GB2045238A - Novel cephalosporins - Google Patents
Novel cephalosporins Download PDFInfo
- Publication number
- GB2045238A GB2045238A GB7940887A GB7940887A GB2045238A GB 2045238 A GB2045238 A GB 2045238A GB 7940887 A GB7940887 A GB 7940887A GB 7940887 A GB7940887 A GB 7940887A GB 2045238 A GB2045238 A GB 2045238A
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- GB
- United Kingdom
- Prior art keywords
- compound
- hydroxyl group
- general formula
- carboxylic acid
- hydrogen atom
- 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
- 229930186147 Cephalosporin Natural products 0.000 title description 11
- 229940124587 cephalosporin Drugs 0.000 title description 11
- 150000001780 cephalosporins Chemical class 0.000 title description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 150000002148 esters Chemical class 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 46
- 239000003242 anti bacterial agent Substances 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims 1
- 150000001342 alkaline earth metals Chemical class 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 claims 1
- 150000007530 organic bases Chemical class 0.000 claims 1
- 150000007513 acids Chemical class 0.000 abstract description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- 230000015572 biosynthetic process Effects 0.000 description 27
- 238000003786 synthesis reaction Methods 0.000 description 27
- -1 4 - hydroxy - 5 oxo -5,6,7,8 - tetrahydroquinoline - 3 - carboxamido Chemical group 0.000 description 20
- 238000012360 testing method Methods 0.000 description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 230000000844 anti-bacterial effect Effects 0.000 description 12
- 239000013078 crystal Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- 239000002609 medium Substances 0.000 description 10
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 9
- VBGYETXWCYRYAB-UHFFFAOYSA-N 4,5-dioxo-1,6,7,8-tetrahydroquinoline-3-carboxylic acid Chemical class C1CCC(=O)C2=C(O)C(C(=O)O)=CN=C21 VBGYETXWCYRYAB-UHFFFAOYSA-N 0.000 description 7
- 241000894006 Bacteria Species 0.000 description 7
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 7
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 230000001580 bacterial effect Effects 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 241000588724 Escherichia coli Species 0.000 description 4
- 241000588747 Klebsiella pneumoniae Species 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 235000010633 broth Nutrition 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- RCYRGXOFTDOXQZ-UHFFFAOYSA-N 1,6,7,8-tetrahydroquinoline-4,5-dione Chemical compound N1C=CC(=O)C2=C1CCCC2=O RCYRGXOFTDOXQZ-UHFFFAOYSA-N 0.000 description 3
- 208000035473 Communicable disease Diseases 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 230000036765 blood level Effects 0.000 description 3
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 description 3
- 229960001139 cefazolin Drugs 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000009102 absorption Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 229960003669 carbenicillin Drugs 0.000 description 2
- 150000001782 cephems Chemical class 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OMAFFHIGWTVZOH-UHFFFAOYSA-N 1-methyltetrazole Chemical compound CN1C=NN=N1 OMAFFHIGWTVZOH-UHFFFAOYSA-N 0.000 description 1
- LDDXLFZUYAPDNP-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxymethylidene]propanedioic acid Chemical compound CC(C)(C)OC=C(C(O)=O)C(O)=O LDDXLFZUYAPDNP-UHFFFAOYSA-N 0.000 description 1
- ZZMRPOAHZITKBV-UHFFFAOYSA-N 3-aminocyclohex-2-en-1-one Chemical compound NC1=CC(=O)CCC1 ZZMRPOAHZITKBV-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000193755 Bacillus cereus Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000588919 Citrobacter freundii Species 0.000 description 1
- LJCWONGJFPCTTL-SSDOTTSWSA-N D-4-hydroxyphenylglycine Chemical compound [O-]C(=O)[C@H]([NH3+])C1=CC=C(O)C=C1 LJCWONGJFPCTTL-SSDOTTSWSA-N 0.000 description 1
- ZGUNAGUHMKGQNY-SSDOTTSWSA-N D-alpha-phenylglycine Chemical compound OC(=O)[C@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-SSDOTTSWSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 241000588697 Enterobacter cloacae Species 0.000 description 1
- 241000194032 Enterococcus faecalis Species 0.000 description 1
- 241000588915 Klebsiella aerogenes Species 0.000 description 1
- 241000196833 Kocuria rhizophila DC2201 Species 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical class NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000588772 Morganella morganii Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000588767 Proteus vulgaris Species 0.000 description 1
- 241000588777 Providencia rettgeri Species 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- 241001354013 Salmonella enterica subsp. enterica serovar Enteritidis Species 0.000 description 1
- 101100391171 Schizosaccharomyces pombe (strain 972 / ATCC 24843) for3 gene Proteins 0.000 description 1
- 241000607715 Serratia marcescens Species 0.000 description 1
- 241000607762 Shigella flexneri Species 0.000 description 1
- 241000122973 Stenotrophomonas maltophilia Species 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012911 assay medium Substances 0.000 description 1
- 229940075612 bacillus cereus Drugs 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- RTYJTGSCYUUYAL-YCAHSCEMSA-L carbenicillin disodium Chemical compound [Na+].[Na+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)C(C([O-])=O)C1=CC=CC=C1 RTYJTGSCYUUYAL-YCAHSCEMSA-L 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000010227 cup method (microbiological evaluation) Methods 0.000 description 1
- NFWNKZGKJXKUKP-UHFFFAOYSA-N diethyl 2-[[(3-oxocyclohexen-1-yl)amino]methylidene]propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)=CNC1=CC(=O)CCC1 NFWNKZGKJXKUKP-UHFFFAOYSA-N 0.000 description 1
- 229940092559 enterobacter aerogenes Drugs 0.000 description 1
- 150000002168 ethanoic acid esters Chemical class 0.000 description 1
- TWWYDAMKOZTNLB-UHFFFAOYSA-N ethyl 4,5-dioxo-1,6,7,8-tetrahydroquinoline-3-carboxylate Chemical compound C1CCC(=O)C2=C1NC=C(C(=O)OCC)C2=O TWWYDAMKOZTNLB-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011356 non-aqueous organic solvent Substances 0.000 description 1
- 229930185482 poranic acid Natural products 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229940007042 proteus vulgaris Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention comprises cephalosporanic acids of the general formula <IMAGE> wherein A represents <IMAGE> and Y represents a hydrogen atom or a hydroxyl group, and the biologically acceptable salts and esters thereof.
Description
SPECIFICATION
Novel cephalosporins
This invention relates to novel cephalosporins, and more specifically, to cephalosporanic acids of the general formula
wherein Y represents a hydrogen atom or a hydroxyl group, and A represents
and the biologically acceptable salts or esters thereof.
In recent years, the number of infectious diseases
caused by Pseudomonas aeruginosa has increased,
and these infectious diseases are often difficult to
cure. It is desired therefore to develop drugs which
are effective for infectious diseases caused by
Pseudomonas aeruginosa with reduced side-effects.
It is known from J. Antibiotics,23 (3), 137(1970), etc. that cephalosporin-type compounds such as
cephazoline (for example, sodium cephazoline,
sodium 7 [1 - (1 H) - tetrazoylacetamido .3-[2 -(5- methyl - 1,3,4 - thiadiazoyl) - thiomethyl -A3- cephem - 4 - carboxylate; to be abbreviated CEZ) are
effective as therapeutic agents for infections caused
by Gram-positive or Gram-negative bacteria. These
agents, however, are ineffective for infections
caused byPseudomonas aeruginosa, and no
cephalosporin-type compound effective against
Pseudomonas aeruginosa has been marketed.It is
known, on the other hand, from "Antimicrobial
Agents and Chemistry"-1 967,609(1968) and ibid.-1 968,388 (1968) that carbenicillin (for example,
sodium carbenicillin, disodium - a - carboxy - benzyl
penicillin, to be abbreviated CB-PC) has been used
mainly for the treatment of infections caused by
Pseudomonas aeruginosa. Since, however, this drug
has a low activity on Pseudomonas aeruginosa, it
must be administered in high doses. Moreover, it is
ineffective for Pseudomonas aeruginosa-induced
infections of difficultly curable nature.
It is desired therefor to provide a drug which has a
strong antibacterial activity on Gram-positive and
Gram-negative bacteria and a high activity on
Pseudomonas aeruginosa.
The present invention provides the cephalos
poranic acids of general formula (1), and the biologi .calls acceptable salts and esters thereof.
Examples of the cephalosporanic acids of general
formula (1) include 7 -[D - (-) - tx - (4 - hydroxy - 5
oxo -5,6,7,8 - tetrahydroquinoline - 3 - carboxamido)
- phenylacetamido] - 3 - [[(1 - methyl - 1 H - tetrazol - 5 - yl)thio] methyl] - A3 - cephem - 4 - carboxylic acid, 7 [D - (-) - a - (4 - hydroxy - 5 - oxo - 5,6,7,8 - tetrahydro quinoline - 3 - carboxamido) - a - (4 - hydroxyphenyl) -acetamido] -3-[[(1 - methyl - 1H-tetrazol-5- yl)thio] methyl] - A3 - cephem - 4 - carboxylic acid, 7 [D - (-) - a - (4 - hydroxy -5 - oxo -5,6,7,8 - tetrahydro quinoline - 3 - carboxamido) - a - (4 - hydroxyphenyl)acetamido] - 3 - acetoxymethyl - A3 cephem - 4 - carboxylic acid, and 7 - [D - (-) - a - (4 hydroxy -5 - oxo -5,6,7,8 - tetrahydroquinoline - 3 - carboxamido) - a - (4 - hydroxyphenyl) - acetamido] 3 - [2 - (5 - methyl - 1,3,4 - thiadiazolyl)thiomethyl) - A3 - cephem - 4 - carboxylic acid.
The biologically acceptable salts of the cephalosporanic acids of general formula (1) include alkali metal salts such as lithium, sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; basic amino acid salts such as lysine, arginine or ornithine salts; and ordinary organic base salts such as triethylamine, benzylamine or procaine salts.
The biologically acceptable esters of the cephalosporanic acids of general formula (1) contain ordinary ester groups known in the field of cephalosporins. The ester groups, may, for example, be those expressed by the following general formula
wherein R1 represents a hydrogen atom or a lower aklyl group having 1 to 5 carbon atoms, R2 represents a lower alkyl group having 1 to 5 carbon atoms, and X represents an oxygen or sulfur atom.
The cephalosporin compounds of this invention have a broad range of antibacterial spectrum and a strong antibacterial activity against Gram-negative bacteria, especially bacteria of the genus
Pseudomonas. Hence, they are useful as therapeutic agents for infections by these bacteria.
The cephalosporin in accordance with this invention can be produced by reacting a compound of the general formula
wherein Y and A are as defined in general formula (1), or a salt or reactive derivative thereof, with a reactive derivative of 4 - hydroxy - 5 - oxo - 5,6,7,8 tetrahydroquinoline - 3 - carboxylic acid of the general formula
The cephalosporin of the invention can also be produced by reacting a compound of the general formula
wherein A is as defined in general formula (1), or a salt or reactive derivative thereof, with a reactive derivative of a carboxylic acid of the general formula
wherein Y is as defined in general formula (1).
The compounds of general formulae (2) and (4) are known in the art. 4 - Hydroxy - 5 - oxo - 5,6,7,8 tetrahydroquinoline - 3 - carboxylic acid of general formula (3) is a novel compound, and can be prepared, for example, by preparing diethyl N - (3 - oxo 1 - cyclohexen - 1 - yl)amino - methylenemalonate from 3 - amino - 2 - cyclohexenone and dimethyl ethoxymethylenemalonic acid, heating this product to cyclize it to ethyl 4 - hydroxy - 5 - oxo - 5,6,7,8 tetrahydroquinoline - 3 - carboxylate, and hydrolyzins this product. Examples of the reactive derivatives of 4 - hydroxy - 5 - oxo - 5,6,7,8 - tetrahydroquinoline - 3 - carboxylic acid of formula (3) include its acid halides, mixed acid anhydrides, and active esters.
The reaction of the compound of formula (2) or its salt or ester with the reactive derivative of the quinoline carboxylic acid of formula (3) is carried out usually in a reaction solvent. Suitable reaction solvents include, for example, tetrahydrofuran, methylene chloride, chloroform, dioxane, acetic acid esters, and dimethylformamide.
The reaction of the cephalosporanic acid of general formula (4) or its salt or reactive derivative with the reactive derivative of the carboxylic acid of formula (5) is carried out in an aqueous solvent or a non-aqueous organic solvent. The carboxylic acid of general formula (5) can be prepared by reacting D (-) - phenylglycine or D - (-) - 4 - hydroxyphenylglycine with the reactive derivative of the quinoline carboxylic acid of formula (3). Suitable reactive derivatives of the carboxylic acid of general formula (5) include acid halides, mixed anhydrides, and active esters.
The following Synthesis Examples specifically illustrate the process for producing cephalosporins in accordance with this invention.
Synthesis Example 1
Synthesis of 7 - [D - (-) - a - (4 - hydroxy - 5 - oxo 5,6,7,8 - tetrahydroquinoline - 3 - carboxamide)phenylacetamido] - 3 - [[(1 - methyl - 1 H - tetrazol - 5 - yl)thio] methyl] - A3 - cephem - 4 - carboxylic acid:
To 20 ml of methylene chloride were added 0.60 g of 4 - hydroxy - 5 - oxo - 5,6,7,8 - tetrahydroquinoline - 3 - carboxylic acid and 0.65 g of triethylamine. The mixture was cooled to -150Cto -10 C, and a solution of 0.69 g of ethyl chloroformate in 5 ml of methylene chloride was added dropwise.The mixture was stirred at -15"C to -10"C for30 minutes, and a solution of 1.6 9 of 7 - [D - (-) - a - amino - phenylacetamido] - 3 - [[(1 - methyl - 1 H - tetrazol - G - yl) - thio] methyl] - A3 - cephem - 4 - carboxylic acid in 20 ml of methylene chloride and 0.88 g of triethylamine. The reaction was carried out at15tC to 0 C for 1.5 hours, and then the solvent was distilled off. Water (50 ml) was added, and the pH of the mixture was adjusted to 2 with 40% phosphoric acid.
The crystals which precipitated were collected by filtration. Then, the crystals were purified by using a column filled with silica gel to afford 0.12 g of the captioned product.
The infrared absorption spectrum of this product, determined by the KBrtablet method, had maximum absorptions at 1790, 1690 (with shoulder), 1620, 1540, 1505, 1410, 1365, 1185,820, and 705 cm-'.
Synthesis Example 2
Synthesis of 7 - [D - (-) - a - (4 - hydroxy - 5 - oxo 5,6,7,8 - tetrahydroquinoline - 3- carboxamide) - a - (4 - hydroxy - phenyl)acetamido] - 3 - [[(1 - methyl 1 H - tetrazol - 5 - yl)thio] - methyl] - A3 - cephem - 4 carboxylic acid:
In 200 ml of dimethyl formamide were suspended 10.0 g of 4 - hydroxy - 5 - oxo - 5,6,7,8 - tetrahydroquinoline - 3 - carboxylic acid and 6.12 g of N - hydroxysuccinimide. The suspension was cooled to -10 C, and a solution of 6.9 g of thionyl chloride in 50 ml of dimethylformamide was added dropwise.
The mixture was stirred at 0 to 5"C for 24 hours, and then at room temperature for 3 hours, and cooled to below 1000. Pyridine (10.1 g) was added dropwise, and the mixture was stirred at room temperature for 4 hours, followed by cooling. The crystals which precipitated were collected by filtration to afford 9.74 g of yellow crystals having a melting point of 252 to 255"C (decomp.; uncorrected). In 50 ml of dimethylformamide were suspended 3.51 g of the resulting yellow crystals and 5.50 g of 7 - [D - (-) - a - amino - a (4 - hydroxyphenyl)acetamido] - 3 - [[(1 - methyl - 1 H - tetrazol - 5 - yl)thio]- methyl] - 93 - cephem - 4 - carboxylic acid.The suspension was cooled two 200 to OOC, and a solution of 2.12 g of triethylamine in 5 ml of dimethylformamide was added dropwise. The mixture was stirred at into O"C for 30 minutes, and the reaction mixture was poured into 500 ml of acetone. Ether (500 ml) was added, and the crystals that precipitated were collected by filtration. The crystals were purified by using a column packed with silica gel to afford 2.0 g of the captioned product.
The infrared absorption spectrum of this product had maximum absorptions at 1790, 1690, 1620, 1520, 1500,1360,1240, 1190 and 820 cm-l.
Synthesis Example 3
Synthesis of 7 - [D - (-) - a - (4 - hydroxy - 5 - oxo 5,6,7,8 - tetrahydroquinoline - 3 - carboxamide) - a (4 - hydroxyphenyl)acetamido] - 3 - acetoxymethyl - Q3 - cephem - 4 - carboxylic acid:
In 200 ml of dimethylformamide were suspended 10.0 g of 4 - hydroxy - 5 - oxo - 5,6,7,8 - tetrahydroquinoline - 3 - carboxylic acid and 6.12 g of
N-hydroxysuccinimide, and the suspension was cooled to - 10 C. A solution of 6.9 g of thionyl chloride in 50 ml of dimethylformamide was added dropwise.The mixture was stirred at 0 to 5"C for 24
hours and at room temperature for3 hours, and then
cooled to below 10 C. Pyridine (10.1 g) was added dropwise, and the mixture was stirred at room temperature for4 hours.
The mixture was cooled, and the crystals that precipitated were collected by filtration to afford 9.74 g of yellow crystals having a melting point of 252 to 255"C (decomp.; uncorrected). These yellow crystals (0.500 g) and 0.880 g of the trifluoroacetate of 7 -[D (-) - a - amino - a - (4 - hydroxyphenyl)acetamido] - 3 acetoxy - methyl - A3 - cephem - 4 - carboxylic acid were suspended in 10 ml of dimethylformamide, and the suspension was cooled to -10 C to -SOC. A solution of 0.499 g of triethylamine in 3 ml of dimethylformamide was added dropwise. The mixture was stirred at -10 C to -5 C for 1 hour, and the reaction mixture was poured into 70 ml of acetone.Ether (70 ml) was added, and the crystals which precipitated were collected by filtration. The crystals were purified by using a column packed with silica gel to afford 0.330 g of the captioned product.
The nuclear magnetic resonance spectrum (DMSO-d6, 60 MC, TMS) had signals at 8 1.7-2.65 (4H, m), 2.0 (3H, s), 2.7-3.2 (2H, m), 3.2-3.6 (2H, bs), 3.2-3.6 (2H, bs), 4A-5.3 (3H, m), 5.5-6.0 (2H, m), 6.69 (2H, d, J = 75 Hz), 7.24 (2H, d, J = 75 Hz), 8.33 (1 H, bs), 9.0-9.5 (1H, m) and 10.8-11.2 (1H, m).
Synthesis Example 4 Synthesis of 7 - [D - (-) - a - (4 - hydroxy - 5 - oxo 5,6,7,8 - tetrahydroquinoline - 3 - carboxamido) - a (4- hydroxyphenyl)acetamido] - 3 - [2 - (5 - methyl - 1,3,4 - thiadiazolyl) - thiomethyl] - A3 - cephem - 4 carboxylic acid:
An active ester (0.608 g) obtained by the same method as in Synthesis Example 3 from 4 - hydroxy 5 - oxo - 5,6,7,8 - tetrahydroquinoline - 3 - carboxylic acid and N-hydroxyuccinimide, and 0.986 g of 7 - [D (-) - a - amino - a - (4 - hydroxyphenyl)acetamido] - 3 [2 - (5 - methyl - 1,3,4 - thiadiazolyl]thiomethyl] - A3 cephem - 4 - carboxylic acid were suspended in 10 ml of dimethylformamide. The suspension was cooled to -10 C, and a solution of 0.202 g of triethylamine in 2 ml of dimethylformamide was added dropwise.The mixture was stirred art 1000 for 1 hour, and post-treated and purified in the same way as in Synthesis Example3 to afford 0.807 g of the captioned product.
The nuclear magnetic resonance spectrum (DMSO-d6, 60 MC, TMS) had signals ata 1.7-3.2 (6H, m), 2.65 (3H, s), 3.4-3.8 (2H, m), 4.04.7 (2H, m), 5.0 (1 H, d, J = 4.5 Hz), 5.5-5.9 (2H, m), 6.68 (2H, d, J = 7.5 Hz), 7.24 (2H, d, J = 7.5 Hz), 8.34 H, bs), 9.0-9.5(1 H, m) and 10.7-11.1(1 H, m).
The antibacterial activities of the cephalosporins of this invention were measured using the sodium salts of the compounds obtained in Synthesis
Examples 1 to 4. The procedure and the results are shown in Referential Example 1.
Referential Example 1
Carbenicillin sodium salt (CB-PC) and cephazoline sodium salt (CEZ) were used as controls.
The antibacterial activities of the test compounds against various Gram-positive and Gram-negative bacteria were determined in a customary manner by the minimum growth inhibitory concentration method (MIC method).
The experimental procedure was as follows:
A commercially available heart infusion agar medium (to be abbreviated HIA medium) was used as an assay medium, and a commercially available trypto-soy bouillon medium (to be abbreviated TSB) was used as a medium for the growth of test bacterial strains.
The test compound was diluted with the melted
HIA medium to 100 jug/ml as a maximum concentration, and then serially diluted double. The dilutions were poured into sterilized Petri dishes respectively and allowed to cool and solidify to prepare plates containing the test compound.
The test bacterial strain was cultivated at 37"C for 18 to 24 hours in the TSB medium. The culture broth was diluted to 50 to 500 times with a freshly prepared TSB culture medium, and one platinum loopful of the dilution was inoculated in each of the plates containing the test compound. The plate was incubated at 3700 for 18 hours, and the state of growth of the strain on the plate was observed, and the minimum growth inhibitory concentration (MIC) of the test compound was determined. The results are shown in Table 1.
Table 1
Test compounds Minimum growth inhibitory concentration {ligiml) Synthesis Synthesis Synthesis Synthesis Test bacteria Example 1 Example2 Example3 Example4 CB-PC CEZ Staphylococcus aureus 1.56 1.56 1.56 0.78 1.56 0.20 (FDA 209P) Staphylococcusaureus 3.13 3.13 3.13 3.13 12.5 0.78 (Y-8) Streptococcusfaecalis 25 25 25 12.5 50 25 (Hoshi) Bacilluscereus 25 12.5 25 12.5 100 100 (IAM 1792) Escherichia coli (K-12) 0.78 0.39 1.56 0.39 6.25 3.13 Escherichia coli (NIHJ) 0.78 0.78 1.56 0.78 6.25 3.13 Escherichia coli (26RO3) 1.56 0.78 3.13 1.56 3.13 50 Escherichia coli (14H114) 6.25 6.25 - - > 100 6.25 Klebsiella pneumoniae 0.20 0.39 1.56 0.78 > 100 1.56 (ATCC 10031) Klebsiella pneumoniae 1.56 0.78 3.13 1.56 100 3.13 (Horino) Klebsiella pneumoniae 0.78 0.78 - - 25 3.13 (B-172) Klebsiella pneumoniae - - 3.13 1.56 50 3.13 (F-5089) Shigellaflexneri (K-A) 0.20 0.10 0.39 0.20 1.56 1.56 Salmonella enteritidis 0.78 0.39 0.78 0.20 1.56 1.56 (KB-21) Proteus vulgaris (OX-19) 1.56 0.78 1.56 0.78 6.25 1.56 Proteus rettgeri (T-2) 1.56 1.56 3.13 1.56 3.13 12.5 Proteus morganii (C-39) 3.13 3.13 12.5 6.25 6.25 > 100 Pseudomonas aeruginosa 12.5 12.5 12.5 6.25 100 > 100 (IFO-3901) Pseudomonas aeruginosa 1.56 1.56 3.13 1.56 25 > 100 (S-1) Pseudomonas aeruginosa 3.13 1.56 1.56 3.13 25 > 100 (395) Pseudomonas aeruginosa 12.5 6.25 12.5 12.5 > 100 > 100 (NCTC 7244) Pseudomonas aeruginosa 12.5 12.5 12.5 12.5 > 100 > 100 (ATCC 10145) Pseudomonas aeruginosa 12.5 12.5 12.5 12.5 > 100 > 100 (718) Pseudomonas aeruginosa 6.25 3.13 12.5 6.25 > 100 > 100 (F1629) Enterobacter cloacae (D-49) 6.25 3.13 - - 100 > 100 Enterobacteraerogenes 0.20 0.20 0.39 0.39 1.56 3.13 (IFO 3320) Citrobacterfreundii (F-34) 0.78 0.39 - - 3.13 50 Serratia marcescens (S-33) 3.13 3.13 25 12.5 6.25 > 100 Pseudomonas maltophilia 3.13 6.25 6.25 3.13 25 > 100 (F-6257) It is seen from Table 1 that the compounds of this invention have a broad range of antibacterial spectrum, and their antibacterial activities are of high level. In particular, they have much better antibacterial activity againstPseudomonas aeruginosa strains than CB-PC and CEZ, and are useful as anti
Pseudomonas aeruginosa drugs.
Referential Example 2 shows that the compounds of th is invention have superior antibacterial activity againstPseudomonas aeruginosa strains.
Referential Example 2
The compounds obtained in Synthesis Examples 1 to 4 were tested in the following manner.
A suspension ofPseudomonas aeruginosa (NCTC 7244) cultivated at 370C for 18 hours in a heart infusion broth medium (HIM medium) in a final amount of 105, 106 and 107 cells/ml in an HIB medium containing each of the test compounds which was obtained in the same way as in Referential Example 1 except that the maximum concentration of the test compound was 200,ug/ml. The bacterial strain was cultivated at 37"C for 18 hours, and the turbidity of the culture broth was evaluated with the naked eye. The minimum concentration of the test compound at which no turbidity was noted was defined as MIC.
After the determination of MIC, one platinum loopful of each of the culture broths in various concentrations was taken out from the test tubes, and inoculated in a separately provided plate of an HIA medium not containing the test compound, and incubated at 37"C for 18 hours. The growth of the bacterial strain was evaluated. The minimum concentration of the test compound among those plates which did not show growth of the bacterial strain was defined as the minimum bactericidal concentration (MBC) of the test compound.
The results are shown in Table 2 from which it is seen that the bactericidal activity of the compounds of this invention is strong.
Table2
Amount of the bacterial strain inoculated (cells/ml) 105 106 107 Compound of MIC 12.5 12.5 25 Synthesis Example 1 MBC 12.5 12.5 > 200 Compound of MIC 6.25 6.25 12.5 Synthesis Example 2 MBC 6.25 12.5 > 200 Compound of MIC 12.5 12.5 25 Synthesis Example3 MBC 12.5 25 > 200 Compound of MIC 12.5 12.5 > 200 Synthesis Example 4 MBC 12.5 12.5 > 200 MIC 50 100 200 CB-PC MBC 100 100 > 200 MIC > 200 > 200 > 200 CEZ MBC > 200 > 200 > 200 The following Experimental Examples illustrate the concentrations of the compounds of this invention in blood in rats and their acute toxicities in mice.
Experimental Example 1
The compounds of this invention prepared in
Synthesis Examples 1 to 4 were each administered intramuscularly to rats, and the concentrations of the compounds in the blood were determined.
Each of the test compounds was intramuscularly injected into the femoral part of rats in a customary manner in a dose of 20 mg/kg for each rat. The blood was drawn by incising the cervical artery and vein at the end of 15 minutes, 30 minutes, 60 minutes, 120 minutes, and 240 minutes after the injection. The separated sera were used for the measurement of the blood level of the test compounds. The concentrations of the test compounds in the sera were determined by a thin-layer cup method using Micrococcus luteus ATCC 9341 as an assay microorganism.
The results are shown in Table 3.
It is seen from the results that the state of the blood levels of the compounds of this invention in rats is of the high level-retaining type, and the compounds of this invention are useful for the treatment of infections.
Table3
Blood level after administration (average value + standard deviation"ag/ml) Test Dose compound (mg/kg; i.m.) 15 minutes 30 minutes 60 minutes 120 minutes 240 minutes Synthesis Examplel 20 12.1 t3.6 10.5i2.2 9.1 i3.2 4.8i2.1 - Synthesis Example2 20 2001.4 14.42.5 8.04.0 3.21.2 - Synthesis Example3 20 14.0 2.2 8.8 3.1 6.8 2.2 2.2 1.0 - Synthesis Example4 20 22.8i2.6 16.1 + 3.0 7.6 + 1.8 2.5 + Experimental Example 2
Each of the compounds of this invention obtained in Synthesis Examples 1 to 4 was intravenously administered to ICR male mice having a body weight of 25 g in groups each consisting of 10 mice, and the 50 /O lethal dose (LDso) was estimated. Each of the compounds was administered intravenously to the tail of each mouse in a customary manner in a dose of 500 mg/kg and 1000 mg/kg, and over two weeks from then, the states of the mice were observed. It was consequently estimated that the LDso values of each of these compounds was at least 1000 mg/kg.
As is apparent from the foregoing description, the cephalosporins of this invention have very good antibacterial activity, and are useful as antibacterial agents. They can be used not only for the treatment and prevention of bacterial infections of mammals including humans but also as disinfections. In administration to humans, the dose of the cephalosporin of this invention is 100 mg to 2000 mg, preferably 250 mg to 1000 mg, per administration. Desirably, it is administered several times a day.
Pharmaceuticals containing the compound of this invention as an active ingredient may be in the form of solids such as tablets, capsules and powders or liquids such as injections or suspensions. Additives usually employed in the art, such as vehicles, stabilizers and wetting agents may be used.
Claims (13)
1. A cephalosporic acid of the general formula
wherein A represents
and Y represents a hydrogen atom or a hydroxyl group, and the biologically acceptable salt and ester thereof.
2. The salt of claim 1 which is a salt of an alkali metal, an alkaline earth metal, a basic amino acid or an organic base.
3. The ester of claim 1 which has an ester group of the formula
wherein R' represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms, R2 represents a lower alkyl group having 1 to 5 carbon atoms, and X represents an oxygen or sulfur atom.
4. The compound of claim 1 whereinYrepresents a hydrogen atom and A represents
5. The compound of claim 1 wherein Y represents a hydroxyl group and A represnts
6. The compound of claim 1 wherein Y represents a hydroxyl group and A represents
7. The compound of claim 1 wherein Y represents a hydroxyl group, and A represents
8. An antibacterial agent comprising as an active ingredient a cephalosporanic acid of the general formula
wherein A represents
and Y represents a hydrogen atom or a hydroxyl group, or the biologically acceptable salt or esters thereof.
9. The antibacterial agent of claim 8 wherein Y represents a hydrogen atom and A represents
10. The antibacterial agent of claim 8 wherein Y represents a hydroxyl group and A represents
11. A cephalosporanic acid or a biologically acceptable salt or ester thereof according to claim 1, substantially as exemplified herein.
12. An anti-bacterial agent according to claim 8, substantially as exemplified herein.
13. An anti-bacterial agent comprising a compound according to any one of claims 2 to 7 and 11.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP14605378A JPS5572195A (en) | 1978-11-28 | 1978-11-28 | Novel cephalosporin and antibacterial comprising it as active constituent |
JP4727579A JPS55139389A (en) | 1979-04-19 | 1979-04-19 | Novel cephalosporin |
Publications (2)
Publication Number | Publication Date |
---|---|
GB2045238A true GB2045238A (en) | 1980-10-29 |
GB2045238B GB2045238B (en) | 1982-12-01 |
Family
ID=26387444
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB7940887A Expired GB2045238B (en) | 1978-11-28 | 1979-11-27 | Cephalosporins |
Country Status (4)
Country | Link |
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DE (1) | DE2947979A1 (en) |
FR (1) | FR2442853A1 (en) |
GB (1) | GB2045238B (en) |
IT (1) | IT1126415B (en) |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS4935392A (en) * | 1972-08-02 | 1974-04-01 | ||
CA1022544A (en) * | 1972-12-21 | 1977-12-13 | Yukiyasu Murakami | Process of preparing a heterocyclic acyl group-substituted cephalosporin derivative |
CH606001A5 (en) * | 1974-05-13 | 1978-10-13 | Ciba Geigy Ag | |
CA1074784A (en) * | 1974-09-06 | 1980-04-01 | Sumitomo Chemical Company | N-ACYLAMINO-.alpha.-ARYLACETAMIDO CEPHALOSPORINS |
-
1979
- 1979-11-27 GB GB7940887A patent/GB2045238B/en not_active Expired
- 1979-11-28 IT IT27660/79A patent/IT1126415B/en active
- 1979-11-28 DE DE19792947979 patent/DE2947979A1/en not_active Withdrawn
- 1979-11-28 FR FR7929256A patent/FR2442853A1/en active Granted
Also Published As
Publication number | Publication date |
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FR2442853B1 (en) | 1983-07-01 |
IT1126415B (en) | 1986-05-21 |
DE2947979A1 (en) | 1980-06-04 |
GB2045238B (en) | 1982-12-01 |
IT7927660A0 (en) | 1979-11-28 |
FR2442853A1 (en) | 1980-06-27 |
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