents. The said carrier or diluent is selected on the basis of the intended method. introduction.  For example, in the case of the administration of this preparation, the proposed antibacterial compound may be used in: the form of tablets, capsules, lozenges, powders, syrups, elixirs, solutions and suspensions. d.  in accordance with usual pharmaceutical practice.  The proportional ratio of the active ingredient to its content naturally depends on the chemical nature, solubility and stability of the active ingredient, as well as on the intended dose.  In the case of tablets for oral administration, carriers commonly used include lactose, citric acid sodium, and salts of phosphoric acid.  Typically, tablets use such disintegrants as starch, and lubricants, such as magnesium stearate, sodium lauryl sulfate, and talc.  For oral administration in the form of capsules, useful diluents are lactose and high molecular weight polyethylene glycols, for example polyethylene glycol having a molecular weight of 2000-4000.  Due to the good solubility and stability of the crystalline dihydrate salts of benzenesulfonic acid, sultamicillin is particularly preferred (the method of administering this drug for treating children is oral administration in the form of an aqueous suspension.  To prepare such suspensions, the crystalline dihydrate of formula (1) can be combined with buffer solutions, emulsifying and suspended with dosing agents.  If desired, certain sweetening and / or flavoring agents may be added.  The resulting suspension can be stored in the presence of water, especially in a refrigerator, for considerable periods of time. However, the preferred method is to store the mixture as dry.  8 powder until needed when it is mixed with an appropriate diluent, for example.  measures with water.  As mentioned earlier, the proposed antibacterial compounds are intended for use in the treatment of humans and their daily doses do not differ significantly from other penicillin antibiotics used in the clinic.  The appropriate dose for a given person is ultimately determined by the attending physician and it varies depending on the age, weight and response of each patient, as well as the nature and severity of the patient's symptoms of the disease.  The predated compounds are usually used for oral administration in doses of 20100 mg per kilogram patient weight per day and parenterally in doses of 10-100 mg per kilogram patient weight per day, o6tji4Ho in several divided doses.  In some cases it may be necessary to use.  dose beyond these ranges.   The following examples and methods of preparation serve only for further illustration.  Infrared spectra (3R) were measured on disks of potassium bromide (KBr disks), and diagnostic absorption bands are indicated in the Bp iHOBbK numbers ().  Nuclear Magnetic Resonance Spectra (NM5) were measured at 60 MHz for solutions in deuterated chloroform (CDCB-j) or deuterated dimethyl sulfoxide (DMSO-dg), and the positions of the peaks are indicated in parts per million down from tetramethylsilane.  Dd designations of peak shapes are used in the form of slips, which specify abbreviations: S singular, f doublet, i triplet, and quartet, P1 multiplet.  Example 1  Benzenesulfonic acid dihydrate salt of 1,1-dioxopenic1-lanyloxymethyl-6-1) - (2-amino-2-phenylacetamido L-penicillanate. .  To 6.31 g (0.01 moi) of hydrochloride salt of 1,1-dioxopenicillanoyloxymethyl-6-p- (2-amino-2-phenylacetamido) ne. 40 ml of water was added to the nitsillat, and the mixture was stirred for about 15 minutes.  The insoluble matter (about 0.75 g of resin) was removed by filtration, and a solution of 1.58 g (0.01 mol) of benzenesulfonic acid in 10 ml of water was added to the filtrate.  The resulting sticky mixture was stirred with a glass rod until the salt hardened and broke into small pieces.  Stirring was continued for 1 h (magnetic stirrer), after which the solid was collected by filtration and washed well with water.  The washed solid was dried under a nitrogen atmosphere, whereby 5.8 g (77%) of a colorless product was obtained, t, bm, 138c (decomp.).  Nuclear Magnetic Resonance Spectrum H (DKBO-dfe) in parts per million (delta): 1.38 (5.6H), 1.45 (5.6H) j3.0. 3.9 (m, 2H); 4.4 (s, 1K); 4.5 (s, 1H); 4.95-5.28 (m, 2H) -, 5.3-5.66 (t, 2P), 5.89 (5.2H); 7.15-7.75 (m, 10H), infrared spectrum: nudzhol (a trademark for a firm of mineral oil manufactured by the company) is a wide band at 1805-1770 cm, X-ray powder diffraction: peaks, degrees 2, 3; 11.4 12.2; 13.4; 15.5; 16.2 16.9, 17.1; 18.3} 18.9; 19.8: 20.6, 22.3, 22.7; 23.4; 25.4; 26.7; 27.3; 29.6; 30.5. .  31.7; 33.5; 34.4, 35.1; 36.1; 37.5; 38.6 and 44.7. Example 2 4-Chlorobenzenesulfonic acid 1,1-dioxo penicillanoyl oxymethyl-6-B- (2-amino 2-phenylacetymido) penicillanate dihydrate salt -amino-2-phenylacetamido) penicillanate in 150 ml of ethyl acetate: A solution of 4.85 g (25.25 mmol) of 4-chlorobenzenesulfonic acid in 25 ml of ethyl acetate and 6 ml of water was added over 10 minutes.  After the addition was complete, another 50 ml of ethyl acetate was introduced into the mixture, after which the resulting mixture was stirred at room temperature overnight.  Colorless crystals were collected by means of filters. The filter cake was suspended in 200 ml of ethyl ether and filtered again.  After air drying, 13.7 g of colorless crystals were obtained, 10 g of crystals were dissolved in 100 ml of methanol at room temperature.  At the cloud point, water (about 200 ml) was added, and the resulting 0-10 solution was stirred at room temperature for 2 hours, and during this time the product crystallized.  After filtration and natural drying overnight, 7.5 g of product was obtained.  Nuclear Magnetic Resonance H (OM50-с1) in parts per million (delta): 1.36 (S, 6H) i 1.47 (5, 6H); 3.34 (broad 5H); 3.74 ((3 (3.1N, Hz, 17 Hz), 4.40 (5.1N), 4.51 (5.1N); 5.08 (t, 2H) 5.48 (t, 2H , Dftgq 4 Hz when applied); 5.86 (5.2H), 7.45 (rri, 9H).  Calculated,%: C 45.22; H 4.77; / 6.81J 5 11.68; eg 4.31.  1 Mz (;;, 2Н20 Found;%:. C 45.04; H 4.83; M 6.86; 5 11.74, - ce 4.27.  Water (Karl Fischer) 4.98 (theoretical result 4.37).  X-ray powder diffraction: peaks, 2 theta degrees: 8.9; 10.8; 11.3; 13.2-, 15.5; 16.0; 17.1; 18.0; 19.3; 20.0; 22.4; 22.7; 23, 3; 26.0; 27.9; 30.0; 30.5; 34.1; 34.5; 35.9 j 37.3; 38.5 and 44.8.  Example 3  A mixture of 6.31 g (0.01 mol) of 1, 1-dioxopenicillanoyloxymethyl-6G - (2-amino-2-fench1-acetamido) penicillanate hydrochloride salt and 40 mp of water was stirred for 20 minutes and filtered, was slowly added to the filtrate a solution of 1.80 g (0.01 mol) of sodium benzenesulfonate in 10 mp of water.  The resulting mixture was stirred for 2 hours, filtered, the fitrotic cake was washed with water and dried in a vacuum oven at 45 ° C, whereby crystalline dihydrate benzenesulfonic acid 1,1-dioxopenyl cyllanoyloxymetal-b -) - (2-amino-2-phenylacetamido) 3 was obtained penicillanate.  i The use of potassium 4-chlorobenzenesulfonate instead of sodium benzenesulfonate in the above procedure allows to obtain the 4-chlorobenzenesulfonic acid salt of 1,1-dioxopenicillanoylmethyl-6-13- (2-amino-2-phenylacetamido) -penicillanate According to the method presented in Example 2, it is possible to obtain a crystalline dihydrate, Example 4, A solution of 64.1 g (0.108 mol) of 1,1-dioxopenicillanoyloxymethyl-6-D - (2-amino-2-phenyl acetamido) penicillanate in 1400 ml of these.  acetate (apparent pH = 7.6 was adjusted to pH 2.5 by adding 325 MP of a solution of 18.0 g of benzenesulfonic acid (90% technical grade) in 400 ml of ethyl acetate.  The resulting pale yellow suspension was cooled to 5 ° C and granulated at this temperature for 60 minutes.  The resulting suspension was washed with an equal amount of water, after which it was separated, and the ethyl acetate layer was cooled to.  The thick white suspension obtained was filtered, the filter cake was washed with hexane (4x100 mp) and dried under vacuum at 35 ° C overnight, resulting in 42 g of the benzenesulfonic acid crystalline salt, the analysis of which showed the presence of 4.67 water (Karl Fischer method) , the percentage of volatile substances (BO drying in vacuum for 3 hours was 5.00%.  .  Calculated,%: C, 470; H, 5.11; N 7.10; S 12.19.  C, H, 0,, M (5 ,. 2H, 0 Found,%: C 47.14, H 5.21; M 7.12; 5 11.92.  Example 5  Suspension for oral administration.  A dry mixture was prepared containing the following ingredients, g: Crystalline dihydrate salt of benzenesulfonic acid sultamicillin6, 80 Saccharose20.00 Mannitol10.00 Sodium citrate0.40 Powder of magnesium silicate hydroxide and silicate of aluminum (Vigum, S) 5.00 Kaolin 2.00.  Sodium Saccharin 2.00 Artificial flavoring powder. 0.10 The dry mixture was stored in closed boxes until needed, when this mixture was diluted with water to a volume of 100 ml.  This suspension was characterized by an equivalent concentration of 50 mg / ml sultamicillin.  Preparation of the preparation A, Hydrochloride salt and the free base of 1,1-dioxapenylillanoyl-oximethyl-6-D- (2-amino-2-phenyl acetamido)) -penicillanate.  To a solution of 3.465 p (0.005 mol) 1,1-dioxopenicillanoshoxymethyl6-B - (-methyl-2-methoxycarbonylvinylamino-2-fench1-acetamido) penicillanate in 50 ml of acetone was added 5.5 MP 1.0 N.  hydrochloric acid solution and 5 ml of water, after which the mixture was stirred at room temperature for 30 minutes.  The acetone was vacuum-filtered, the aqueous residue was washed with ethyl ether, filtered and lyophilized to obtain the hydrochloride salt of the indicated compound.  Alternatively, the aqueous residue obtained by evaporation of the acetone was washed with ethyl acetate and ethyl ether.  Methypene chloride was added to the aqueous layer, the mixture was cooled, and 460 mg of sodium bicarbonate was added in portions.  The aqueous phase was separated, extracted again with methylene chloride, the combined organic layers were dried (MrfSOx), and the solvent was evaporated in vacuo, resulting in a free base of the title compound.
    15
     table 2
    1138030
    Crystal salt
    权利要求:
    Claims (3)
    [1]
    1. METHOD FOR PRODUCING ADDITIVE SOPY OF SULTAMICILLIN BENZENESULPHACID ACID OF THE FORMULA
    4-ХС b Н 4 50 3 Н'8..2Н g 0 where X is the hydrogen or chlorine atom;
    B-compound of the formula
    C 6 H 5 - CH-C0NH ~ ^ _
    NH 2 L wherein the compound of formula V or its hydrohalide is reacted with benzyl zolsulfokislotoy formula '4 - XC 6 H 4 SO 3 H wherein X is as defined above, in an aqueous, organic or water-organic medium at room temperature or a compound of hydrohalide of formula B is reacted with an alkaline salt of benzenesulfonic acid of the formula
    4 - XC 6 H 4 SO 3 H J where X has the indicated meanings in an aqueous medium at room temperature. . ''
    [2]
    2. The method according to π. · 1, including the fact that, as the hydrohalide of the compound of formula B, its hydrochloride is used and it is reacted with the sodium salt of benzene sulfonic acid of the formula
    [3]
    4-XC 6 H 4 5O e N, where X has the indicated meanings.
    >
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    同族专利:
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    申请号 | 申请日 | 专利标题
    US06/371,156|US4432987A|1982-04-23|1982-04-23|Crystalline benzenesulfonate salts of sultamicillin|
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