GB2063871A - Cephalosporin antibiotic - Google Patents
Cephalosporin antibiotic Download PDFInfo
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- GB2063871A GB2063871A GB8031703A GB8031703A GB2063871A GB 2063871 A GB2063871 A GB 2063871A GB 8031703 A GB8031703 A GB 8031703A GB 8031703 A GB8031703 A GB 8031703A GB 2063871 A GB2063871 A GB 2063871A
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- ceph
- aminothiazol
- pentahydrate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
- C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Description
1 GB 2 063 871 A 1
SPECIFICATION
Improvements in or relating to a cephalosporin antibiotic This invention relates to improvements in or relating to (6R,7R)-7-[(Z)-2(2-aminothiazol-4-yi)-2-(2ca rboxypro p-2-oxyi m! n o)aceta m idol -3-(lpyridi n i u m-methyi)ceph-3-em-4-ca rboxyl ate of formula A1 1,H 12 S N H H C/ CONH CH N C11---2 N 11.. 1 3 NO O-C-COOH t'N 1 k; 0 2 ccdg (I) This compound, which is variously referred to as'ceftazidime' and 'GR 2026X, has been found to have broad spectrum antibiotic activity and, in particular, unusually high activity against gram-negative organisms, including many P-lactamase-producing gram-negative strains, as described in our UK Patent Specification No. 2025398. The compound possesses excellent activity against organisms normally difficult to combat with P-lactam antibiotics, such as indole-positive Proteus, Serratia, Providence and especially 25 Pseudamonas organisms, and its antibacterial properties are not impaired by human serum. Moreover, the effect of increased inocula against the compound is low and the compound is rapidly bactericidal at concentrations close to the minimum inhibitory concentration. It is weti distributed in the bodies of small rodents giving useful therapeutic levels after subcutaneous injection. Experimental infections in mice with gram-negative bacteria have been successfully treated using the compound and, in particular, excellent 30 protection has been obtained against strains of Pseudomonas aeruginosa, an organism normally not susceptible to treatment with cephalosporin antibiotics. This protection was comparable with the treatment with an aminoglycoside such as amikacin. Acute toxicity tests with the compound in mice gave LID5() values in excess of 6 g/kg. No nephrotoxicity has been observed in rats at dosages of 2.0 g/kg. In studies in human volunteers the compound has shown good pharmacokinetic properties, giving high and long lasting serum 35 levels after injection. The long serum half-life suggests that less frequent dosages might be required for less serious infections. Early clinical results suggestthatthe compound reproduces in the clinic the excellent antibiotic properties demonstrated in vitro and in experimental animals.
UK Patent Specification No. 2025398 also discloses solvates and non-toxic salts, e.g. base salts and acid addition salts, of the above-mentioned cephalosporin compound.
UK Patent Specification No. 2025398 discloses, interali,, a method for the preparation of the above-mentioned cephalosporin compound (1) as well as solvates and non- toxic salts thereof, which comprises:
acylating a compound of formula 45 H H S H N 2 OtN (D 50 0 coo C H 2 N3 preferably as the bishydrochloride acid addition salt, with an acid of formula 2 GB 2 063 871 A 2 R 5 C. COOH CH 2 0--C. COOR 10 H 3 (wherein R' represents an amino or protected amino group; and R 2 represents a carboxyl blocking group) or with an acylating agent corresponding thereto; whereafterthe following reactions may be carried out 15 i) removal of any amino-protecting group and the carboxyl blocking group R 2, and, if desired, ii) conversion of a carboxyl group into a non-toxic salt.
The desired compound of formula (1) above of UK Patent Specification No. 2025398 was obtained as an amorphous solid and its stability was not particularly satisfactory, especially at elevated temperatures.
It has now been found that (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-y])-2-(2carboxyprop-2oxyimino)acetamidol-3-(1-pyridiniummethyi)ceph-3-em-4-carboxyiate (1) can be advantageously prepared and isolated in the form of a crystalline hydrate, which by analysis is a pentahydrate, which pentahydrate forms one aspect of the invention.
The new hydrate of the cephalosporin compound (1) is of superior quality in terms of its crystallinity and stability, as well as being of increased purity. In particular, the new hydrate has been found to have a well-defined crystalline structure and it has been found to be remarkably stable even when stored at a temperature of 500C for an extended period. These properties renderthe hydrate of value in pharmaceutical use.
It has been found that the new crystalline hydrate can be conveniently prepared from a solution of a salt of the above cephalosporin compound. Thus, in another aspect the invention provides a process for the preparation of (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yi)-2-(2-carboxyprop-2oxyimino)acetamido l-3-(1- pyridiniummethyi)ceph-3-em-4-carboxylate pentahydrate which comprises adjusting the pH of a solution of an acid or base salt of (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yi)-2-(2carboxyprop-2-oxyimino)acetamido l-3-(1 - pyrid in i u m methyl)cep h-3-em-4-ca rboxyl ate in an aqueous medium to 2.7 to 4.8, conveniently 3.0 to 4.0, preferably 3.3 to 4, e.g. about 3.7, and crystallising the desired pentahydrate. For example, it has been found 35 that the desired crystalline hydrate may be precipitated from an aqueous solution of acid addition salt on addition of an organic or inorganic base to a pH in the above ranges preferably, 3.0 to 4.0.
Bases which may be used in the precipitation include, for example, inorganic bases such as alkali or alkaline earth metal hydroxides, carbonates or bicarbonates e.g. sodium carbonate, sodium bicarbonate and sodium hydroxide. A starting acid addition salt may be formed with an organic or inorganic acid. Examples 40 of organic acids which may be used include carboxylic and sulphonic acids such as formic, trifluoroacetic, toluene-p-sulphonic or methanesulphonic acids. Examples of inorganic acids which may be used include mineral acids such as hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid. A particularly suitable acid addition salt is the bishydrochloride of compound (1), which may be obtained in highly pure form.
Alternatively the new pentahydrate may be prepared by addition of an acid to a solution of a base salt of 45 compound (1) in an aqueous medium to a pH in the above ranges, preferably 3.5 to 4.2. Acids which may be used for this purpose include organic and inorganic acids such as, for example, hydrochloric acid and sulphuric acid. Starting base salts include, for example, alkali metal salts, e.g. sodium and potassium salts; alkaline earth metal salts, e.g. a calcium salt, amino acid salts e.g. lysine and arginine salts; and organic base salts e.g. ammonium, triethylamine, procaine, phenethylbenzylamine, dibenzyiethylenediamine, ethanoia mine, diethanolamine and N-methyl-glucosamine salts.
The aqueous medium may contain a water-miscible organic solvent e.g. in an amount up to 60% by volume. Examples of organic solvents include alcohols such as ethanol or isopropanol, ethers such as tetra hydrofu ran, dioxan or diethyl ether, esters such as N,N- dimethy[formarnide or N,N-dimethylacetamide, sulphoxides such as dimethyisulphoxide, and nitriles such as acetonitrile.
The precipitation is preferably effected at a temperature of from 0 to WC, e.g. Wto 4WC, conveniently at about 24C, followed where necessary by a step of cooling to enhance crystal yield to a temperature in the range from Wto 1 O'C.
After precipitation, the pentahydrate product may be recovered by filtration and washed and dried in conventional manner. For example the hydrate may conveniently be dried by air drying, careful drying under 60 reduced pressure or, preferably, in a sterile inert gas atmosphere such as sterile nitrogen.
The salts for use in the preparation of the new pentahydrate according to the invention may be prepared by a process disclosed in the above-mentioned UK Patent Specification No. 2025398, i.e. by a process corresponding to the method above mentioned. The hydrochloride may be prepared in the form of a highly stable crystalline bishydrochloride product by crystallisation from a medium comprising acetone and formic 65 a- 3 GB 2 063 871 A 3 acid e.g. under the conditions described in the Preparation 1 below.
The new crystalline pentahydrate according to the invention has been subjected to X-ray powder diffraction studies. The product of the following Example 2 was used to obtain a Debye Scherrer powder diffraction photograph by exposure for 12 hours to CoKct radiation and a second photograph by exposure for 5 3 hours to CuKa radiation. The line intensities were compared against a set of standards to give the relative intensities shown in the following Table:- TABLE
Vvalue Intensity Vvalue Intensity 10 (A) (A) 15.9 m 3.24 2vw 9.9 S 3.18 W 8.7 S 3.13 W 15 7.9 tr 3.01 m 6.7 md 2.87 m 6.3 W 2.77 m 5.95 m 2.72 W 5.74 W 2.69 wd 20 5.42 W 2.52 m 5.18 m 2.43 W 4.71 m 2.33 W 4.50 m 2.29 vw 4.37 tr 2.26 vw 25 4.15 tr 2.23 vw 4.10 S 2.19 W 4.01 m 2.13 vw 3.93 W 2.07 W 3.86 S 2.03 W 30 3.68 S 1.97 vw 3.41 W 1.94 vw 3.33 2vw 3.29 2vw 35 s=strong, m=medium, w=weak, v=very, 2v=vv, d=diffuse, tr=trace The new pentahydrate according to the invention has also been characterised by its infrared spectrum.
The infrared spectrum of the product of the following Example 2 in Nujol was obtained and this is shown in the Figure of the accompanying drawing.
Thefollowing Examples serve to illustrate the preparation of the pentahydrate according to the invention.
Preparations 1 and 2 illustratethe preparation of acid addition salt starting materials forthe preparation of the pentahydrate. In the Preparations and Examples all temperatures are in 'C, and TFA is trifluoroacetic acid. Water contents were determined by the Karl Fischer method.
Proton magnetic resonance (p.m.r.) spectra were determined at 100 MHz. The integrals are in agreement 45 with the assignments, coupling constants, J, are in Hz, the signs not being determined: s = singlet, t = triplet, d = doublet, dd = double doublet, m = multiplet and ABq = AB quartet. Amberlite L.A.2 is a weakly basic high molecular weight secondary amine sold by Rohm and Haas, Philadelphia USA. Hyflo Super-Cel is a diatomaceous silica filter aid sold by Johns-Manville, USA.
PREPARATION 1 (6R,7R)-7-[(Z)-2-(2-Aminothiazol-4-yl)-2-(2-carboxyprop2oxyimino)acetamido l-3-(1- pyridiniummethyl)ceph-3-em-4-carboxylate bishydrochloride Formic acid (84 mi) was added with stirring to (6R,7R)-7-[(Z)-2-(2- tritylaminothiazol-4-V])-2-(2-t- butoxyca rbonyl pro p-2-oxyi m in o)aceta m idol-3-(1 -pyrid in iu m m ethyi)ceph-3-em-4-ca rboxylate N,N dimethylformamide solvate (41.8 g), water cooling being employed to maintain the temperature below 28'.
The resulting solution was cooled to 200, and concentrated hydrochloric acid (17.0 ml) added with stirring over 5 minutes. The mixture was stirred for 3 hours at room temperature, then filtered to remove triphenyl methanol. The filtrate was added to stirred acetone (800 mi). The triphenyl methanol was washed with formic acid (3 x 7 mi), and the combined washings were added to the filtrate-acetone mixture. The resulting suspension was stirred for 1.25 hours, then filtered. The crystalline solid was washed with acetone and dried in vacuo to give the title compound (20.2 g), Chlorine, found: 11.0%; calculated for C22H24N607S2C12: 11.5%; Xmax (pH 6 phosphate buffer) 257 nm (E]% 347), Xinf at 240 (E]% 310) and 290 nm em em (E',% 150).
em 4 GB 2 063 871 A PREPARATION 2 (6R,7R)-7-[(Z)-2-(2-Aminothiazol-4-yl)-2-(2-carboxyprop-2oxyiminojacetamido l-3-(1pyridiniummethyl)ceph-3-em-4-carboxylate Hydrosulphate a) Formic acid (98-100%,150 mi) was added to (6R,7R)-7-[(Z)2-(2-tritylaminothiazol-4-yi)-2-(2-t- butoxyca rbonyl-prop-2-oxyi m i no)-acetam idol-3-(1 -pyrd in iu m methyi)ceph-3-em-4-ca rboxyl ate N,Ndimethyl-formamide solvate (80 g) and the mixture stirred till clear and cooled to 150C. Water (12.6 mi) and conc. sulphuric acid (12.6 m]) were added to the solution and thetemperature roseto 250 and stirring was continued at this temperature for 5 hours.
The suspension was filtered and the solid washed with formic acid (98100%,46 m] in several portions).
The combined filtrate and wash were diluted with isopropanol (200 m]) and the resultant solution dripped into stirred isopropanol (1400 mi) over 20 minutes. lsopropyl ether (400 mi) was added to the suspension and stirring was continued for a further 10 minutes before the solid was filtered off. The bed was washed with isopropanol (3 x 200 mi) and dried for 16 hours in vacuo at 40'to give the title compound (51.02 g) as a cream solid. H20 (by Karl Fischer) 4.2%; sulphur 15.2%, C22H22N607S2 H2S04 2H20 requires H20 5.3%; S, 14.13%.
b) The product from stage (a) was heated in methanol (10 mi) with gentle swirling. After keeping the suspension at room temperature for 2 hours followed by 30 minutes at OOC, the solid was collected by filtration, washed with cold methanol and dried in vacuo at 40'for 3 hours to give the crystalline title compound (0.9 g). Found: C, 38.53; H, 3.70; N, 12. 36; S, 14.1; H20,4.5; C22H22N607S2 H2S042H20 requires C, 38.8; H, 4.15; N, 12.34; S, 14.13; H20,5.3. Xmax (pH 6.0 phosphate buffer) 257 nm (E]% 325),241 nm P% em em 292),289nrn P'G 144). r RFA) 0.90 (d, J=6 Hz, 2 H), 1.32 (t, J=7 Hz, 1 H) and 1.80 (t, J=7 Hz, 2 H) (pyridyl M, 20 em 1.40 (d, J=8 Hz, 1 H; NHCO), 2.60 (s, 1 H; thiazoly] H), 3.72 and 4.50 (ABq, J=14 Hz, 2 H; -CH2N<), 3.84 (m, 1 H; 7-M 4.54 (d, J=5 Hz, 1 H; 6-H), 6.06 and 6.54 (ABq, J=18 Hz, 2 H; 2-H, 8.20 (s, 6 H; C(CH3)2).
All the following Examples illustrate the preparation of (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2oxyimino)acetamido l-3-(1pyridiniummethyl)ceph-3-em-4-carboxylatepentahydrate.
Example 1
The bishydrochloride (2.56 g), prepared as in Preparation 1, dissolved in distilled water (8 mi) was stirred for 2 to 3 minutes until clear, whereafter 98% formic acid (1.0 m]) was added. This mixture was stirred with a liquid anion exchange resin, 'Am berl ite' L.A.2, (4 mi) in diisopropyl ether (8 mi), allowed to settle and separated. The aqueous layer was extracted with diisopropyl ether (2 x 5 m]) and the resin layer was back-washed with distilled water (5 mi), which in turn was extracted with the two diisopropyl ether extracts.
The combined aqueous layers (pH ca. 2.4), which contained the formate salt, were stirred during the addition of ammonia solution (8 to 10 drops) to pH 3.7 and the clear solution allowed to crystallise slowly at ambient temperature for one hour and then at 0' overnight.
The title compoundwas collected by filtration, washed with chilled distilled water (2 x 6 m]), and with acetone (2 x 10 mO and dried at ambient temperature in an air oven for 2 hours to yield a crystalline solid (2.0 g), Xmjx (pH 6 buffer) 257 nm (E1%. 348);.u(D20 + TFA) 0.98,136 and 1.84 (pyridinium protons), 2.80 em (-thiazoie), 4.05 (C7-H), 4.15 and 4.58 (-CH2-),4.64 (C6-H), 6.21 and 6. 67 (C2-H) and 8.40 (-(CH3)2); vmax (Nujol) 4 V R.
1760 (P-Iactam), 1710 (C02H), 1645 and 1538 (CONH) and 1620 cm-1 (CO-); water (Karl Fischer) 13.6%; 40 residual chlorine, 0.1 %; C22H22N607S2. 5 H20 requires water, 14.1 %. 2 Example 2
The bishydrochloride, prepared as in Preparation 1, (2.0 g) was dissolved in distilled water (12 mU and stirred during the addition of ammonia solution to pH 3.5. The clear solution was allowed to crystallise at ambient temperature for 0.5 hour; the pH was adjusted to 3.8 with ammonia solution and the suspension was then kept at 0' for 1 hour.
The title compoundwas collected by filtration, washed with chilled water (10 m]) and with acetone and dried at ambient temperature in vacuo for 3 hours to yield 1.54 g of crystalline solid;.,,a,, (pH 6 buffer) 257 nm (El, 356); -r(D20 + TFA), resembles Example 1 above; V,,,a,, (Nujol) see figure; water (Karl Fischer method) 13.8%; residual chlorine <0.1 %; found C, 41.5; H, 4.73; N, 13. 17%, C22H22N607S2,5 H20 requires C, 41.5; H, 5.05; N, 112; H20,14.1 %. A Debye Scherrer X-ray powder diffraction photograph was obtained on the product; the results are given above.
Example 3
The bishydroch lo ride prepared as in Preparation 1 (2.0 g) was dissolved in distilled water (6 mi) and stirred during the slow addition of 2N-sodium hydroxide solution to a pH of 3.8. When crystallisation was well established, the pH which had risen to 4.5, was brought back to 3.8 with 2Whydrochloric acid (a few drops).
The suspension was cooled in ice and the title compoundwas collected by filtration, washed with ice water (10 mi) and with acetone and dried at room temperature in an air oven for 2 hours to yield 1.56 g of crystalline solid; X.. ax (pH 6 buffer) 257 rim (E1% 354); -r(D20 + TFA) resembles Example 1 above; water (Karl em Fischer) 14.4%; residual chlorine, <0.1%.
GB 2 063 871 A 5 Example 4
The bishydrochloride prepared as in Preparation 1 (4.0 g) was dissolved in distilled water (14 m]) and stirred during the addition of saturated aqueous sodium bicarbonate solution (13 mi) to pH 3.8. The product crystallised rapidly and the suspension was cooled in ice. The title compoundwas collected by filtration, washed with ice-cold water (20 mi) and with acetone and dried at room temperature in an air oven for 2 hours to yield 3.19 of crystalline solid ax (pH 6 buffer) 257 rim (E]% 358), 241 nm (E]% 322), 290 nm (E]% e5 em em 157). Water (Karl Fischer) 13.9%, v,,., (Nujol) resembles Example 1 above.
Example 5
The hydrosulphate (10 g) prepared as in Preparation 2(a) was dissolved in water (20 r-,yt) and cooled with 10 stirring to 150C. Ammonia solution (SG 0.88) was added to the stirred solution adjusting to pH 3.75 with the temperature rising to 250C. Seeds of the title compoundwere added and the mixture chilled for 16 hours at ca. 00. The suspension was readjusted to pH 3.75 with a little more ammonia solution, then filtered. The bed was washed with cold water (2 x 15 mi) and acetone (50 mi). The product was dried for 6 hours at ambient temperature in an air oven to afford the title pentahydrate (3.8 g). Water 14.2%, -c resembles that of Example 1 15 above.
Example 6
The crystalline hydrosulphate (9.4 g), prepared as in Preparation 2(b) was dissolved in water (19 mi) with the addition of a few drops of ammonia solution (SG 0.88). The stirred solution was cooled to 150 and further 20 ammonia solution added with stirring to pH 3.75 at 25% Seeds of the title compoundwere added and the mixture chilled at ca. O'for 16 hours. The suspension was readjusted to pH 3.75 with a few drops of 2N sulphuric acid and then filtered. The bed was washed with ice cold water (2 x 15 m]) and acetone (50 mi). The product was dried for 6 hours at ambient temperature in an air oven to afford the title pentahydrate (5.6 g).
Water 14.0%..r resembles that of Example 1.
Example 7
The bishydrochloride prepared as in Preparation 1 (10 g) was dissolved in distilled water (40 mi) and stirred during the addition of 2N NaOH (20 mi) to pH 6. The solution of the sodium saitthus obtained was kept at ambient temperature for 3 hours then clarified byfiltration. Thefiltratewas stirred whilst2N HCl (7 30 mi) was added to pH 3.8. The suspension was refrigerated for 2 hours and the precipitate collected by filtration, washed with ice-cold water (50 mi) and with acetone (50 mi) and dried at room temperature in an air oven for 2 hours to yield crystalline title compound (8.01 g);.c (D201T.F.A.) resembles Example 1 above; water 14.1 %.
Example 8
The bishydrochloride prepared as in Preparation 1 (20 g) was dissolved in distilled water (50 mO and stirred during the addition of 2N NaOH (ca. 40 ml) to pH 6 to give a solution of the sodium salt. Sodium dithionite (20 mg) was added and the solution cooled to 20'. 5N H2S04 was added to the stirred solution to pH 3.8. The suspension was aged at ambient temperature for 11/2 hours, cooled to 10' and the title compound 40 collected by filtration, washed with ice-cold water (60 mi) and with acetone (60 ml) and dried at room temperature in an air oven to yield crystalline title compound (16.6 g);. r (T.F.A.) resembles Example 1 above; water 14.2%.
Example 9
A solution of the bishydrochforide prepared as in Preparation 1 (10 9) in ice-cold distilled water (20 mO was brought to pH 6 by the addition of 2N KOH (ca. 24 mi). The solution of the potassium salt thus produced was clarified by filtration with 'Hyflo Super-Cel'(1 g) with a water wash (10 ml). The filtrate was acidified to pH 3.5 by the addition of 2N H2S04 (ca. 8 mi) was seeded with the title compound (0.05 g). Crystallisation was effected without stirring for 1 hour. The pH was then readjusted to 3.5 and the suspension cooled to 5'. The 50 title compoundwas collected by filtration, washed with ice-cold water (40 m]) followed by acetone (40 mi) and dried in an air oven at ambient temperature to yield 7.84 g; H20 14. 2%,.c(T.F.A.) resembles Example 1 above.
Example 10
A solution of the bishydrochloride prepared as in Preparation 1 (10 g) in ice-cold distilled water (20 mi) was brought to pH 7.2 by the addition of 2N-ammonium hydroxide solution (ca. 24 mi). The solution of the ammonium salt thus produced was clarified and the filtrate treated with 2N H2S04 as in Example 9 above to yield the title compound (5.93 g); H20 14.2%, T (T.F.A.) resembles Example 1 above.
Example 11
A solution of the bishydrochloride prepared as in Preparation 1 (10 g) in ice-cold water (40 mi) was brought to pH 6.5 by the dropwise addition of triethylamine (6.55 mi). The solution of the triethylamine salt thus obtained was clarified as in Example 9 above and the filtrate was acidified to pH 3.5 by the addition of 2N HCI (ca. 8 mi) and the product isolated as above to yield the title compound (7.13 g); H20 14.1%, T(T.F.A.) 65 6 GB 2 063 871 A 6 resembles Example 1 above.
Example 12
Asolution ofthe bishydrochloride prepared as in Preparation 1 (10 g) in ice-coldwater (20 mi)was brought -.0 pH 6 bythe dropwise addition of 2N NaOH (ca. 24 m]). The solution of the sodium saitthus obtainedwas clarified byfiltration with'Hyflo Super- CeVO g) with awaterwash (10 mi).The solution was cooledto -2' and acidifiedto pH 3.5 bytheaddition of 2N H2S04 (ca 8 mi) and seeded with the title compound. The solution was stirred atO'for3 hours.The title compound was collected by filtration, washed with ice-cold water (40 mi)followed byacetone (40 mi) and dried in an airoven at ambient temperature to yield 7.84g; H20 14.2%, -c (T.F.A.) resembles Example 1 above.
Example 13
Asolution of the bishydrochloride prepared as in Preparation 1 (10g) in distilled water (20 m[) was brought to pH 6 bythe addition of 2N NaOH (ca. 24 mi). The solution ofthe sodium saitthus obtainedwas clarified by filtration with'Hyflo Super-Cel'(1 g) with awaterwash (10 mi). Thesolutionwas heatedto 39'and acidified is to pH 3.5with 2N H2S04 (ca. 8 mO and seeded with the title compound (50 mg). Crystallisation was effected at 4C stirring was continued for one hour and the pH readjusted to 3.5. The suspension was filtered and the residue was washed with ice-cold water (40 mO followed by acetone (40 mi) and dried in an air oven at ambient temperature to yield title compound (2.11 g); H20 14.1 %; T(T.F.A.) resembles Example 1 above.
Example 14
After 1 hour at 40', the suspension obtained as in Example 13 was allowed to cool to 25'during one hour and then cooled to 5'for one hour. The title compoundwas collected by filtration, washed with ice-cold water (40 m]) followed by acetone (40 m]) and dried in an air oven at ambient temperature to yield 6.9 g; H20 14.3%; r (T.F.A.) resembles Example 1 above.
W_ fl Example 15
A solution of the bishydrochloride prepared as in Preparation 1 (2.0 kg) was dissolved in freshly distilled water (5 1) and basified to pH 6 with 2N sodium hydroxide solution (approximately 4.8 1) keeping the solution at about 14-150C. The solution of sodium salt thus obtained was sterilised by passage through a membrane filter (0.22 [tm pore size) followed by a freshly distilled water wash (0. 5 1). Subsequent operations were carried out aseptically. The filtered solution was adjusted to pH 3.75 with 2N hydrochloric acid (approximately 1.2 1), seeded with sterile title compound (20 mg) at 14- WC and then stirred until crystallisation was established. The mixture was cooled to approximately WC and maintained overnight at this temperature (without stirring). The pH was re-adjusted to pH 3.75 as necessary. The title compound was 35 collected by filtration using fibre free nylon mesh and washed with ice- cold water for injections (approximately 5.5 1) and sterile acetone (approximately 5.5 1). The product was dried in a stream of sterile filtered nitrogen until the acetone content was less than 0.2% to yield sterile title compound (1.48 kg); H20 14.55%;.r (T.F.A.) resembles Example 1 above.
Example 16 Bishydroch 1 o ride (5 g) prepared as in Preparation 1 was dissolved in mixtures of distilled water and acetone (20 m] in toto) containing various proportions of acetone from 5% to 60% of the mixture, and the solution cooled to 15'. The pH value was adjusted to 3.5 by the addition of 2N NaOH solution and the mixture 45 immediately seeded with authentic title compound (0.015 g). The mixture, now at 21 -230, was kept for 90 minutes without stirring then cooled to U'with stirring, and the pH re-adjusted to 3.5. After keeping for a further one hour at Y, the solid product was isolated by filtration, washed with water at 5' (25 m[) and finally with acetone (25 m[). Drying to constant weight in the air oven at ambient temperature afforded the title compound. 50 Following the above procedure, the title compound has been obtained from the bishyd roch lo ride by crystallisation from water containing the following: ethanol, isopropanol, tetrahydrofuran, dioxan, diethyl ether and ethyl acetate.
Example 17 55 Samples of the bishydrochloride (5 g) prepared as in Preparation 1 were dissolved in distilled water (20 m] each) and the resulting solutions chilled to Wwith rapid stirring. The pH values of the solutions were adjusted by the dropwise addition of 2N NaOH. After seeding with authentic title compound (0.015 g), the mixtures were kept for 90 minutes at ambient temperature without stirring. They were then cooled to Wwith stirring and the pH values re-adjusted before keeping for a further hour at Wwithout stirring. 60 Title compound isolated by suction filtration was in each case washed with distilled water (25 mi) at 5' and 60 then with acetone (25 mi) before drying to constant weight in the air oven at ambient temperature. In the table below are noted yields of the title compound obtained at a variety of pH values, together with water contents. The p.m.r. spectra resembled those of Example 1.
g 7 GB 2 063 871 A 7 TABLE pH Yield (mlm%) Water Content (%) 2.7 13.2 14.15 5 2.9 65.8 13.95 3.2 81.6 13.95 3.6 80 14.05 3.8 77.8 14.1 4.1 57.6 14,2 10 4.35 15.8 14.2 Example 18
Samples of the bishydrochloride (5 g) prepared as in Preparation 1, were dissolved in distilled water (10 mi) each) and the resulting solutions chilled to 7'with rapid stirring. After adjusting to pH 6 bythe dropwise 15 addition of 2N sodium hydroxide the resulting solutions of sodium salt were keptwithout stirring for 10 minutes. They were then acidified to pre-determined pH values bythe dropwise addition of 2N sulphuric acid and immediately seeded with authentic title compound (0.015 g). After keeping at room temperature for40 minutes without stirring, the mixtures were cooled to 5'with stirring and the pH values re-adjusted before keeping for a further 2 hours at 50 without stirring. The title compound isolated by suction filtration was in each case washed with distilled water (25 m[) at 5'and then with acetone (25 mi) before drying to constant weight in the air oven overnight at ambient temperature.
In the table below are noted yields of the title compound obtained at a variety of pH values, together with water contents. The p.m.r. spectra resembled those of Example 1.
TABLE pH Yield (m/m%) Water Content % 3.2 18.8 13.6 30 3.4 52.8 13.65 3.8 82.8 13.35 4.2 72.0 13.95 4.7 21.0 13.7 4.8 8.8 13.85 35 Pharmaceutical formulations The crystalline pentahydrate of the present invention exhibits the antibiotic properties of the abovementioned compound (1) and may be used for treating a variety of diseases caused by pathogenic bacteria in human beings and animals, such as respiratory tract infectionsand urinary tract infections.
In another aspect, the present invention provides pharmaceutical compositions containing the new pentahydrate adapted for use in human or veterinary medicine. Such compositions may be presented in conventional manner with the aid of any necessary pharmaceutical carriers or excipients.
The antibiotic pentahydrate compound according to the invention may be formulated for injection and may be presented in unit dose form in ampoules, or in multi-dose containers if necessary with an added preservative.
The compositions may also take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Desirably the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use. Preferably such powder formulations may contain an appropriate non-toxic 50 base in order to improve the water- solubility of the active ingredient and/or to ensure that when the powder is constituted with water, the pH of the resulting aqueous formulation is physiologically acceptable. Alternatively, the base may be present in the water with which the powder is constituted. The base may be, for example, an inorganic base such as sodium carbonate, sodium bicarbonate, trisodium orthophosphate or sodium sulphite or an organic base such as lysine, lysine acetate, tromethamine, arginine or sodium glycinate.
The antibiotic compound may also be formulated as suppositories e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
For medication of the eyes or ears, the preparations may be formulated as individual capsules, in liquid or semi-liquid form, or as drops.
Compositions for veterinary medicine may also, for example, be formulated as intramammary preparations in either long acting or quick-release bases.
The compositions may contain from 0.1% upwards, e.g. 0.1 -99%, of the active material, depending on the method of administration. When the compositions comprise dosage units, each unit will preferably contain 50-1500 mg of the active ingredient. The dosage as employed for adult human treatment will preferably 8 GB 2 063 871 A 8 range from 500 to 6000 mg per day, depending on the route and frequency of administration. For example, in adult human treatment 1000 to 3000 mg per day administered intravenously or intramuscularly should normally suffice. In treating Pseudomonas infections higher daily doses may be required.
The antibiotic compound according to the invention may be administered in combination with other 5 therapeutic agents such as antibiotics, for example penicillins or other cephalosporins.
The following Formulations illustrate the pharmaceutical compositions:FORMULATION A, for injection Formula per vial 10 (6R,7R)-7-[(Z)-2-(2Aminothiazol-4-yi)-2-(2-carboxyprop-2oxyimino)acetamidol-3-(1pyridiniummethyi)-ceph-3-em-4carboxylate pentahydrate Sodium carbonate (anhydrous) c 582 mg 58 mg Method The cephalosporin hydrate was blended with sodium carbonate and filled into a glass vial. The vial headspace was purged with nitrogen and a combination seal applied by crimping. The product was dissolved, as for administration, by addition of 2 mi Waterfor Injections.
FORMULATION B, Injection twin-pack a) Fill sterile (6R,7R)-7-[(Z)-2-(2aminothiazol-4-y])-2-(2-carboxyprop-2-oxyimino)acetamido]-3-(1pyrid in iu m methyi)ceph-3-em-4-carboxyl ate pentahydrate aseptically into glass vials under a blanket of sterile nitrogen, such that each vial contains an amount equivalent to 500 mg of the anhydrous cephalosporin. Close the vials using rubber disks or plugs, held in position by aluminium overseals, thereby 25 preventing gaseous exchange or ingress of microorganisms. b) Prepare a 3.84% w/v solution of sodium bicarbonate, clarify by filtration and fill 2.15 mi into clean ampoules. Pass carbon dioxide into the contents of each ampoule for one minute before sealing. Sterilise the ampoules by autoclaving and check for clarity. c) Constitute the cephalosporin antibiotic shortly before administration by dissolving in 2.0 mi of the 30 sodium bicarbonate solution.
FORMULATION C, for injection Formula per vial (6R,7R)-7-[(Z)-2-(2Aminothiazol-4-yi)-2-(2-carboxyprop35 2-oxyimino)acetamidol-3-(1pyridiniummethyi)ceph3-em-4-carboxylate pentahydrate L-Arginine 582 mg 167 mg Method The cephalosporin was blended with L-arginine and filled into a glass vial. The vial headspace was purged 40 with nitrogen and a combination seal applied by crimping. The product was dissolved as for administration, by the addition of 1.5 mi Water for Injection.
FORMULATION D, for injection Formula per vial (6R,7R)-7-[(Z)-2-(2-Aminothiazol-4-yi)-2-(2-carboxyprop2oxyimino)acetamidol-3-(1 -pyridiniummethyi)ceph-3-em-4carboxylate pentahydrate L-Arginine Sodium dihydrogen phosphate dihydrate 582 mg 167 mg mg Method Mix the sterile L-arginine and sterile sodium dihydrogen phosphate under aseptic conditions. Blend aseptically the resultant powder mix with the sterile cephalosporin. Fill aseptically into glass vials under a 55 blanket of sterile nitrogen. Close the vials using rubber discs, or plugs, held in position by aluminium overseals, thereby preventing gaseous exchange or ingress of microorganisms. Reconstitute the product by dissolving in Water for Injections or other suitable sterile vehicle shortly before administration.
Claims (10)
1. (6R,7R)-7-[(Z)-2-(2-Aminothiazol-4-y])-2-(2-carboxyprop-2oxyimino)acetamido l-3-(1- pyridiniummethyi)-ceph-3-em-4-carboxylate pentahydrate.
2. A process for the preparation of the pentahydrate according to claim 1 which comprises adjusting the pH of a solution of an acid or base salt of (6R,7R)-7-[(Z)-2-(2- aminothiazol-4-yi)-2-(2-carboxyprop-2oxyimino)acetamidol-3-(1-pyridiniummethyi)-ceph-3-em-4-carboxylate in an aqueous medium to 2.7 to 4.8 65 9 GB 2 063 871 A 9 and crystallising the desired pentahydrate.
3. A process according to claim 2 wherein an acid salt of (6R,7R)-7-[(Z)2-(2-aminothiazol-4-yi)-2-(2ca rboxyp rop-2-oxyi m i no)aceta mid ol-3-0 pyrid in iLl m m ethyl)ceph-3-em-4-ca rboxyl ate is used and the pH adjusted to 3.0 to 4.0.
4. A process according to claim 2 wherein abase salt of (6R,7R)-7-[(Z)-2(2-aminothiazol-4-yi)-2-(2carboxyprop-2-oxyimino)acetamidol-3-(1 -pyridi n i u m methyl)ceph-3-em-4-ca rboxyl ate is used and the pH adj u sted to 3.5 to 4.2.
5. A process for the preparation of the penta hydrate according to claim 1 which comprises adjusting the pH of a solution of an acid or base salt of (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yi)-2-(2-carboxyprop-2oxyimino)acetamido]-3-(1-pyridiniummethyi)ceph-3-em-4-carboxylate in an aqueous medium to 3.3 to 4.0 10 and crystallising the desired pentahydrate.
6. A pharmaceutical composition which comprises as active ingredient (6R, 7R)-7-[(Z)-2-(2-aminothiazol- 4-yl)-2-(2-ca rboxyp ro p-2-oxyi m in o)aceta m idol-3-(1 -pyrid in W m methyl)cep h-3-em-4-ca rboxyl ate pentahy drate adapted for use in human or veterinary medicine.
7. A process according to anyone of claims 2 to 5 substantially as herein described.
8. A process for the preparation of (6R,7R)-7-[(Z)-2-(2-aminothiazol-4y])-2-(2-carboxyprop-2oxyimino)acetamido]-3-(1-pyridiniummethyl)ceph-3-em-4-carboxylate pentahydrate substantially as herein described in any one of Examples 1 to 18.
9. A composition according to claim 5 substantially as herein described.
10. A pharmaceutical composition which comprises as active ingredient (6R, 7R)-7-[(Z)-2-(2-aminothiazol4-yi)-2-(2-carboxyprop-2-oxyimino)acetamidol-3-(1-pyrid in W m m ethyl)ceph-3-em-4-ca rboxyl ate pentahy drate substantially as herein described in any one of Formulations A to D.
Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited, Croydon, Surrey, 1981. Published by The Patent Office, 25 Southampton Buildings, London, WC2A 'I AY, from which copies may be obtained.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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GB7934204 | 1979-10-02 |
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GB2063871A true GB2063871A (en) | 1981-06-10 |
GB2063871B GB2063871B (en) | 1983-06-02 |
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Application Number | Title | Priority Date | Filing Date |
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GB8031703A Expired GB2063871B (en) | 1979-10-02 | 1980-10-01 | Cephalosporin antibiotic |
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US (1) | US4329453A (en) |
JP (1) | JPS5657791A (en) |
KR (1) | KR840001776B1 (en) |
AT (1) | AT368161B (en) |
AU (1) | AU539519B2 (en) |
BE (1) | BE885489A (en) |
BG (1) | BG33586A3 (en) |
CA (1) | CA1142919A (en) |
CH (1) | CH645118A5 (en) |
CS (1) | CS214721B2 (en) |
CY (1) | CY1338A (en) |
DD (1) | DD153376A5 (en) |
DE (1) | DE3037102C2 (en) |
DK (1) | DK155525C (en) |
EC (1) | ECSP941099A (en) |
ES (1) | ES8106908A1 (en) |
FI (1) | FI71157C (en) |
FR (1) | FR2466467A1 (en) |
GB (1) | GB2063871B (en) |
GR (1) | GR69123B (en) |
HK (1) | HK78686A (en) |
HU (1) | HU184835B (en) |
IT (1) | IT1144006B (en) |
KE (1) | KE3641A (en) |
MX (1) | MX6545E (en) |
MY (1) | MY8500315A (en) |
NL (1) | NL190329C (en) |
NO (1) | NO156246C (en) |
PL (1) | PL126606B1 (en) |
PT (1) | PT71860B (en) |
RO (1) | RO82721B (en) |
SE (1) | SE449614B (en) |
SU (1) | SU942599A3 (en) |
UA (1) | UA7208A1 (en) |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3332616A1 (en) * | 1982-09-10 | 1984-03-15 | Glaxo Group Ltd | PHARMACEUTICAL COMPOSITIONS |
US4474954A (en) * | 1981-12-07 | 1984-10-02 | Bristol-Myers Company | Intermediates for cephalosporin derivatives |
US4668782A (en) * | 1984-05-02 | 1987-05-26 | Teijin Limited | Anhydrous crystalline or crystalline hemihydrate monohydrate or trihydrate of cephalosporin derivative |
US4769450A (en) * | 1984-03-09 | 1988-09-06 | Glaxo Group Limited | Process for recovering ceftazidime |
CN1328281C (en) * | 2004-11-16 | 2007-07-25 | 广州白云山制药股份有限公司 | Ceftazidime pentahydrate purifying method |
Families Citing this family (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4443444A (en) * | 1980-08-11 | 1984-04-17 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
US4427677A (en) | 1980-12-31 | 1984-01-24 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
US4394503A (en) | 1981-12-07 | 1983-07-19 | Bristol-Myers Company | Cephalosporin derivatives |
JPS58198489A (en) * | 1982-05-14 | 1983-11-18 | Meiji Seika Kaisha Ltd | 7beta-(2d-2-amino-2-carboxyethylthioacetamide)-7alpha-methoxy-3-(1- methyl-1h-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic sodium salt heptahydrate and its preparation |
DE3313818A1 (en) * | 1983-04-16 | 1984-10-18 | Hoechst Ag, 6230 Frankfurt | NEW CEFTAZIDIM CRYSTAL MODIFICATION |
DE3313816A1 (en) * | 1983-04-16 | 1984-10-18 | Hoechst Ag, 6230 Frankfurt | NEW CEFTAZIDIM CRYSTAL MODIFICATION |
US4537959A (en) * | 1984-03-26 | 1985-08-27 | Eli Lilly And Company | Crystalline cephalosporin antibiotic salt |
US4616080A (en) * | 1984-07-02 | 1986-10-07 | Eli Lilly And Company | Simplified process of forming crystalline ceftazidime pentahydrate |
DE3577656D1 (en) * | 1984-07-23 | 1990-06-21 | Lilly Co Eli | PHARMACEUTICAL COMPOSITIONS OF CEFTAZIDIM. |
US4626534A (en) * | 1984-07-23 | 1986-12-02 | Eli Lilly And Company | Pharmaceutical formulation |
EP0187450B1 (en) * | 1984-11-08 | 1991-01-30 | Eli Lilly And Company | Process for the preparation of crystalline ceftazidime pentahydrate |
US4659813A (en) * | 1984-11-08 | 1987-04-21 | Eli Lilly And Company | Crystallization process for ceftazidime derivative |
WO1988010263A1 (en) * | 1987-06-25 | 1988-12-29 | Banyu Pharmaceutical Co., Ltd. | Crystalline cephalosporin compounds, process for their preparation, and intermediates for their preparation |
US4910301A (en) * | 1985-08-05 | 1990-03-20 | Bristol-Myers Company | Cefepime cephalosporin salts |
US5244891A (en) * | 1985-08-05 | 1993-09-14 | Bristol-Myers Squibb Company | Injectable compositions of cefepime dihydrochloride hydrate |
US4994451A (en) * | 1988-01-19 | 1991-02-19 | Bristol-Myers Company | Cephalosporin salts and injectable compositions |
AT387390B (en) * | 1986-10-07 | 1989-01-10 | Biochemie Gmbh | METHOD FOR PRODUCING THE ANTIBIOTIC (6R, 7R) -7- (2- (2-AMINO-4-THIAZOLYL) -2- (2-CARBOXY |
US4954624A (en) * | 1986-10-07 | 1990-09-04 | Sandoz Ltd. | Process for the production of cephalosporin derivatives |
EP0278656B1 (en) * | 1987-02-02 | 1992-06-03 | Eli Lilly And Company | Process for preparing ceftazidime pentahydrate |
US5021564A (en) * | 1987-02-02 | 1991-06-04 | Eli Lilly And Company | Process for preparing ceftazidime pentahydrate |
WO1988010262A1 (en) * | 1987-06-25 | 1988-12-29 | Banyu Pharmaceutical Co., Ltd. | Crystalline cephalosporin compound |
GB8802622D0 (en) * | 1988-02-05 | 1988-03-02 | Glaxo Group Ltd | Chemical compound |
KR940000112B1 (en) * | 1990-07-05 | 1994-01-05 | 주식회사 대웅제약 | 3-substituted cephem compounds |
US5831085A (en) * | 1997-01-16 | 1998-11-03 | Lupin Laboratories Limited | Process for manufacture of cephalosporin such as ceftazidime and intermediate thereof |
CN102924483B (en) * | 2012-10-31 | 2015-06-17 | 海南合瑞制药股份有限公司 | Ceftazidime crystal compound, preparation method of compound and pharmaceutical composition of compound in sterile mixed powder form |
CN102875576A (en) * | 2012-10-31 | 2013-01-16 | 苏州致君万庆药业有限公司 | Synthesis of antibiotic ceftazidime, ceftazidime for injection and preparation method of ceftazidime |
CN104876949A (en) * | 2015-05-28 | 2015-09-02 | 浙江长典医药有限公司 | Ceftazidime compound entity and preparation thereof for children |
CN106420658A (en) * | 2016-09-23 | 2017-02-22 | 临沂草之美医药科技有限公司 | Ceftazidime capsule for treating surgical infection |
CN109111467A (en) * | 2017-06-22 | 2019-01-01 | 宁应 | One kind 51/4His acridine compound of head spore and its drug combination preparation |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AR228726A1 (en) * | 1978-05-26 | 1983-04-15 | Glaxo Group Ltd | PROCEDURE FOR THE PREPARATION OF ANTIBIOTIC (6R, 7R) -7 - ((Z) -2- (2-AMINOTIAZOL-4-IL) -2- (2-CARBOXIPROP-2-OXIIMINO) ACETAMIDO) -3- (1- PIRIDINIOMETIL) CEF-3-EM-4-CARBOXILATO |
-
1980
- 1980-09-09 US US06/185,883 patent/US4329453A/en not_active Expired - Lifetime
- 1980-10-01 CY CY1338A patent/CY1338A/en unknown
- 1980-10-01 PT PT71860A patent/PT71860B/en unknown
- 1980-10-01 AT AT0490080A patent/AT368161B/en not_active IP Right Cessation
- 1980-10-01 ZA ZA00806081A patent/ZA806081B/en unknown
- 1980-10-01 GR GR63023A patent/GR69123B/el unknown
- 1980-10-01 CH CH734180A patent/CH645118A5/en not_active IP Right Cessation
- 1980-10-01 FR FR8021033A patent/FR2466467A1/en active Granted
- 1980-10-01 PL PL1980227019A patent/PL126606B1/en unknown
- 1980-10-01 DE DE3037102A patent/DE3037102C2/en not_active Expired
- 1980-10-01 CA CA000361346A patent/CA1142919A/en not_active Expired
- 1980-10-01 SE SE8006861A patent/SE449614B/en not_active IP Right Cessation
- 1980-10-01 YU YU2497/80A patent/YU42357B/en unknown
- 1980-10-01 UA UA2987392A patent/UA7208A1/en unknown
- 1980-10-01 FI FI803126A patent/FI71157C/en not_active IP Right Cessation
- 1980-10-01 DK DK414780A patent/DK155525C/en not_active IP Right Cessation
- 1980-10-01 MX MX809068U patent/MX6545E/en unknown
- 1980-10-01 IT IT49783/80A patent/IT1144006B/en active Protection Beyond IP Right Term
- 1980-10-01 ES ES495534A patent/ES8106908A1/en not_active Expired
- 1980-10-01 AU AU62882/80A patent/AU539519B2/en not_active Expired
- 1980-10-01 NL NLAANVRAGE8005443,A patent/NL190329C/en not_active IP Right Cessation
- 1980-10-01 NO NO802913A patent/NO156246C/en unknown
- 1980-10-01 RO RO102255A patent/RO82721B/en unknown
- 1980-10-01 GB GB8031703A patent/GB2063871B/en not_active Expired
- 1980-10-01 SU SU802987392A patent/SU942599A3/en active
- 1980-10-01 BE BE0/202301A patent/BE885489A/en not_active IP Right Cessation
- 1980-10-01 HU HU802393A patent/HU184835B/en unknown
- 1980-10-01 BG BG8049206A patent/BG33586A3/en unknown
- 1980-10-01 CS CS806627A patent/CS214721B2/en unknown
- 1980-10-01 JP JP13822480A patent/JPS5657791A/en active Granted
- 1980-10-01 DD DD80224266A patent/DD153376A5/en not_active IP Right Cessation
- 1980-10-02 KR KR1019800003810A patent/KR840001776B1/en active
-
1985
- 1985-12-30 MY MY315/85A patent/MY8500315A/en unknown
-
1986
- 1986-05-29 KE KE3641A patent/KE3641A/en unknown
- 1986-10-16 HK HK786/86A patent/HK78686A/en not_active IP Right Cessation
-
1994
- 1994-05-26 EC EC1994001099A patent/ECSP941099A/en unknown
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4474954A (en) * | 1981-12-07 | 1984-10-02 | Bristol-Myers Company | Intermediates for cephalosporin derivatives |
DE3332616A1 (en) * | 1982-09-10 | 1984-03-15 | Glaxo Group Ltd | PHARMACEUTICAL COMPOSITIONS |
US4769450A (en) * | 1984-03-09 | 1988-09-06 | Glaxo Group Limited | Process for recovering ceftazidime |
US4668782A (en) * | 1984-05-02 | 1987-05-26 | Teijin Limited | Anhydrous crystalline or crystalline hemihydrate monohydrate or trihydrate of cephalosporin derivative |
CN1328281C (en) * | 2004-11-16 | 2007-07-25 | 广州白云山制药股份有限公司 | Ceftazidime pentahydrate purifying method |
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PE20 | Patent expired after termination of 20 years |
Effective date: 20000930 |