GB2064513A - Cephalosporin antibiotic - Google Patents
Cephalosporin antibiotic Download PDFInfo
- Publication number
- GB2064513A GB2064513A GB8031706A GB8031706A GB2064513A GB 2064513 A GB2064513 A GB 2064513A GB 8031706 A GB8031706 A GB 8031706A GB 8031706 A GB8031706 A GB 8031706A GB 2064513 A GB2064513 A GB 2064513A
- Authority
- GB
- United Kingdom
- Prior art keywords
- bishydrochloride
- clme
- crystalline
- dtd
- relative intensity
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
-
- 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
.DTD:
GB 2 064 513 A 1 .DTD:
SPECIFICATION Improvements in or Relating to a Cephalosporin Antibiotic .DTD:
This invention relates to improvements in or relating to (6R,7R)-7-[(Z)-2(2-aminothiazol-4-yl)-2(2-carboxyprop-2-oxyimino)acetamidoj -3-(1pyridiniummethyl)ceph-3-em-4-carboxylate of formula NH 2 g N CONH C N H 3 O N CH 2 110-C-COOH This compound, which is variously referred to as 'ceftazidime' and 'GR 20263', has been found to have broad spectrum antibiotic activity and, in particular, unusually high activity against gram-negative organisms, including many A-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 /3-lactam antibiotics, such as indolepositive Proteus, Serratia, 10 Providence and especially Pseudomonas 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 well 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 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 LDSO 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 20 compound has shown good pharmaco-kinetic properties, giving high and long lasting serum levels after injection. The long serum half-life suggests that less frequent dosages might be required for less serious infections. Early clinical results suggest that the compound reproduces in the clinic the excellent antibiotic properties demonstrated in vitro and in experimental animals.
.DTD:
UK Patent Specification No. 2025398 also discloses solvates and non-toxic salts, e.g. base salts 25 and acid addition salts, of the above-mentioned cephalosporin compound.
.DTD:
UK Patent Specification No. 2025398 discloses, inter alia, a method for the preparation of the above-mentioned cephalosporin compound (I) as well as solvates and non- toxic salts thereof, which comprises:
.DTD:
acylating a compound of formula H2N i o N / CH211 cooe preferably as the bishydrochloride acid addition salt, with an acid of formula s '-c. cooH C3 'C. COOR CH 3 2 (wherein R' represents an amino or protected amino group; and RZ represents a carboxyl blocking group) or with an acylating agent corresponding thereto; whereafter the following reactions maybe 35 carried out i) removal of any amino-protecting group and the carboxyl blocking group R2, and, if desired, ii) conversion of a carboxyl group into a non-toxic salt.
.DTD:
2 GB 2 064 513 A 2 The desired compound of formula (I) above and its bishydrochloride salt of UK Patent Specification No. 2025398 were obtained as amorphous solids and their stability was not particularly satisfactory, especially at elevated temperatures.
.DTD:
It has now been found that (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2carboxyprop-2 oxyimino)acetamidoj-3-(1-pyridiniummethyl)ceph-3-em-4-carboxylate (I) bishydrochloride can be advantageously prepared and isolated in crystalline form.
.DTD:
The crystalline form of the bishydrochloride compound is of generally superior quality in terms of its purity and stability. In particular, the new form of hydrochloride has been found to have a well defined crystalline structure and it has been found to be remarkably stable even when stored for an extended period at a temperature of 50 C. These properties render it of value in pharmaceutical use as 10 well as in the preparation of other active cephalosporin compounds.
.DTD:
It has been found that the new crystalline bishydrochloride salt of the above cephalosporin compound can be prepared under controlled conditions. For example, it has been found that the desired crystalline bishydrochloride may be prepared by crystallisation from a suitable medium, for example comprising acetone and formic acid. It has also been found possible to recrystallise the crystalline bishydrochloride from a variety of media. Examples of other media for crystallisation or recrystallisation include industrial methylated spirit and mixtures of methanol, n-propanol and diisopropyl ether.
.DTD:
Crystallisation of the dihydrochloride is preferably effected at a temperature of from 10 to 35 C, conveniently at about 20 C, followed by a step of cooling, to enhance crystal yield, to a temperature in 20 the range from 0 to 15 C.
.DTD:
After precipitation, the crystalline bishydrochloride product may be recovered by filtration and washed and dried in conventional manner.
.DTD:
The bishydrochloride salt for use in the preparation of the new crystalline bishydrochloride 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 involving the method abovementioned.
.DTD:
The new crystalline bishydrochloride 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 CoKa radiation and a second photograph by exposure for 3 hours to CuKa radiation. The line intensities were compared against a 30 set of standards to give the relative intensities in the following Table.
.DTD:
Table d'value Relative Intensity 'd'value Relative Intensity I I 1100 1100 10.6 93 2.76 12 35 7.9 22 2.73 10 6.6 30 2.65 15 6.4 10 2.59 5 5.65 45 2.53 3 5.43 15 2.48 7 40 5.07 10 2.43 10 4.90 10 2.39 trace 4.70 12 2.35 7 4.54 10 2.26 10 4.25 100 2.24 trace 45 4.12 30 2.19 4 3.97 30 diffuse 2.11 2 3.89 65 2.09 4 3.82 25 2.06 2 3.75 35 2.03 2 50 3.60 35 1.963 2 3.51 35 1.919 2 3.34 10 diffuse 1.886 1 3.26 18 diffuse 1.870 1 3.07 25 1.836 1 55 2.95 22 1.812 1 2.87 5 1.776 1 2.81 10 1.748 1 The new salt 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 60 the figure of the accompanying drawing.
.DTD:
3 GB 2 064 513 A 3 The crystalline bishydrochloride of the present invention may be used in the preparation of a crystalline pentahydrate of the compound of formula I by addition of an organic or inorganic base to an aqueous solution of the bishydrochloride to a pH of 3.3 to 4.0, preferably about 3.7. The resulting pentahydrate has also been found to have a well-defined crystalline structure. This pentahydrate has been found to be remarkably stable even when stored at a temperature of 50 C for an extended period. 5 The pentahydrate exhibits the antibiotic properties of the above- mentioned compound (I) and finds utility as an antibiotic in like manner.
.DTD:
The following Examples serve to illustrate the preparation of the bishydrochloride according to the invention. All temperatures are in C.
.DTD:
Proton magnetic resonance (p.m.r.) spectra were determined at 100 MHz. The integrals are in 10 agreement with the assignments, coupling constants, J, are in Hz, the signs not being determined:
.DTD:
s=singlet, t=triplet, d=doublet, dd=double doublet, m=multiplet and ABq=AB quartet. All the - following Examples illustrate the preparation of (6R,7R)-7-((Z)-2-(2- aminothiazo%4-yl)-2-(2 carboxyprop-2-oxyimino)acetamidol-3-(1 pyridiniummethyl)ceph-3-em-4carboxy/ate bishydrochloride. 15 Example 1 .DTD:
Formic acid (84 ml) was added with stirring to (6R,7R)-7-[(Z/-2-(2tritylaminothiazol-4-yl)-2-(2-tbutoxycarbonylprop-2-oxyminolacetamido]-3-(1-pyridiniummethyl)ceph-3-em-4ca rboxylate N,N dimethylformamide solvate (41.8 g), water cooling being employed to maintain the temperature below 28 . The resulting solution was cooled to 20 , and concentrated hydrochloric acid 117.0 ml) added 20 with stirring over 5 minutes. The mixture was stirred for 3 hours at room temperature, then filtered to remove triphenylmethanol. The filtrate was added to stirred acetone (800 ml). The triphenylmethanol was washed with formic acid (3x7 ml), 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) z(D20) 0.95 (d, J6Hz, 25 pyridinium 2- and 6-H), 1.29 (dd, J6Hz, pyridinium 4-H), 1.80 (dd, J6Hz, pyridinium 3- and 5-H), 2.77 (s, thiazole 5-H), 4.02 (d, JSHz, 7-H), 4.10 and 4.47 (ABq, J16Hz, 3-CHz), 4.59 (d, JSHz, 6-H), 6.17 and 6.54 (ABq, J18Hz, 2-H2) and 8.36 (s, C(CH3)2); Chlorine found: 1 1.0%; calculated for CzZHZ4N60,S2C12: 1 1.5%;..1,maX (pH 6 phosphate buffer) 257 nm (E;%m 347), ..1,;äf at 240 (E;% m 310) and 290 nm (El%m 150).
.DTD:
Example 2 (6R,7R)-7-[(Z)-2-(2-t-Butoxycarbonylprop-2-oxymino)-2-(2tritylaminothiazol-4 -yl)acetamido]3 (1-pyridiniummethyl)ceph-3-em-4-carboxylate N,N-dimethylformamide solvate (5 g) was added to stirred formic acid (10 ml). When the solution had cleared, concentrated hydrochloric acid (2.1 ml) was added dropwise over 2 minutes and the resultant suspension stirred at ambient temperature for a further 3 hours. The suspension was filtered and the filter bed washed with several small washes of formic acid (totalling 2.5 ml).
.DTD:
The filtrate was poured into industrial methylated spirit (100 ml) and then the solvent evaporated in vacuo on a rotary evaporator (water pump vacuum, bath temperature 40 ) to give an oil. Ethyl acetate (50 ml) was added and evaporation continued. This process was repeated with further ethyl 40 acetate (2x50 ml) till a foam resulted. The foam was taken up in industrial methylated spirit (100 ml) and evaporation continued carefully till signs of crystallisation were observed. The cloudy solution was refrigerated overnight and the white solid isolated by filtration and dried at 40 in vacuo to afford the title compound (150 mg).
.DTD:
Further careful evaporation of the liquors gave a second small crop of the title compound (150 45 mg). The residual industrial methylated spirit liquors were blown with a stream of nitrogen and a copious crop of crystalline material separated. This was isolated by filtration and dried in vacuo at 40 to afford the title compound (1.6 g). Amax (pH 6 phosphate buffer) 257 nm (Ell%m 348), and A;r'f 243 nm (E,I m 316) and A;,,f 290 nm (Elm 152); pmr resembled that in Example 1, chlorine assay 1 1.3%, water by Karl Fischer 3.0%. Debye-Scherrer powder diffraction X-ray photographs showed the material to the 50 crystalline.
.DTD:
Example 3 .DTD:
Crystalline solid title compound (0.5 g), prepared as in Example 1 above, was dissolved in methanol (5 ml), n-propanol (15 ml) was added, and the solution treated with diisopropyl ether (20 ml) over20 minutes. The suspension was warmed to 50 and stirred at ambient temperature for 30 minutes. The suspension was filtered and washed to give the recrystallised title compound. (0.48 g). Amax (pH 6 phosphate) 257 (E;% m 349, e21,660) and A;äf at 245 (Ell% 321, a 19,920) and 285 (E;% m 170, s 10,550); i(D20) identical to that of Example 1; impurities by high pressure liquid chromatography 1.2%, water content by Karl Fischer method 4.0%; chlorine, found: 10.6 (CZZH24NsO,SZC12 1.4 HZO, requires 10.9%.
.DTD:
4 GB 2 064 513 A 4 Pharmaceutical Formulations The crystalline bishydrochloride of the present invention exhibits the antibiotic properties of the above-mentioned compound (I) and may be used for treating a variety of diseases caused by pathogenic bacteria in human beings and animals, such as respiratory tract infections and urinary tract infections.
.DTD:
In another aspect, the present invention provides pharmaceutical compositions containing the new bishydrochloride 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.
.DTD:
The antibiotic bishydrochloride compound according to the invention may be formulated for injection and may be presented in unit dose form in ampoules, or in multidose containers if necessary with an added preservative.
.DTD:
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. Alternatively the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use. 15 Desirably, such powder formulations may contain an appropriate non-toxic 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.
.DTD:
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 or sodium 20 acetate, or an organic base such as lysine or lysine acetate.
.DTD:
The antibiotic compound may also be formulated as suppositories e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
.DTD:
For medication of the eyes or ears, the preparations may be formulated as individual capsules, in liquid or semi-liquid form, or drops.
.DTD:
Compositions for veterinary medicine may also, for example, be formulated as intramammary preparations in either long acting or quick-release bases.
.DTD:
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 30 human treatment will preferably 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.
.DTD:
The antibiotic compound according to the invention may be administered in combination with 35 other therapeutic agents such as antibiotics, for example penicillins or other cephalosporins.
.DTD:
.CLME:
Claims (6)
1. ((6R,7R)-7-[(Z)-2-(Aminothiazol-4-yl)-2-(2-carboxyprop-2oxyimino)acetamidoj -3-(1 pyridiniummethyl)ceph-3-em-4-carboxylate in the form of a crystalline bishydrochloride which substantially exhibits the following 'd' values and relative intensities when subjected to Debye Scherrer 40 powder X-ray diffraction using CoKa radiation:
.CLME:
d'value Relative Intensity 'd'value Relative Intensity I I (A) () (A) () 1100 1100 10.6 93
2.76 12 7.9 22 2.73 10 45 6.6 30 2.65 15 6.4 10 2.59 5 5.65 45 2.53 3 5.43 15 2.48 7 5.07 10 2.43 10 50 4.90 10 2.39 trace 4.70 12 2.35 7 4.54 10 2.26 10 4.25 100 2.24 trace 4.12 30 2.19 4 55 3.97 30 diffuse 2.11 2 3.89 65 2.09 4 3.82 25 2.06 2 3.75 35 2.03 2 3.60 35 1.963 2 60 GB 2 064 513 A 5 d' value Relative Intensity 'd' value Relative Intensity 1 1100 3.51 35 1.919 2 3.34 10 diffuse 1.886 1 3.26 18 diffuse 1.870 1 5 3.07 25 1.836 1 2.95 22 1.812 1 2.87 5 1.776 1 2.81 10 1.748 1 2. A process for the preparation of the crystalline bishydrochloride as defined in claim 1 which 10 comprises crystallising the desired bishydrochloride from (6R,7R)-7-[(Z)- 2-(2-aminothiazol-4-yl)-2-(2 carboxyprop-2-oxyi mi no)aceta mido]-3-(1-pyrid iniu m methyl)ceph-3-em-4carboxylate bishydrochloride in a medium selected from formic acid and acetone, industrial methylated spirit, and mixtures of methanol, n-propanol and diisopropyl ether.
.CLME:
3. A pharmaceutical composition which comprises as active ingredient the crystalline 15 bishydrochloride as defined in claim 1 adapted for use in human or veterinary medicine.
.CLME:
4. Use of the crystalline bishydrochloride as defined in claim 1 in the preparation of (6R,7R)-7 [(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-(1pyr idiniummethyl)ceph-3 em-4-carboxylate pentahydrate.
.CLME:
5. A process according to claim 2 substantially as herein described.
.CLME:
6. A process for the preparation of the crystalline bishydrochloride according to claim 1 substantially as herein described in any one of the Examples.
.CLME:
Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1981. Published by the Patent Office, Southampton Buildings, London, WC2A 1 AY, from which copies may be obtained.
.CLME:
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB7934203 | 1979-10-02 |
Publications (2)
Publication Number | Publication Date |
---|---|
GB2064513A true GB2064513A (en) | 1981-06-17 |
GB2064513B GB2064513B (en) | 1983-09-14 |
Family
ID=10508245
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB8031706A Expired GB2064513B (en) | 1979-10-02 | 1980-10-01 | Cephalosporin antibiotic |
Country Status (14)
Country | Link |
---|---|
US (1) | US4467086A (en) |
JP (1) | JPS5657789A (en) |
AU (1) | AU540382B2 (en) |
BE (1) | BE885488A (en) |
CH (1) | CH644609A5 (en) |
DE (1) | DE3037104C2 (en) |
FR (1) | FR2466469A1 (en) |
GB (1) | GB2064513B (en) |
IE (1) | IE50269B1 (en) |
IT (1) | IT1128569B (en) |
NL (1) | NL8005439A (en) |
NZ (1) | NZ195116A (en) |
SE (1) | SE449996B (en) |
ZA (1) | ZA806082B (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4394503A (en) | 1981-12-07 | 1983-07-19 | Bristol-Myers Company | Cephalosporin derivatives |
US4400503A (en) | 1981-10-30 | 1983-08-23 | Eli Lilly And Company | Purification of syn-7-[[(2-amino-4-thiazolyl)(methoxyimino) acetyl]amino]-3-methyl-3-cephem-4-carboxylic acid |
US4474954A (en) * | 1981-12-07 | 1984-10-02 | Bristol-Myers Company | Intermediates for cephalosporin derivatives |
US4537959A (en) * | 1984-03-26 | 1985-08-27 | Eli Lilly And Company | Crystalline cephalosporin antibiotic salt |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4963542A (en) * | 1976-09-08 | 1990-10-16 | Takeda Chemical Industries, Ltd. | Cephalosporin derivatives |
BE883453A (en) * | 1979-05-25 | 1980-11-24 | Glaxo Group Ltd | INTERMEDIATE COMPOUNDS FOR THE PREPARATION OF CEPHALOSPORINS |
US4594417A (en) * | 1981-10-30 | 1986-06-10 | Eli Lilly Company | Crystalline antibiotic salt |
DE3248281A1 (en) * | 1982-12-28 | 1984-06-28 | Hoechst Ag, 6230 Frankfurt | CRYSTALIZED CEPHEMIC ACID ADDITION SALTS AND METHOD FOR THE PRODUCTION THEREOF |
DE3313816A1 (en) * | 1983-04-16 | 1984-10-18 | Hoechst Ag, 6230 Frankfurt | NEW CEFTAZIDIM CRYSTAL MODIFICATION |
DE3313818A1 (en) * | 1983-04-16 | 1984-10-18 | Hoechst Ag, 6230 Frankfurt | NEW CEFTAZIDIM CRYSTAL MODIFICATION |
US4616080A (en) * | 1984-07-02 | 1986-10-07 | Eli Lilly And Company | Simplified process of forming crystalline ceftazidime pentahydrate |
US5244891A (en) * | 1985-08-05 | 1993-09-14 | Bristol-Myers Squibb Company | Injectable compositions of cefepime dihydrochloride hydrate |
AT387022B (en) * | 1986-06-04 | 1988-11-25 | Biochemie Gmbh | METHOD FOR PRODUCING A NEW CRYSTALLINE SHAPE OF A CEFALOSPORINE DERIVATIVE |
DE3706020A1 (en) * | 1987-02-25 | 1988-09-08 | Hoechst Ag | CRYSTALLIZED CEPHEMIC ACID ADDITION SALTS AND METHOD FOR THE PRODUCTION THEREOF |
GB8802622D0 (en) * | 1988-02-05 | 1988-03-02 | Glaxo Group Ltd | Chemical compound |
JPH02101081A (en) * | 1988-10-08 | 1990-04-12 | Meiji Seika Kaisha Ltd | Crystalline dihydrochloride of cephalosporin derivative and production thereof |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AR229883A1 (en) * | 1978-05-26 | 1983-12-30 | 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 -PIRIDINOMETIL) -CEF-3-EM-4-CARBOXYLATE |
BE883453A (en) * | 1979-05-25 | 1980-11-24 | Glaxo Group Ltd | INTERMEDIATE COMPOUNDS FOR THE PREPARATION OF CEPHALOSPORINS |
-
1980
- 1980-10-01 ZA ZA00806082A patent/ZA806082B/en unknown
- 1980-10-01 FR FR8021038A patent/FR2466469A1/en active Granted
- 1980-10-01 JP JP13822280A patent/JPS5657789A/en active Granted
- 1980-10-01 NZ NZ195116A patent/NZ195116A/en unknown
- 1980-10-01 CH CH734080A patent/CH644609A5/en not_active IP Right Cessation
- 1980-10-01 DE DE3037104A patent/DE3037104C2/en not_active Expired
- 1980-10-01 NL NL8005439A patent/NL8005439A/en not_active Application Discontinuation
- 1980-10-01 BE BE0/202300A patent/BE885488A/en not_active IP Right Cessation
- 1980-10-01 AU AU62880/80A patent/AU540382B2/en not_active Ceased
- 1980-10-01 SE SE8006860A patent/SE449996B/en not_active IP Right Cessation
- 1980-10-01 IT IT49782/80A patent/IT1128569B/en active
- 1980-10-01 GB GB8031706A patent/GB2064513B/en not_active Expired
- 1980-10-01 IE IE2051/80A patent/IE50269B1/en not_active IP Right Cessation
-
1982
- 1982-08-16 US US06/408,519 patent/US4467086A/en not_active Expired - Lifetime
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4400503A (en) | 1981-10-30 | 1983-08-23 | Eli Lilly And Company | Purification of syn-7-[[(2-amino-4-thiazolyl)(methoxyimino) acetyl]amino]-3-methyl-3-cephem-4-carboxylic acid |
US4394503A (en) | 1981-12-07 | 1983-07-19 | Bristol-Myers Company | Cephalosporin derivatives |
US4474954A (en) * | 1981-12-07 | 1984-10-02 | Bristol-Myers Company | Intermediates for cephalosporin derivatives |
US4537959A (en) * | 1984-03-26 | 1985-08-27 | Eli Lilly And Company | Crystalline cephalosporin antibiotic salt |
Also Published As
Publication number | Publication date |
---|---|
IE50269B1 (en) | 1986-03-19 |
SE449996B (en) | 1987-06-01 |
DE3037104C2 (en) | 1986-04-30 |
ZA806082B (en) | 1982-05-26 |
US4467086A (en) | 1984-08-21 |
CH644609A5 (en) | 1984-08-15 |
IT8049782A0 (en) | 1980-10-01 |
BE885488A (en) | 1981-04-01 |
SE8006860L (en) | 1981-04-03 |
GB2064513B (en) | 1983-09-14 |
JPH0245634B2 (en) | 1990-10-11 |
AU6288080A (en) | 1981-04-09 |
AU540382B2 (en) | 1984-11-15 |
DE3037104A1 (en) | 1981-04-16 |
JPS5657789A (en) | 1981-05-20 |
FR2466469B1 (en) | 1984-02-10 |
NZ195116A (en) | 1982-09-07 |
FR2466469A1 (en) | 1981-04-10 |
NL8005439A (en) | 1981-04-06 |
IT1128569B (en) | 1986-05-28 |
IE802051L (en) | 1981-04-02 |
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