NO143833B - EXTINGUISHING DEVICE. - Google Patents
EXTINGUISHING DEVICE. Download PDFInfo
- Publication number
- NO143833B NO143833B NO763061A NO763061A NO143833B NO 143833 B NO143833 B NO 143833B NO 763061 A NO763061 A NO 763061A NO 763061 A NO763061 A NO 763061A NO 143833 B NO143833 B NO 143833B
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- Norway
- Prior art keywords
- acid
- general formula
- carbon atoms
- aminocephalosporanic
- cephalosporin
- Prior art date
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- 239000002253 acid Substances 0.000 claims description 22
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical class S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 150000001718 carbodiimides Chemical class 0.000 claims description 3
- 150000004820 halides Chemical class 0.000 claims description 3
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 150000001540 azides Chemical class 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 22
- 150000001875 compounds Chemical class 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- HOKIDJSKDBPKTQ-GLXFQSAKSA-M cephalosporin C(1-) Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)CCC[C@@H]([NH3+])C([O-])=O)[C@@H]12 HOKIDJSKDBPKTQ-GLXFQSAKSA-M 0.000 description 9
- HOKIDJSKDBPKTQ-GLXFQSAKSA-N Cephalosporin C Natural products S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CCC[C@@H](N)C(O)=O)[C@@H]12 HOKIDJSKDBPKTQ-GLXFQSAKSA-N 0.000 description 8
- 108010087702 Penicillinase Proteins 0.000 description 7
- 229950009506 penicillinase Drugs 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- -1 S-substituted mercaptoacetamido group Chemical group 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 229930182555 Penicillin Natural products 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 150000002960 penicillins Chemical class 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 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 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- TWOLQIUHVMTAAE-UHFFFAOYSA-N 2-phenylsulfanylacetyl chloride Chemical compound ClC(=O)CSC1=CC=CC=C1 TWOLQIUHVMTAAE-UHFFFAOYSA-N 0.000 description 1
- ABFDTYJJUSUWRB-UHFFFAOYSA-N 4-[[4-(dimethylamino)phenyl]iminomethylideneamino]-n,n-dimethylaniline Chemical compound C1=CC(N(C)C)=CC=C1N=C=NC1=CC=C(N(C)C)C=C1 ABFDTYJJUSUWRB-UHFFFAOYSA-N 0.000 description 1
- NXNZBSJCMSODTO-UHFFFAOYSA-N 5,6-dihydro-2h-1,3-thiazine Chemical group C1CC=NCS1 NXNZBSJCMSODTO-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000193755 Bacillus cereus Species 0.000 description 1
- JUDJWPISYRQGCZ-UHFFFAOYSA-N CC1=CC=C(C(C(Cl)=O)S)C=C1 Chemical compound CC1=CC=C(C(C(Cl)=O)S)C=C1 JUDJWPISYRQGCZ-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 150000003842 bromide salts Chemical class 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 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 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 1
- 229910000071 diazene Inorganic materials 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 150000003952 β-lactams Chemical group 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A62—LIFE-SAVING; FIRE-FIGHTING
- A62C—FIRE-FIGHTING
- A62C31/00—Delivery of fire-extinguishing material
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Business, Economics & Management (AREA)
- Emergency Management (AREA)
- Fire-Extinguishing By Fire Departments, And Fire-Extinguishing Equipment And Control Thereof (AREA)
- Vehicle Waterproofing, Decoration, And Sanitation Devices (AREA)
- Bidet-Like Cleaning Device And Other Flush Toilet Accessories (AREA)
- Electrical Discharge Machining, Electrochemical Machining, And Combined Machining (AREA)
Abstract
Slukkeinnretning.Extinguishing device.
Description
Denne oppfinnelse angår en analogifremgangsmåte for fremstilling av nye 7-aminocefalosporansyrederivater med den generelle formel I og salter derav med farmasøytisk egnede baser. This invention relates to an analogous process for the preparation of new 7-aminocephalosporanic acid derivatives of the general formula I and salts thereof with pharmaceutically suitable bases.
I formel I betyr R et fenylradikal, et cykloalkylradikal med In formula I, R means a phenyl radical, a cycloalkyl radical with
4-6 karbonatomer, hvilke radikaler kan være substituert med en alkylgruppe med 1-4 karbonatomer, eller et alkylradikal 4-6 carbon atoms, which radicals may be substituted with an alkyl group of 1-4 carbon atoms, or an alkyl radical
med 1-10 karbonatomer. De nye forbindelser fremstilles i henhold til oppfinnelsen ved at 7-aminocefalosporansyre eller et with 1-10 carbon atoms. The new compounds are produced according to the invention by 7-aminocephalosporanic acid or et
salt derav acyleres med et syrehalogenid, -anhydrid eller -azid eller en aktivert ester av en syre av den generelle formel II salt thereof is acylated with an acid halide, anhydride or azide or an activated ester of an acid of the general formula II
eller med en syre av den generelle formel II i nærvær av et karbodiimid, og eventuelt omvandles den erholdte syre av den generelle formel I ved omsetning med en base til et salt. or with an acid of the general formula II in the presence of a carbodiimide, and optionally the obtained acid of the general formula I is converted by reaction with a base into a salt.
Saltene av forbindelsene med formel I omfatter f.eks. vannoppløslige salter som f.eks. natrium-, kalium-, litium-, ammonium- og substituerte ammoniumsalter, så vel som de mindre vannoppløselige salter som kalsium-, barium-, prokain-, kinin- The salts of the compounds of formula I comprise e.g. water-soluble salts such as sodium, potassium, lithium, ammonium and substituted ammonium salts, as well as the less water-soluble salts such as calcium, barium, procaine, quinine
og dibenzyletylendiaminsaltene. and the dibenzylethylenediamine salts.
De nye forbindelser fremstilt i henhold til fore-liggende oppfinnelse er beslektet med cefalosporin C for så vidt som de inneholder 5,6-dihydro-2H-l,3-tiazinringen med en til-leiret fl-laktaminring i 2,3-stillingen, som er karakteristisk for cefalosporin C. I motsetning til cefalosporin C, som inneholder 5'-amino-N'-adipamylgruppen i 7-stillingen, er imidlertid forbindelsene fremstilt i henhold til oppfinnelsen karakterisert ved en S-substituert merkaptoacetamidogruppe i 7-stillingen. I motsetning til cefalosporin C, som har en relativt lav anti-bakteriell virkning, er videre forbindelsene fremstilt i henhold til oppfinnelsen høyeffektive antibakterielle midler. De er videre karakterisert ved penicillinase-motstandsevne, syrestabilitet og aktivitet overfor et bredt område av mikroorganismer. The new compounds produced according to the present invention are related to cephalosporin C in so far as they contain the 5,6-dihydro-2H-1,3-thiazine ring with an attached fl-lactamine ring in the 2,3 position, which is characteristic of cephalosporin C. In contrast to cephalosporin C, which contains the 5'-amino-N'-adipamyl group in the 7-position, however, the compounds produced according to the invention are characterized by an S-substituted mercaptoacetamido group in the 7-position. In contrast to cephalosporin C, which has a relatively low antibacterial effect, the compounds produced according to the invention are also highly effective antibacterial agents. They are further characterized by penicillinase resistance, acid stability and activity against a wide range of microorganisms.
De følgende kjente penicillinforbindelser og forbindelser fremstilt ifølge oppfinnelsen ble sammenlignet med hver-andre med hensyn til bestandighet i nærvær av penicillinase: 6- [fenylmerkaptoacetamido]-penicillansyre, . 7- [fenylmerkaptoacetamido]-cefalosporansyre, 6- [n-butylmerkaptoacetamido]-penicillansyre, 7- [n-butylmerkaptoacetamido]-cefalosporansyre, 7-[(1'-metylcyklobutyl)-merkaptoacetamido]-cefalo-sporansyre . The following known penicillin compounds and compounds prepared according to the invention were compared with each other with respect to stability in the presence of penicillinase: 6-[phenylmercaptoacetamido]-penicillanic acid, . 7-[phenylmercaptoacetamido]-cephalosporanic acid, 6-[n-butylmercaptoacetamido]-penicillanic acid, 7-[n-butylmercaptoacetamido]-cephalosporanic acid, 7-[(1'-methylcyclobutyl)-mercaptoacetamido]-cephalosporanic acid .
Ved hvert forsøk ble den aktuelle forbindelse oppløst At each trial, the relevant compound was dissolved
i vann til en konsentrasjon på 1000 mikrog/ml, og penicillinase (Riker Laboratories, fra Bacillus cereus) ble tilsatt i en konsentrasjon på 1000 enheter pr ml. Oppløsningene ble bragt inn i en termostat som ble holdt på 37°C. Fra tid til annen ble det tatt ut prøver til analyse, og den mengde av prøveforbindqlsen som var til stede i prøven, ble bestemt ved hjelp av hydraksyl-aminmetoden som påviser Æ-laktamstrukturen [Ford, Ind. Eng. Chem. in water to a concentration of 1000 microg/ml, and penicillinase (Riker Laboratories, from Bacillus cereus) was added at a concentration of 1000 units per ml. The solutions were brought into a thermostat which was kept at 37°C. From time to time samples were taken for analysis, and the amount of the test compound present in the sample was determined by means of the hydroxylamine method which demonstrates the β-lactam structure [Ford, Ind. Meadow. Chem.
(analytical Edition) , bind 19, 1947, side 1004 til 1006 ]. (analytical Edition), volume 19, 1947, pages 1004 to 1006].
Det ble funnet at perdcillinforbindelsene ble fullstendig nedbrutt av penicillinase i løpet av 30 minutter, mens cefalosporinforbindelsene forble uangrepet. It was found that the perdcillin compounds were completely degraded by penicillinase within 30 minutes, while the cephalosporin compounds remained unaffected.
En parallell forsøksrekke med vandige oppløsninger A parallel series of experiments with aqueous solutions
som bare inneholdt prøveforbindelsene, viste at det i fravær av pericillinase ikke fant sted noen betydelig nedbrytning av noen av prøveforbindelsene. containing only the test compounds showed that in the absence of pericillinase no significant degradation of any of the test compounds took place.
Ved videre forsøk ble det fastslått av forbindelsene fremstilt i henhold til oppfinnelsen også er bedre enn den kjente forbindelse 6-( a- fenoksypropionamido)-penicillansyre som finnes i handelen. Sistnevnte anvendes til behandling av infeksjoner In further tests, it was established that the compounds produced according to the invention are also better than the known compound 6-(a-phenoxypropionamido)-penicillanic acid which is available in the trade. The latter is used to treat infections
med penicillinresistente stafylokokker, og for dette formål representerer den en forbedring sammenlignet med de tidligere anvendte penicilliner. Den ble imidlertid - slik som følgende forsøk viser - likeledes nedbrutt av penicillinase, imidlertid ikke så raskt som de ovennevnte penicilliners with penicillin-resistant staphylococci, and for this purpose it represents an improvement compared to the previously used penicillins. However, it was - as the following experiment shows - likewise broken down by penicillinase, however not as quickly as the above-mentioned penicillins
Forsøket ble utført med bare uvesentlige endringer The experiment was carried out with only minor changes
i forhold til de ovenfor beskrevne forsøk. Penicillinet ble oppløst i vann- til en konsentrasjon på 500 mikrog pr ml. En 5 in relation to the experiments described above. The penicillin was dissolved in water to a concentration of 500 microg per ml. A 5
o o
ml porsjon av oppløsningen ble bragt mn i en termostat pa 37 C ml portion of the solution was placed in a thermostat at 37 C
og tilsatt 500 enheter penicillinase. For analyse ble det straks, tatt en prøve, og ytterligere prøver ble tatt efter 10, and added 500 units of penicillinase. For analysis, a sample was taken immediately, and further samples were taken after 10,
15 og 30,minutter. Den mengde penicillin som var tilbake i de 15 and 30 minutes. The amount of penicillin that was left in them
forskjellige prøver, ble bestemt ved den ovenfor beskrevne fremgangsmåte ifølge Ford. different samples, was determined by the method described above according to Ford.
De følgende resultater viser at 6-( a- fenoksypropion-amido) -penicillansyre inaktiveres temmelig raskt av penicillinase, mens cefalosporinene som fremstilles i henhold til oppfinnelsen, som angitt ovenfor, var helt bestandige: The following results show that 6-(α-phenoxypropionamido)-penicillanic acid is inactivated rather quickly by penicillinase, while the cephalosporins produced according to the invention, as stated above, were completely resistant:
Cefalosporin C kan fremstilles ved å dyrke en cefalosporin C-produserende organisme i et passende næringsmedium, slik som beskrevet i britisk patent nr. 810 196, publisert 11. mars 1959. Cephalosporin C can be prepared by culturing a cephalosporin C-producing organism in a suitable nutrient medium, as described in British Patent No. 810,196, published March 11, 1959.
Fra de forskjellige cefalosporin C-forbindelser som From the various cephalosporin C compounds which
på denne måten er tilgjengelige, fåes den tilsvarende kjerne lett ved å kløve 5<1->amino-N'-adipamylsidekjeden mellom dens amidonitrogen og dens amidokarbonylgruppe. Således kan det fåes 7-aminocefalosporansyre ved å oppvarme cefalosporin C i en lengre periode i nærvær av en mineralsyre og i fravær av lys, i henhold til den fremgangsmåte som er beskrevet i belgisk patent 593 777. are thus available, the corresponding core is readily obtained by cleaving the 5<1->amino-N'-adipamyl side chain between its amido nitrogen and its amidocarbonyl group. Thus, 7-aminocephalosporanic acid can be obtained by heating cephalosporin C for a longer period in the presence of a mineral acid and in the absence of light, according to the method described in Belgian patent 593 777.
Et passende acyleringsmiddel er syrehalogenidet av A suitable acylating agent is the acid halide of
en syre av formel II. Acyleringen utføres i vann eller i et passende organisk oppløsningsmiddel, fortrinnsvis under i alt vesentlig nøytrale forhold, og fortrinnsvis ved redusert temperatur, dvs. over frysepunktet til reaksjonsblandingen og opp an acid of formula II. The acylation is carried out in water or in a suitable organic solvent, preferably under essentially neutral conditions, and preferably at a reduced temperature, i.e. above the freezing point of the reaction mixture and up
o o
til ca-20 C. Ved en typisk fremgangsmåte oppløses 7-aminocefalosporansyre eller en av dennes derivater som her definert, sammen med en tilstrekkelig mengde av natriumbikarbonat eller et annet passende alkali for å påskynne oppløsningen, i vandig 50% aceton og konsentrasjon av 7-aminocefalosporansyren er ca 1 til ca 4 vekt%. Oppløsningen avkjøles til ca 0 til 5°C, og en oppløsning av acyleringsmidlet tilsettes med et overskudd av ca 20% under omrøring og avkjøling. Blandingens pH kan opprettholdes hvis den har en tendens til å variere, rundt nøytralpunktet ved at det bobles inn karbondioksyd. Efter at tilsetningen av acyleringsmidlet er fullstendig, fortsettes omrøringen av reaksjonsblandingen, og blandingen får anledning til å oppvarme seg til romtemperatur. Reaksjonsproduktet surgjøres derpå til pH ca 2 og ekstraheres med organisk oppløsningsmiddel som f.eks. etylacetat. Etylacetat-ekstrakten reguleres til pH ca 5,5 med en base som inneholder det ønskede kation i sluttproduktet og ekstraheres med vann. Vann-oppløsningen fraskilles og inndampes til tørrhet. Residuet opp-tas i en minimumsmengde vann og det ønskede produkt utfelles ved å tilsette et stort overskudd av aceton og om nødvendig eter. to about -20 C. In a typical method, 7-aminocephalosporanic acid or one of its derivatives as defined here is dissolved, together with a sufficient amount of sodium bicarbonate or another suitable alkali to accelerate the dissolution, in aqueous 50% acetone and concentration of 7- the aminocephalosporanic acid is about 1 to about 4% by weight. The solution is cooled to about 0 to 5°C, and a solution of the acylating agent is added with an excess of about 20% while stirring and cooling. The pH of the mixture can be maintained, if it tends to vary, around the neutral point by bubbling in carbon dioxide. After the addition of the acylating agent is complete, stirring of the reaction mixture is continued, and the mixture is allowed to warm to room temperature. The reaction product is then acidified to pH approx. 2 and extracted with an organic solvent such as e.g. ethyl acetate. The ethyl acetate extract is adjusted to a pH of about 5.5 with a base containing the desired cation in the final product and extracted with water. The water solution is separated and evaporated to dryness. The residue is taken up in a minimum amount of water and the desired product is precipitated by adding a large excess of acetone and, if necessary, ether.
Det krystallinske produkt som herved fåes, filtreres, vaskes med aceton og tørkes. The crystalline product thus obtained is filtered, washed with acetone and dried.
Syrebromidene av syrer med den generelle formel II The acid bromides of acids of the general formula II
kan anvendes på lignende måte som syrekloridene. Acyleringen kan også utføres under anvendelse av selve syrene med den generelle formel II sammen med en ekvimolar mengde av et karbo- can be used in a similar way to the acid chlorides. The acylation can also be carried out using the acids themselves of the general formula II together with an equimolar amount of a carbo-
diimid, f.eks. med N,N'-diisopropylkarbodiimid, N,N'-dicyklo-heksylkarbodiimid, N,N'-bis-(p-dimetylaminofenyl)-karbodiimid, N-etyl-N'-(4"-etylmorfolinyl)-karbodiimid, idet acyleringen i diimide, e.g. with N,N'-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide, N,N'-bis-(p-dimethylaminophenyl)carbodiimide, N-ethyl-N'-(4"-ethylmorpholinyl)carbodiimide, the acylation in
disse tilfeller forløper ved romtemperatur. these cases proceed at room temperature.
Fremstillingen av acyleringsmidlet som er nødvendig The preparation of the acylating agent required
ved fremgangsmåten i henhold til oppfinnelsen, er enten be- in the method according to the invention, either be-
skrevet i litteraturen eller utføres analogt med en kjent fremgangsmåte. written in the literature or carried out analogously to a known procedure.
De følgende eksempler skal tjene til å illustrere oppfinnelsen ytterligere. The following examples shall serve to further illustrate the invention.
Eksempel 1 Example 1
7- fenylmerkaptoacetamidocefalosporahsyré 7- phenylmercaptoacetamidocephalosporahic acid
7-aminocefalosporansyre (12,05 g) og natriumbikar- 7-aminocephalosporanic acid (12.05 g) and sodium bicar-
bonat (8,20 g) ble oppløst i en blanding av 200 ml vann og 160 ml aceton. Oppløsningen ble avkjølt på et.isbad, og fenyl-merkaptoacetylklorid (7,85 g, oppløst i 40 ml aceton) ble til- bonate (8.20 g) was dissolved in a mixture of 200 ml of water and 160 ml of acetone. The solution was cooled in an ice bath, and phenyl mercaptoacetyl chloride (7.85 g, dissolved in 40 ml of acetone) was added to
satt under omrøring i løpet av 45 minutter,hvorefter omrøringen ble fortsatt i 2,5 timer under oppvarmning av blandingen til romtemperatur. Acetonen ble derpå utdrevet ved vanlig temperatur, under anvendelse av en roterende kolbefordamper ved redusert trykk. Den resulterende vandige oppløsning ble surgjort til pH stirred for 45 minutes, after which stirring was continued for 2.5 hours while heating the mixture to room temperature. The acetone was then driven off at ordinary temperature using a rotary flask evaporator at reduced pressure. The resulting aqueous solution was acidified to pH
2,0 med konsentrert saltsyre og ekstrahert med 200 ml etyl- 2.0 with concentrated hydrochloric acid and extracted with 200 ml of ethyl
acetat. Etylacetatfasen ble fraskilt, pH regulert til 5,5 med 0,5 N vandig kaliumhydroksydoppløsnihg og ekstrahert med 150 ml vann. Den vandige ekstrakt ble fraskilt og inndampet til tørr- acetate. The ethyl acetate phase was separated, pH adjusted to 5.5 with 0.5 N aqueous potassium hydroxide solution and extracted with 150 ml of water. The aqueous extract was separated and evaporated to dryness
het ved romtemperatur og redusert trykk. Residuet ble oppløst hot at room temperature and reduced pressure. The residue was dissolved
i en minimumsmengde vann og fortynnet med et stort overskudd in a minimum amount of water and diluted with a large excess
aceton. Den resulterende krystallinske utfeining ble filtrert acetone. The resulting crystalline precipitate was filtered
fra, vasket med aceton og atter oppløst og utfelt, hvorefter den from, washed with acetone and again dissolved and precipitated, after which the
ble tørket. Produktet var kaliumsaltet av 7-f enylmerkaptoacetamido-cef alosporansyre og veiet 6,85 g. was dried. The product was the potassium salt of 7-phenylmercaptoacetamido-cephalosporanic acid and weighed 6.85 g.
Eksempel 2 Example 2
7-aminocefalosporansyre (1,2 g, 80% renhet) ble 7-Aminocephalosporanic acid (1.2 g, 80% purity) was
suspendert i 50 ml vann og oppløst ved tilsetning av natriumbikarbonat (1,0 g). Aceton (50 ml) ble derpå tilsatt, og opp- suspended in 50 ml of water and dissolved by the addition of sodium bicarbonate (1.0 g). Acetone (50 ml) was then added, and up-
■ rr >^ a ■ rr >^ a
løsningen ble avkjølt til 5°C og omrørt under tilsetning av 0,743 g o-tolylmerkaptoacetylklorid i 15 ml aceton i løpet av en time. Omrøring ble fortsatt i en time ved 5°C, og acetonet ble derpå fjernet ved fordampning i en roterende kolbefordamper under vakuum ved vanlig temperatur. Etylacetat (75 ml) ble tilsatt, efterfulgt av regulering av pH til 2. Efter omhyggelig blanding ble lagene skilt. Etylacetatfasen ble påny ekstrahert med 75 ml vann og en tilstrekkelig mengde vandig 1 N kalium-hydroksydoppløsning så at pH var 5,5. Vannlaget ble fraskilt og inndampet til et halvfast produkt i en roterende kolbe-for-damper under vakuum ved vanlig temperatur. Residuet ble oppløst i metanol, fortynnet med isopropylalkohol og utdrevet så at det var i det vesentlige fritt for oppløsningsmiddel. Kaliumsaltet av 7-o-tolylmerkaptoacetamidocefalosporansyre ble derved oppnådd som et hvitt pulver som veiet 850 mg og hadde et maksimum i det ultrafiolette absorpsjonsspektrum med 245 nyu (£ = 10,200). the solution was cooled to 5°C and stirred while adding 0.743 g of o-tolyl mercaptoacetyl chloride in 15 ml of acetone over the course of one hour. Stirring was continued for one hour at 5°C, and the acetone was then removed by evaporation in a rotary flask evaporator under vacuum at room temperature. Ethyl acetate (75 mL) was added, followed by adjusting the pH to 2. After thorough mixing, the layers were separated. The ethyl acetate phase was re-extracted with 75 ml of water and a sufficient amount of aqueous 1 N potassium hydroxide solution so that the pH was 5.5. The aqueous layer was separated and evaporated to a semi-solid product in a rotary flask evaporator under vacuum at room temperature. The residue was dissolved in methanol, diluted with isopropyl alcohol and expelled so that it was essentially free of solvent. The potassium salt of 7-o-tolyl mercaptoacetamidocephalosporanic acid was thereby obtained as a white powder weighing 850 mg and having a maximum in the ultraviolet absorption spectrum at 245 nyu (£ = 10.200).
Eksempel 3 Example 3
7-m-tolylmerkaptoacetamidocefalosporansyre ble fremstilt som kaliumsaltet ved reaksjon av 7-aminocefalosporansyre (1,0 g), natriumbikarbonat (810 mg) og m-tolylmerkaptoacetylklorid (700 mg) i henhold til den fremgangsmåte og de betingelser som er beskrevet i eksempel 1. Produktet veiet 400 mg og hadde et maksimum i det ultrafiolette absorpsjonsspektrum ved 250 nyu (£ = 12 000) . 7-m-tolylmercaptoacetamidocephalosporanic acid was prepared as the potassium salt by reaction of 7-aminocephalosporanic acid (1.0 g), sodium bicarbonate (810 mg) and m-tolyl mercaptoacetyl chloride (700 mg) according to the method and conditions described in example 1. The product weighed 400 mg and had a maximum in the ultraviolet absorption spectrum at 250 nyu (£ = 12,000).
Eksempel 4 Example 4
7-p-tolylmerkaptoacetamidocefalosporansyre ble fremstilt som kaliumsaltet ved reaksjon av 7-aminocefalosporansyre 7-p-tolylmercaptoacetamidocephalosporanic acid was prepared as the potassium salt by reaction of 7-aminocephalosporanic acid
- (1.2 g, 80% renhet), natriumbikarbonat (1,0 g) og p-tolylmerkaptoacetylklorid (700 mg) i henhold til den fremgangsmåte og under de betingelser som er beskrevet i eksempel 1. Produktet veiet 840 mg og hadde et maksimum i det ultrafiolette absorpsjonsspektrum ved 251 nyu (£ = 11 060). ^ - (1.2 g, 80% purity), sodium bicarbonate (1.0 g) and p-tolyl mercaptoacetyl chloride (700 mg) according to the procedure and under the conditions described in Example 1. The product weighed 840 mg and had a maximum in the ultraviolet absorption spectrum at 251 nyu (£ = 11,060). ^
Eksempel 5 Example 5
7-(l'-metylcyklobutylmerkaptoacetamido)cefalosporan-syre ble fremstilt som kaliumsaltet ved reaksjon av 7-aminocefalosporansyre (1,089), natriumbikårbonat (0,701 g) og 1-metylcyklo-butylmerkaptoacetylklorid (0,714 g) i henhold til den fremgangs- 7-(1'-Methylcyclobutylmercaptoacetamido)cephalosporanic acid was prepared as the potassium salt by reaction of 7-aminocephalosporanic acid (1.08 g), sodium bicarbonate (0.701 g) and 1-methylcyclobutylmercaptoacetyl chloride (0.714 g) according to the procedure
måte og under de betingelser som er beskrevet i eksempel 1. Produktet veiet 1,2 g og hadde et maksimum i det ultrafiolette absorpsjonsspektrum ved 259 nyu (£ = 7600). manner and under the conditions described in Example 1. The product weighed 1.2 g and had a maximum in the ultraviolet absorption spectrum at 259 nyu (£ = 7600).
SAMMENLIGNINGSEKSEMPEL COMPARISON EXAMPLE
I det følgende er foretatt en sammenligning mellom forbindelsene (med kodenummer angitt foran) In the following, a comparison has been made between the connections (with code numbers indicated in front)
44304 -natrium-cefalosporin C 44304 -sodium cephalosporin C
37414 -kalium-7-fenylacetamidocefalosporanat 37414 -potassium 7-phenylacetamidocephalosporanate
(belgisk patent 593 777) (Belgian patent 593 777)
og en forbindelse fremstilt i henhold til oppfinnelsen and a compound prepared according to the invention
3 742 7 -kalium-7-fenylmerkaptoacetamido-cefalosporanat 3 742 7 -potassium 7-phenylmercaptoacetamido-cephalosporanate
Undersøkelsene ble foretatt som gradientplate-forsøk, og aktiviteten er angitt i mikrog/ml. The investigations were carried out as gradient plate experiments, and the activity is indicated in microg/ml.
GRAMPOSITIVE GRAM POSITIVE
Pencillin G-resistente Staphylococcus aureus-stammer. Pencillin G-resistant Staphylococcus aureus strains.
Disse data viser at 37427 , fremstilt i henhold til oppfinnelsen, er noe mer aktiv enn 7-fenylacetamido-cefalosporansyresaltet (37414) ifølge belgisk patent 593.777 overfor disse 3 stammer av denne grampositive organisme. De viser også at cefalosporin C selv er et meget svakt antibiotikum. These data show that 37427, produced according to the invention, is somewhat more active than the 7-phenylacetamido-cephalosporanic acid salt (37414) according to Belgian patent 593,777 against these 3 strains of this gram-positive organism. They also show that cephalosporin C itself is a very weak antibiotic.
GRAMNEGATIVE ORGANISMER GRAM NEGATIVE ORGANISMS
Forklaringer: Explanations:
X-68 .-Aerobacter aerogenes X-68 .—Aerobacter aerogenes
X-253 -Vibro metschnikovii X-253 -Vibro metschnikovii
X-47 -Salmonella enteritidis X-47 -Salmonella enteritidis
X-87 -Shigella paradysenteriae X-87 -Shigella paradysenteriae
X-83 -Klebsiella pneumoniae X-83 - Klebsiella pneumoniae
Disse siste data viser at forbindelsen fremstilt i henhold til oppfinnelsen er mer aktiv enn fenylacetamidocefalo-sporansyre (37414) overfor X-253. These latest data show that the compound prepared according to the invention is more active than phenylacetamidocephalosporanic acid (37414) against X-253.
Claims (1)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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DE2539825A DE2539825C3 (en) | 1975-09-08 | 1975-09-08 | Extinguishing device with a jet pipe for emitting a powder jet |
Publications (3)
Publication Number | Publication Date |
---|---|
NO763061L NO763061L (en) | 1977-03-09 |
NO143833B true NO143833B (en) | 1981-01-12 |
NO143833C NO143833C (en) | 1981-04-22 |
Family
ID=5955844
Family Applications (1)
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NO763061A NO143833C (en) | 1975-09-08 | 1976-09-07 | EXTINGUISHING DEVICE. |
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AT (1) | AT376888B (en) |
BE (1) | BE845665A (en) |
DE (1) | DE2539825C3 (en) |
FR (1) | FR2322623A1 (en) |
NL (1) | NL7609629A (en) |
NO (1) | NO143833C (en) |
SE (1) | SE413287B (en) |
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SE502165C2 (en) * | 1993-12-13 | 1995-09-04 | Svenska Skum Ab | Hydrostatic bearing for jet cannon |
CN103331007A (en) * | 2013-07-04 | 2013-10-02 | 章丘市消防器材有限责任公司 | Median-multiple fire-fighting foam monitor |
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CH226121A (en) | 1940-05-09 | 1943-03-15 | Redlhammer Hans | Hand fire extinguisher for several extinguishing agents. |
US2832424A (en) * | 1954-04-16 | 1958-04-29 | Gordon F Hurst | Foam-fog applicators |
FR2039459A5 (en) * | 1969-04-01 | 1971-01-15 | Sogreah | |
US3840074A (en) | 1973-09-17 | 1974-10-08 | Rockwood Systems Corp | Three way remote controlled dual agent fire fighting turret |
-
1975
- 1975-09-08 DE DE2539825A patent/DE2539825C3/en not_active Expired
-
1976
- 1976-08-30 NL NL7609629A patent/NL7609629A/en not_active Application Discontinuation
- 1976-08-30 BE BE170200A patent/BE845665A/en unknown
- 1976-09-02 FR FR7626491A patent/FR2322623A1/en active Granted
- 1976-09-03 AT AT0654376A patent/AT376888B/en not_active IP Right Cessation
- 1976-09-06 SE SE7609803-7A patent/SE413287B/en unknown
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Also Published As
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DE2539825B2 (en) | 1980-06-19 |
ATA654376A (en) | 1984-06-15 |
NL7609629A (en) | 1977-03-10 |
DE2539825C3 (en) | 1981-02-26 |
SE7609803L (en) | 1977-03-09 |
SE413287B (en) | 1980-05-19 |
BE845665A (en) | 1976-12-16 |
FR2322623B1 (en) | 1978-10-20 |
NO143833C (en) | 1981-04-22 |
NO763061L (en) | 1977-03-09 |
AT376888B (en) | 1985-01-10 |
FR2322623A1 (en) | 1977-04-01 |
DE2539825A1 (en) | 1977-03-10 |
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