NO142914B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE CEPHALOSPORINES - Google Patents

ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE CEPHALOSPORINES Download PDF

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NO142914B
NO142914B NO251872A NO251872A NO142914B NO 142914 B NO142914 B NO 142914B NO 251872 A NO251872 A NO 251872A NO 251872 A NO251872 A NO 251872A NO 142914 B NO142914 B NO 142914B
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acid
mol
group
reaction
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NO251872A
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NO142914C (en
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Shiro Morimoto
Hiroaki Nomura
Takeshi Fugono
Isao Minami
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Takeda Chemical Industries Ltd
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Priority claimed from JP5346671A external-priority patent/JPS5324439B1/ja
Priority claimed from JP8413071A external-priority patent/JPS5442998B2/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Description

Foreliggende oppfinnelse angår fremstilling av terapeutisk aktive cefalosporiner med formelen: The present invention relates to the production of therapeutically active cephalosporins with the formula:

der R er tienyl eller fenyl og R2 er en pyridiniumgrup-pe, eventuelt substituert med -C0NH2, eller en tiazoliumgruppe, eventuelt substituert med -CH^ og/eller -CI^CHgOH. Oppfinnelsen angår også fremstilling av farmasoytisk akseptable salter derav. where R is thienyl or phenyl and R 2 is a pyridinium group, optionally substituted with -CONH 2 , or a thiazolium group, optionally substituted with -CH 2 and/or -CI 2 CH 2 OH. The invention also relates to the preparation of pharmaceutically acceptable salts thereof.

Helt siden oppdagelsen av cefalosporin C er det utviklet forskjellige derivater av antibiotika av cefalosporintypen som er substituert i 7- og 3-stilling. Imidlertid er forbindelser som er virksomme ved praktiske konsentrasjoner mot Pseudomonas aeruginosa, ennå ikke beskrevet. Ever since the discovery of cephalosporin C, various derivatives of cephalosporin-type antibiotics have been developed which are substituted in the 7- and 3-position. However, compounds active at practical concentrations against Pseudomonas aeruginosa have not yet been described.

Det er nå funnet at de nye cefalosporiner som er representert ved den ovenfor angitte formel I, ikke bare er virksomme ved terapi av forskjellige infeksjons-sykdommer fra Gram-positive og Gram-negative patogene bakterier, men også viser virkninger ved lave konsentrasjoner mot Pseudomonas aeruginosa. I cefalosporinene med formelen I er sulfonsyregruppen i substitutentene i 7-stilling bundet direkte til et asymmetrisk karbonatom. Det er derfor åpenbart at cefalosporinene fremstilt ifolge oppfinnelsen omfatter D-typen, L-typen og DL-typen av cefalosporinforbindelsene. It has now been found that the new cephalosporins represented by the above formula I are not only effective in the therapy of various infectious diseases from Gram-positive and Gram-negative pathogenic bacteria, but also show effects at low concentrations against Pseudomonas aeruginosa . In the cephalosporins with the formula I, the sulfonic acid group in the substituents in the 7-position is bound directly to an asymmetric carbon atom. It is therefore obvious that the cephalosporins produced according to the invention comprise the D-type, the L-type and the DL-type of the cephalosporin compounds.

Cefalosporinene I fremstilles ved innforing av oc-sulfoacylgruppen i 7-stilling og ved omdanning av acetoksygruppen i 3-stilling til den nitrogenholdige heterocykliske gruppe. Omsetningen kan skje forst i 3- eller 7-stilling, deretter fulgt av omsetning i den andre stilling. Fremgangsmåten ifølge oppfinnelsen er kjennetegnet ved det i kravets karakteriserende del angitte. The cephalosporins I are produced by introducing the oc-sulfoacyl group in the 7-position and by converting the acetoxy group in the 3-position to the nitrogen-containing heterocyclic group. The turnover can take place first in position 3 or 7, then followed by turnover in the other position. The method according to the invention is characterized by what is stated in the characterizing part of the claim.

A) Fremgangsmåte til forst å gjennomfore omsetning i 7-stilling og deretter i 3-stilling: 7-aminocefalosporansyre (heretter kalt "7-ACA") omsettes med en cc-sulfokarboksylsyre med formelen: eller med et funksjonelt derivat derav, hvorved det kan oppnås en cefalosporansyre med formelen: A) Procedure for first carrying out reaction in the 7-position and then in the 3-position: 7-aminocephalosporanic acid (hereafter called "7-ACA") is reacted with a cc-sulfocarboxylic acid with the formula: or with a functional derivative thereof, whereby a cephalosporanic acid with the formula can be obtained:

(se belgisk patent nr. 762.725). Så langt det ikke med-forer noen ugunstig virkning på den etterfSigende om-danningsreaksjon i 3-stilling, kan karboksylgruppen i 4-stilling og/eller sulfogruppen i sidekjeden foreligge i form av et salt-, f.eks. med natrium, kalium, magnesium, kalsium, aluminium eller trietylamin. I enkelte tilfelle kan karboksylgruppen i 4-stilling være beskyttet med en estergruppe som lett kan fjernes, f.eks. en benzyl-, |3-metylsulfonyletyl-, benzhydryl- eller trimetylsilyl-gruppe. (see Belgian patent no. 762,725). As long as it does not have any adverse effect on the subsequent conversion reaction in the 3-position, the carboxyl group in the 4-position and/or the sulfo group in the side chain can be in the form of a salt, e.g. with sodium, potassium, magnesium, calcium, aluminum or triethylamine. In some cases, the carboxyl group in the 4-position can be protected with an ester group that can be easily removed, e.g. a benzyl, β-methylsulfonylethyl, benzhydryl or trimethylsilyl group.

Deretter omsettes sulfocefalosporansyren II med en nitrogenholdig heterocyklisk forbindelse R~ med den ovenfor angitte betydning. The sulfocephalosporanic acid II is then reacted with a nitrogen-containing heterocyclic compound R~ with the above meaning.

Reaksjonen mellom sulfocefalosporansyren II og den nitrogenholdige heterocykliske forbindelse R2 gjen-nomføres i henhold til i og for seg kjente fremgangsmåter. Vanligvis er det fordelaktig å utfore reaksjonen i vann eller et sterkt polart opplosningsmiddel. Reaksjonen gjennomfores ved omtrent noytral pH, fortrinnsvis pH 5 - 8. Vanligvis benyttes den nitrogenholdige forbindelse i andeler på omkring 1-10 mol pr. mol sulfocefalosporansyre. Videre kan reaksjonen gjennomføres i nærvær av en katalysator slik som isocyanat, tioisocyanat eller tiolforbindelser i en andel på omkring 1-40 mol, helst omkring 5-20 mol pr. mol sulfocefalosporansyre II, hvorved sluttproduktet kan oppnås i hoyt utbytte. Den ovenfor nevnte katalysator reagerer med gruppen i 3-stilling i sulfocefalosporansyren og danner et funksjonelt derivat. Dette funksjonelle- derivat kan isoleres eller ikke, og omsettes med den nitrogenholdige heterocykliske forbindelse R^. Reaksjonstemperaturen og reaksjonstiden varierer avhengig av typen reaksjonsreagens og av type opplosningsmiddel. I de fleste tilfelle gjennomføres imidlertid reaksjonen i et temperaturområde fra romtemperatur til 100°C, helst 40 - 70°C, i 1 - 48 timer. Det således oppnådde reaksjonsprodukt I renses og gjenvinnes ifolge i og for seg kjente fremgangsmåter slik som opp-losningsmiddelekstraksjon, konsentrasjon, kromatografi, frysetørking og omkrystallisering. B) Fremgangsmåte til forst å gjennomføre omsetningen i 3-stilling og deretter i 7-stilling: Omsetningen av acetoksygruppen i 3-stilling i cefalosporin C kan gjennomføres ifolge de fremgangsmåter som f.eks. er beskrevet i U.S. patent nr. 3.225.038 eller 3.217.000 eller tysk patent nr. 1.817.121. Det resulterende cefalosporin med den nitrogenholdige heterocykliske gruppe i 3-stilling kan lett omdannes til et tilsvarende aminocefalosporansyrederivat med formelen: The reaction between the sulfocephalosporanic acid II and the nitrogen-containing heterocyclic compound R2 is carried out according to methods known per se. Usually it is advantageous to carry out the reaction in water or a strong polar solvent. The reaction is carried out at approximately neutral pH, preferably pH 5 - 8. Usually, the nitrogenous compound is used in proportions of around 1-10 mol per moles of sulfocephalosporanic acid. Furthermore, the reaction can be carried out in the presence of a catalyst such as isocyanate, thioisocyanate or thiol compounds in a proportion of about 1-40 mol, preferably about 5-20 mol per moles of sulfocephalosporanic acid II, whereby the final product can be obtained in high yield. The above-mentioned catalyst reacts with the group in the 3-position of the sulfocephalosporanic acid and forms a functional derivative. This functional derivative may or may not be isolated and reacted with the nitrogen-containing heterocyclic compound R^. The reaction temperature and reaction time vary depending on the type of reaction reagent and the type of solvent. In most cases, however, the reaction is carried out in a temperature range from room temperature to 100°C, preferably 40 - 70°C, for 1 - 48 hours. The thus obtained reaction product I is purified and recovered according to methods known per se, such as solvent extraction, concentration, chromatography, freeze-drying and recrystallization. B) Procedure for first carrying out the conversion in the 3-position and then in the 7-position: The conversion of the acetoxy group in the 3-position in cephalosporin C can be carried out according to the methods which e.g. is described in U.S. Patent No. 3,225,038 or 3,217,000 or German Patent No. 1,817,121. The resulting cephalosporin with the nitrogen-containing heterocyclic group in the 3-position can be easily converted into a corresponding aminocephalosporanic acid derivative of the formula:

ifolge fremgangsmåten som f.eks. er beskrevet i hollandsk according to the procedure as e.g. is described in Dutch

patent nr. 6.401.421, britisk patent nr. 1.041.985 eller U.S. patent nr. 3.575.970. Alternativt kan aminocefalosporansyrederivat IV fremstilles ved deacylering av cefalosporin C og deretter substituering i 3-stilling av den resulterende 7-ACA. Aminocefalosporansyrederivat IV kan foreligge i form av salter og estere, slik som den tidligere nevnte sulfocefalosporansyre II. Patent No. 6,401,421, British Patent No. 1,041,985 or U.S. Pat. Patent No. 3,575,970. Alternatively, aminocephalosporanic acid derivative IV can be prepared by deacylation of cephalosporin C and then substitution in the 3-position of the resulting 7-ACA. Aminocephalosporanic acid derivative IV can exist in the form of salts and esters, such as the previously mentioned sulfocephalosporanic acid II.

Reaksjonen av aminocefalosporansyrederivat The reaction of aminocephalosporanic acid deriv

IV med a-sulfokarboksylsyre V eller et funksjonelt derivat derav kan også gjennomføres ifolge i og for seg kjente fremgangsmåter. I tilfelle a-sulfokarboksylsyre V benyttes i fri form, er det å foretrekke å gjennomføre reaksjonen i nærvær av et kondenseringsmiddel. Konden-seringsmidlet kan f.eks. være N,N'-disubstituert karbo-diimid, f.eks. N,N'-dicykloheksylkarbodiimid; en azo-lidforbindelse, f.eks. N,N'-tionylimidazol; N-etoksy-karbonyl-2-etoksy-l,2-dihydrokinolin, fosforoksyklorid eller alkoksyacetylen. Som reaktiv ester av syren V IV with α-sulfocarboxylic acid V or a functional derivative thereof can also be carried out according to methods known per se. In the event that α-sulfocarboxylic acid V is used in free form, it is preferable to carry out the reaction in the presence of a condensing agent. The condensing agent can e.g. be N,N'-disubstituted carbodiimide, e.g. N,N'-dicyclohexylcarbodiimide; an azo lid compound, e.g. N,N'-thionylimidazole; N-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride or alkoxyacetylene. As reactive ester of the acid V

kan det benyttes karboksylsyrehalogenider, anhydrider, azider og aktive estere. Den ovenfor angitte acylerings-reaksjon skjer fordelaktig og glatt i et opplosningsmiddel. Som opplosningsmiddel benyttes hensiktsmessig et vanlig opplosningsmiddel slik som f.eks. vann, aceton, tetrahydrofuran, dioksan, acetonitril, kloroform, diklor-metan, dikloretylen, pyridin, dimetylanilin, dimetylformamid, dimetylacetamid eller dimetylsulfoksyd. Reaksjonstemperaturen er ikke spesielt begrenset. Vanligvis gjennomføres imidlertid reaksjonen under avkjoling eller ved romtemperatur. Reaksjonsproduktet kan renses og gjenvinnes ved å utnytte egenskapene i sluttproduktet cefalosporin I, f.eks. ved kolonnekromatografi, ekstrak-sjon, utfelling ved de isoelektriske punkt, motstroms-fordeling eller omkrystallisering. carboxylic acid halides, anhydrides, azides and active esters can be used. The above-mentioned acylation reaction takes place advantageously and smoothly in a solvent. A normal solvent such as e.g. water, acetone, tetrahydrofuran, dioxane, acetonitrile, chloroform, dichloromethane, dichloroethylene, pyridine, dimethylaniline, dimethylformamide, dimethylacetamide or dimethylsulfoxide. The reaction temperature is not particularly limited. Usually, however, the reaction is carried out under cooling or at room temperature. The reaction product can be purified and recovered by exploiting the properties of the final product cephalosporin I, e.g. by column chromatography, extraction, precipitation at the isoelectric point, countercurrent distribution or recrystallization.

Cefalosporinene I kan benyttes på samme måte som vanlige cefalosporiner selv om bruken av disse mer eller mindre varierer avhengig av typen nitrogenholdig heterocyklisk gruppe i 3-stilling og/eller acylgruppen i 7-stilling. De foreliggende forbindelser I er bruk-bare som farmasoytika da de har sterkt antibakteriell virkning mot et bredt spektrum av patogene bakterier inkludert Pseudomonas aeruginosa, mot hvilke de van- The cephalosporins I can be used in the same way as ordinary cephalosporins, although the use of these varies more or less depending on the type of nitrogenous heterocyclic group in the 3-position and/or the acyl group in the 7-position. The present compounds I are useful as pharmaceuticals as they have a strong antibacterial effect against a wide spectrum of pathogenic bacteria including Pseudomonas aeruginosa, against which they

lige cefalosporinpreparater i det vesentlige har vært ineffektive. similar cephalosporin preparations have essentially been ineffective.

Cefalosporinene I som fremstilles ifolge oppfinnelsen inngis vanligvis på samme måte som kjente cefalosporinpreparater, men doseringen, doseringsformen osv. varierer med substituentgruppene i 3-stilling og acylgruppene i 7-stilling. F.eks. er den effektive dose av natrium-N-/7-(a-sulfofenylacetamido)-cef-3-em-3-yl-metyl7-pyridinium-4-karboksylat omkring 0,25 g - 2,5 g hver 4. til 6. time for et voksent menneske. The cephalosporins I produced according to the invention are usually administered in the same way as known cephalosporin preparations, but the dosage, dosage form etc. vary with the substituent groups in the 3-position and the acyl groups in the 7-position. E.g. the effective dose of sodium N-(α-sulfophenylacetamido)-cef-3-em-3-yl-methyl-7-pyridinium-4-carboxylate is about 0.25 g - 2.5 g every 4 to 6 .hour for an adult.

Forbindelsene som fremstilles ifolge foreliggende oppfinnelse The compounds produced according to the present invention

ble sammenlignet med typiske forbindelser beskrevet i ålment tilgjengelig norsk soknad 471/71 was compared with typical compounds described in the widely available Norwegian soknad 471/71

Disse forbindelser ble provet mot folgende mikroorganismer: These compounds were tested against the following microorganisms:

Mikroorganismene fra (A) til" og med (D) er Gram-positive bakterier; mikroorganismene fra og med (E) til og med (j) er Gram-negative bakterier. The microorganisms from (A) to (D) inclusive are Gram-positive bacteria; the microorganisms from (E) to (j) inclusive are Gram-negative bacteria.

Den minimale inhiberende konsentrasjon, MIC, for hver av proveforbindelsene (DL-form) ble bestemt ved agarfortynningsmetoden. Næringsagar med en pH 7,0 ble benyttet som provemedium. En lokke av en cellesuspen-sjon inneholdende ca. 1 mg/ml av provemikroorganismen ble benyttet som inokulum, og provemikroorganismen ble dyrket i 18 - 24 timer på næringsagaren. MIC-verdiene (mcg/ml) ble bestemt etter inkubering ved 37°C i 18 timer. The minimal inhibitory concentration, MIC, for each of the test compounds (DL form) was determined by the agar dilution method. Nutrient agar with a pH of 7.0 was used as the test medium. A lure of a cell suspension containing approx. 1 mg/ml of the sample microorganism was used as inoculum, and the sample microorganism was cultivated for 18 - 24 hours on the nutrient agar. The MIC values (mcg/ml) were determined after incubation at 37°C for 18 hours.

Denne overlegenhet overfor Pseudomonas er uventet for fagmannen. This superiority over Pseudomonas is unexpected to the person skilled in the art.

I de folgende eksempler er alle temperaturer ukorrigert. In the following examples, all temperatures are uncorrected.

Eksempel 1 Example 1

(1) Fremstilling av a-sulfobenzylcefalosporin: (1) Preparation of α-sulfobenzylcephalosporin:

En opplosning bestående av 2,5 ml av en 1N-NaOH-opplosning og 5 ml vann blir isavkjolt til 0 - 5°C hvoretter 680 mg 7-aminocefalosporansyre ble opplost i opplesningen under grundig omroring. Til den resulterende opplosning ble det under omroring i lopet av 15 minutter dryppet en opplosning av 585 mg a-sulfofenyl-eddiksyreklorid i 7 ml dietyleter. Deretter ble det vandige sjikt fraseparert, pH-verdien ble justert til 1,5 ved tilsetning av 1N-HC1 og deretter ble det ekstra-hert to ganger med 15 ml n-butanol og ekstrakten ble vasket to ganger med 5 ml hver gang av vann og ekstra-hert med en mettet vandig NaHCO-^-opplSsning. Den resulterende ekstrakt ble justert til en pH-verdi på 6,5, vasket med eter og deretter underkastet frysetørking og det ble oppnådd 385 mg av det onskede produkt i form av natriumsaltet. A solution consisting of 2.5 ml of a 1N-NaOH solution and 5 ml of water is ice-cooled to 0 - 5°C after which 680 mg of 7-aminocephalosporanic acid was dissolved in the reading under thorough stirring. A solution of 585 mg of α-sulfophenylacetic acid chloride in 7 ml of diethyl ether was added dropwise to the resulting solution with stirring over the course of 15 minutes. Then the aqueous layer was separated, the pH value was adjusted to 1.5 by adding 1N-HCl and then it was extracted twice with 15 ml of n-butanol and the extract was washed twice with 5 ml each time of water and extra-hardened with a saturated aqueous NaHCO-^ solution. The resulting extract was adjusted to a pH value of 6.5, washed with ether and then subjected to lyophilization and 385 mg of the desired product in the form of the sodium salt was obtained.

IRvmaks (cm<-1>): 1755 (laktam, acetat), 1612 (-C00"), 1680 (-C0NH-), 1225 (-S02-), 1046 (-S03Na). IR vmax (cm<-1>): 1755 (lactam, acetate), 1612 (-CO0"), 1680 (-CONH-), 1225 (-SO2-), 1046 (-SO3Na).

NMR (D20) ppm: 2,09 (3H, singlett), 3,42 NMR (D 2 O) ppm: 2.09 (3H, singlet), 3.42

(2H, kvartett, J-^18,0 c/s, J"2=18,0 c/s), 4,75 (2H), 5,09 (1H, singlett), 5,10 (1H, dublett, J=4,5 c/s), 5,70 (1H, dublett, J=4,5 c/s), 7,52 (5H, multiplett). (2H, quartet, J-^18.0 c/s, J"2=18.0 c/s), 4.75 (2H), 5.09 (1H, singlet), 5.10 (1H, doublet , J=4.5 c/s), 5.70 (1H, doublet, J=4.5 c/s), 7.52 (5H, multiplet).

UV*maks: 259 m/u (7,1 x 10<5>) UV*max: 259 m/u (7.1 x 10<5>)

(2) Fremstilling av natrium-N-/7-(a-sulfofenylacetamido)-cef-3-em-3-ylmetyl7pyridinium-4-karboksylat: 0,355 g (6,9 x IO"<4> mol) 7-(a-sulfofenyl-acetamido) -cef alosporansyre (a-sulfobenzylcefalosporin), 0,34 g (3,5 x 10~<5> mol) kaliumtiocyanat og 0,15 ml (1,88 x IO<-5> mol) pyridin ble opplost i 0,75 ml vann (pH 6,5). Den resulterende opplosning ble oppvarmet til 60°C i 6 timer, renset kromatografisk ved bruk av en harpikskolonne ("Amberlite XAD-2", 16 x 700 mm, eluer-ingsmiddel: vann, under kontroll av et ultrafiolett spektrometer (240 nyu)). Fraksjonene som inneholdt det onskede cefalosporin ble oppsamlet og deretter frysetorket for å oppnå 126 mg av det onskede produkt. (2) Preparation of sodium N-(α-sulfophenylacetamido)-cef-3-em-3-ylmethyl 7pyridinium-4-carboxylate: 0.355 g (6.9 x 10"<4> mol) 7-(a -sulfophenyl-acetamido)-cephalosporanic acid (α-sulfobenzylcephalosporin), 0.34 g (3.5 x 10~<5> mol) potassium thiocyanate and 0.15 ml (1.88 x 10<-5> mol) pyridine were dissolved in 0.75 ml of water (pH 6.5). The resulting solution was heated to 60°C for 6 hours, purified chromatographically using a resin column ("Amberlite XAD-2", 16 x 700 mm, eluent : water, under the control of an ultraviolet spectrometer (240 nyu)).The fractions containing the desired cephalosporin were collected and then freeze-dried to obtain 126 mg of the desired product.

IR^Scs (dm<_1>): 5400 (OH), 3020 (CH), 1760 ((3-laktam), 1670 (-C0NH-), 1610 (-C00<->), 1525 (skulder), 1490, 1380, 1350 (S02), 1220 (-60 2-) , 1037 (-SOg-), 700 (ingen -SCN oppdaget). IR^Scs (dm<_1>): 5400 (OH), 3020 (CH), 1760 ((3-lactam), 1670 (-C0NH-), 1610 (-C00<->), 1525 (shoulder), 1490 , 1380, 1350 (SO 2 ), 1220 (-60 2- ), 1037 (-SOg-), 700 (no -SCN detected).

NMR (60Mc, D20): 3,02, 3,48 (2H, dublett, <J>1<=J>2=18 c/s, C2 metylen), 5,28, 5,40 (2H J— CH2~), NMR (60Mc, D2O): 3.02, 3.48 (2H, doublet, <J>1<=J>2=18 c/s, C2 methylene), 5.28, 5.40 (2H J— CH2 ~),

5,05 (H, singlett, -C<g>-CO-), 5,07 (1H, dublett, J=5,35.05 (H, singlet, -C<g>-CO-), 5.07 (1H, doublet, J=5.3

S0-.H S0-.H

3 c/s, Cg proton), 5,68 (1H, dublett, J=5,3 c/s, C^ proton), 7,32, 7,45 (5H, fenyl-proton), 7,8 - 9,0 (5H, multiplett, pyridin-proton). 3 c/s, Cg proton), 5.68 (1H, doublet, J=5.3 c/s, C^ proton), 7.32, 7.45 (5H, phenyl proton), 7.8 - 9.0 (5H, multiplet, pyridine proton).

Minimal inhiberende konsentrasjon: Minimum inhibitory concentration:

Eksempel 2 Example 2

0,292 g N-(7-aminocef-3-em-3-ylmetyl)pyridinium- 0.292 g N-(7-aminocef-3-em-3-ylmethyl)pyridinium-

4-karboksylat og 0,17 g natriumhydrogenkarbonat ble opplost i 7 ml vann. Til den resulterende opplosning ble det under avkjoling dryppet 3 ml av en kloroformopp-losning inneholdende 0,234 g a-sulfofenylacetylklorid. Etter fullfort tildrypping ble omrbringen fortsatt ytterligere under avkjoling i 40 minutter for å av-slutte reaksjonen. Etter fjerning av det organiske sjikt ble det vandige sjikt justert til en pH-verdi på 6 og underkastet kromatografi ved bruk av "Amberlite XAD-2", og de resulterende onskede produkthoIdige fraksjoner ble frysetorket, og det ble oppnådd natrium-N-/?-(a-sulfofenylacetamido)cef-3-em-3-ylmetyl)pyridinium-4-karboksylat. 4-carboxylate and 0.17 g of sodium bicarbonate were dissolved in 7 ml of water. To the resulting solution, while cooling, 3 ml of a chloroform solution containing 0.234 g of α-sulfophenylacetyl chloride was added dropwise. After complete dropwise addition, stirring was continued further under cooling for 40 minutes to terminate the reaction. After removal of the organic layer, the aqueous layer was adjusted to a pH value of 6 and subjected to chromatography using "Amberlite XAD-2", and the resulting desired product-containing fractions were freeze-dried to obtain sodium-N-/? -(α-sulfophenylacetamido)cef-3-em-3-ylmethyl)pyridinium-4-carboxylate.

Eksempel 3 Example 3

Fremstilling av natrium-N-7-(a-sulfofenylacet-amido )cef-3-em-3-ylmetyl-4'-karbamoyl-pyridini-um-4-karboksylat': 0,514 g (1 x 10"<3> mol) 7-(a-sulfofenylacet-amido )cefalosporansyre, 0,366 g (3 x 10~<10> mol) isoniko-tinamid og 2,0 g (2,06 x 10 mol) kalsiumtiocyanat ble opplost i 2,5 ml vann. Den resulterende opplosning ble satt hen og oppvarmet i 20 timer i en termostat som ble holdt på 50°C, og deretter renset direkte kromatografisk ved bruk av en "Amberlite XAD-2"-kolonne (16 x 880 mm). Deretter ble de cefalosporinholdige fraksjoner samlet og underkastet frysetorking og det ble oppnådd 270 g av det onskede produkt i form av et blekt gulaktig hvitt pulver. Preparation of sodium N-7-(α-sulfophenylacetamido)cef-3-em-3-ylmethyl-4'-carbamoyl-pyridini-um-4-carboxylate': 0.514 g (1 x 10"<3> mol ) 7-(α-sulfophenylacetamido)cephalosporanic acid, 0.366 g (3 x 10~<10> mol) of isonicotinamide and 2.0 g (2.06 x 10 mol) of calcium thiocyanate were dissolved in 2.5 ml of water. The resulting solution was set aside and heated for 20 hours in a thermostat maintained at 50°C, and then purified directly chromatographically using an "Amberlite XAD-2" column (16 x 880 mm). Thereafter, the cephalosporin-containing fractions were collected and subjected to freeze drying and 270 g of the desired product was obtained in the form of a pale yellowish white powder.

BWmaks (cm<-1>): 3330 (CH, NH), 3200 (OH, bred), 1765 (C=0, (3-laktam), 1680 (-C0NH-), 1610 (-C00~), 1552 (-NH2, deformering), 1455, 1390 (C=C, S02), 1200 (S02, bred), 1120, 1040 (-S03"), 850, 810, 700. BWmax (cm<-1>): 3330 (CH, NH), 3200 (OH, broad), 1765 (C=0, (3-lactam), 1680 (-C0NH-), 1610 (-C00~), 1552 (-NH2, deformation), 1455, 1390 (C=C, SO2), 1200 (SO2, broad), 1120, 1040 (-SO3"), 850, 810, 700.

NMR (60Mc, D90): 2,93 (1H, dublett, j=18 c/s, NMR (60Mc, D90): 2.93 (1H, doublet, j=18 c/s,

, 3,52 (1H, dublett, J=18 c/s, , 5,08 (1H, singlett, 5,35 (1H, , 3.52 (1H, doublet, J=18 c/s, , 5.08 (1H, singlet, 5.35 (1H,

CH2-), 5,50 (1H, CH2-), 5.50 (1H,

J=5 c/s, J_ CH2-), 5,09 (1H, dublett, J=6 c/s, 6-stilling-proton), 5,71 (1H, -dublett, J=4,5 c/s, 7-stilling-proton), 7,25 - 7,6 (5H- multiplett, fenyl), 8,25 (2H, dublett, J=6,5 c/s, pyridin-proton), 9,03 J=5 c/s, J_ CH2-), 5.09 (1H, doublet, J=6 c/s, 6-position proton), 5.71 (1H, -doublet, J=4.5 c/ s, 7-position proton), 7.25 - 7.6 (5H- multiplet, phenyl), 8.25 (2H, doublet, J=6.5 c/s, pyridine proton), 9.03

(2H, dublett, J=6,5 c/s, pyridin-proton). (2H, doublet, J=6.5 c/s, pyridine proton).

Minimal inhiberende konsentrasjon: Minimum inhibitory concentration:

Eksempel 4 Example 4

Eksempel 3 ble gjentatt, bortsett fra at nikotinamid ble brukt i stedet for isonikotinamidet. Den minimale inhiberende konsentrasjon i yug/ml mot Pseudomonas aeruginosa (Pd 1) for den resulterende Example 3 was repeated, except that nicotinamide was used instead of isonicotinamide. The minimum inhibitory concentration in yug/ml against Pseudomonas aeruginosa (Pd 1) for the resulting

forbindelse med gruppen connection with the group

var 1. was 1.

Eksempel 5 Example 5

Fremstilling av natrium-7-(a-sulfo-a-fenyl)-acetamido-3-(4'-metyl-5'-hydroksyetyltiazol-ium)cef-3-em-4-karboksylat: 500 mg (9,69 x 10_Zf mol) dinatrium-7-(a-sulfo-a-fenylacetamido)cefalosporanat, 1,68 g (1,73 x 10~<5> mol) KSCN og 415 mg (2,9 x 10 J mol) tiazolderivat ble opplost i 2 ml vann og satt hen til reaksjon i 18 timer i en termostat som ble holdt på 50°C. Oppløsningen som ble oppnådd på denne måte ble underkastet kromatografi ved bruk av "Amberlite XAD-2"-harpiks og frysetbrket og det ble oppnådd 264 mg av det ovenfor angitte produkt i et utbytte på 42,8%. Preparation of sodium 7-(α-sulfo-α-phenyl)-acetamido-3-(4'-methyl-5'-hydroxyethylthiazolium)cef-3-em-4-carboxylate: 500 mg (9.69 x 10_Zf mol) disodium 7-(α-sulfo-α-phenylacetamido)cephalosporanate, 1.68 g (1.73 x 10~<5> mol) KSCN and 415 mg (2.9 x 10 J mol) thiazole derivative were dissolved in 2 ml of water and allowed to react for 18 hours in a thermostat which was kept at 50°C. The solution thus obtained was subjected to chromatography using "Amberlite XAD-2" resin and frozen, and 264 mg of the above product was obtained in a yield of 42.8%.

IR\>5?L (cm<-1>)<:>3400, 3050, 1170, 1680, IR\>5?L (cm<-1>)<:>3400, 3050, 1170, 1680,

1615, 1530, 1350, 1210, 1110, 1040, 700. 1615, 1530, 1350, 1210, 1110, 1040, 700.

NMR (60Mc, D20): 2,43 (3H, singlett, NMR (60Mc, D2O): 2.43 (3H, singlet,

Eksempel 6 Example 6

(1) Under avkjoling og omroring ble 1,84 g (0,0068 mol) 7-ACA suspendert i 25 ml vann og til sus-pensjonen ble det dråpevis tilsatt 6,8 ml av en 1N-vandig opplosning av natriumhydroksyd for å opplose 7-ACA. På den annen side ble det til en suspensjon av (1) While cooling and stirring, 1.84 g (0.0068 mol) of 7-ACA was suspended in 25 ml of water and to the suspension was added dropwise 6.8 ml of a 1N aqueous solution of sodium hydroxide to dissolve 7-ACA. On the other hand, it turned into a suspension of

1»5 g (0,0068 mol) a-sulfo-3-tienyleddiksyre i 10 ml eter tilsatt 5,5 ml tionylklorid dråpevis samt 3 dråper dimetylformamid, og den resulterende opplosning ble om-rort i 5 timer ved romtemperatur. Reaksjonsopplosningen ble underkastet fordamping til tb'rr tilstand under redusert trykk og det ble oppnådd ct-sulfo-3-tienylacetyl-klorid som rest. Resten ble opplost i 10 ml etylacetat og oppløsningen ble tilsatt dråpevis til den 7-ACA-opp-lbsning som er nevnt ovenfor, fulgt av omroring i 30 minutter. Det vandige sjikt ble separert fra reaksjons-opplbsningen og justert til en pH-verdi på 6,5 ved tilsetning av en mettet vandig opplosning av NaHCO^. Den resulterende opplosning ble renset ved kolonnekromatografi ved bruk av "Amberlite XAD-2" og det ble oppnådd 1,6 g (42%) 7-(a-sulfo-3'-tienylacetamido)cefalosporansyre. 1.5 g (0.0068 mol) of α-sulfo-3-thienylacetic acid in 10 ml of ether was added dropwise with 5.5 ml of thionyl chloride and 3 drops of dimethylformamide, and the resulting solution was stirred for 5 hours at room temperature. The reaction solution was subjected to evaporation to a tb'rr state under reduced pressure and α-sulfo-3-thienylacetyl chloride was obtained as a residue. The residue was dissolved in 10 ml of ethyl acetate and the solution was added dropwise to the 7-ACA solution mentioned above, followed by stirring for 30 minutes. The aqueous layer was separated from the reaction solution and adjusted to a pH value of 6.5 by addition of a saturated aqueous solution of NaHCO 3 . The resulting solution was purified by column chromatography using "Amberlite XAD-2" and 1.6 g (42%) of 7-(α-sulfo-3'-thienylacetamido)cephalosporanic acid was obtained.

1677 (-CONH-), 1605 (-COONa), 1225 (-SO^Na, -OAC), 1043 (SO,Na). 1677 (-CONH-), 1605 (-COONa), 1225 (-SO^Na, -OAC), 1043 (SO,Na).

NMR ^(D20): 2,13 (3H, singlett, -C02CH,), NMR δ(D 2 O): 2.13 (3H, singlet, -CO 2 CH ),

3,54 (2H, bred, 3.54 (2H, wide,

, 5,10 (1H, dublett, J=4,7, c/s, , 5.10 (1H, doublet, J=4.7, c/s,

i in

5,24 (1H, singlett, -ChO, 5,70 (1H, dub- 5.24 (1H, singlet, -ChO, 5.70 (1H, dub-

IM IM

lett, J=4,7 c/s, light, J=4.7 c/s,

), 7,38 - 7,67 (3H, multiplett, (2) 260 mg (0,5 x IO<-3> mol) 7-(a-sulfo-3-tienyl-acetamido)-cefalosporansyre og 97 mg (1 x 10~<5> mol) KSCN ble tilsatt til en opplosning av 240 mg (3 x 10~<5> mol), pyridin opplost i 2 ml vann, og den resulterende opplosning ble satt hen i 24 timer ved 40°C. Reaksjonsbland-ingen ble vasket med eter. Det vandige sjikt ble separert og renset ved kolonnekromatografi ved bruk av "Amberlite XAD-2" og det ble oppnådd natrium-N-/7-(a-sulfo-3-tienylacetamido)cef-3-em-3-ylmetyl7-pyridinium-4-karboksylat. ), 7.38 - 7.67 (3H, multiplet, (2) 260 mg (0.5 x 10<-3> mol) 7-(α-sulfo-3-thienyl-acetamido)-cephalosporanic acid and 97 mg ( 1 x 10~<5> mol) KSCN was added to a solution of 240 mg (3 x 10~<5> mol) pyridine dissolved in 2 ml of water, and the resulting solution was allowed to stand for 24 hours at 40°C The reaction mixture was washed with ether. The aqueous layer was separated and purified by column chromatography using "Amberlite XAD-2" to obtain sodium N-[7-(α-sulfo-3-thienylacetamido)cef-3 -em-3-ylmethyl 7-pyridinium-4-carboxylate.

Minimum inhiberende konsentrasjon: Minimum inhibitory concentration:

), 8,08 (2H, bred, ), 8,54 (1H, bred, , 8,91 (2H, bred, ), 8.08 (2H, wide, ), 8.54 (1H, wide, , 8.91 (2H, wide,

Eksempel 7 Example 7

213 mg (2,5 x IO<-5> mol) tiazol, 97 mg (1 x IO"<5 >mol) KSCN og 260 mg (0,5 x IO"<3> mol) 7-(a-sulfo-3-tienylacetamido)cefalosporansyre ble opplost helt i 0,8 ml vann. Oppløsningen ble satt hen ved 50°C i 20 timer og deretter renset ved kolonnekromatogr^afi ved bruk av "Amberlite XAD-2" og det ble oppnådd 80 mg natrium-N-[ 7-(a-sulfo-3'-tienylacetamido)cef-3-em-3-ylmetyl7tia-zolium-4-karboksylat. 213 mg (2.5 x 10<-5> mol) thiazole, 97 mg (1 x 10"<5 >mol) KSCN and 260 mg (0.5 x 10"<3> mol) 7-(α-sulfo -3-thienylacetamido)cephalosporanic acid was completely dissolved in 0.8 ml of water. The solution was set at 50°C for 20 hours and then purified by column chromatography using "Amberlite XAD-2" and 80 mg of sodium N-[7-(α-sulfo-3'-thienylacetamido) was obtained. cef-3-em-3-ylmethyl7thiazolium-4-carboxylate.

i<R>^maks (cm<-1>): 1757 (p-laktam), 1670 (-C0NH-, -N=C), 1617 (-COONa), 1038 (-SO^Na). i<R>^max (cm<-1>): 1757 (p-lactam), 1670 (-C0NH-, -N=C), 1617 (-COONa), 1038 (-SO^Na).

NMR £ (D20): 3,5 (2H, NMR δ (D 2 O): 3.5 (2H,

T T T T

), 5,1 (1H, ), 5.1 (1H,

), 5,25 (1H, singlett, -CH< ), 5,3 (2H, ), 5.25 (1H, singlet, -CH< ), 5.3 (2H,

SO^Na SO^Na

-CH2-N), 5,7 (1H, ), 7,37 - 7,6 (3H, tiofen), 8,15, 8,35, 10,0 (1H, hver, -CH2-N), 5.7 (1H, ), 7.37 - 7.6 (3H, thiophene), 8.15, 8.35, 10.0 (1H, each,

Eksempel 8 Example 8

420 mg (3 x 10~<3> mol) 4-(3-hydroksy-etyl-5-metyltiazol, 485 mg (5 x 10~<5> mol) KSCN og 260 mg (0,5 x 10 _ - z mol) 7-(a-sulfo-3-tienylacetamido)-cefalosporansyre ble opplost i 1 ml vann og den på denne måte oppnådde opplosning ble satt hen ved 50°C i 10 timer. Reaksjonsopplosningen ble renset ved kolonnekromatogra- 420 mg (3 x 10~<3> mol) 4-(3-hydroxy-ethyl-5-methylthiazole, 485 mg (5 x 10~<5> mol) KSCN and 260 mg (0.5 x 10 _ - z mol) 7-(α-sulfo-3-thienylacetamido)-cephalosporanic acid was dissolved in 1 ml of water and the solution obtained in this way was placed at 50° C. for 10 hours. The reaction solution was purified by column chromatography

fi ved bruk av "Amberlite XAD-2" og det ble oppnådd natrium-N-/7-(a-sulfo-3'-tienylacetamido)cef-3-em-yl-metyl7-4"-(3-hydroksyetyl-5"-metyl-tiazolium-4-karboksylat. fi using "Amberlite XAD-2" and sodium-N-[7-(a-sulfo-3'-thienylacetamido)cef-3-em-yl-methyl7-4"-(3-hydroxyethyl-5 "-methyl-thiazolium-4-carboxylate.

IR^maks (cm<_1>): 1760 (P-laktam), 1675 IR^max (cm<_1>): 1760 (P-lactam), 1675

+ +

(-CONH-, -N=C), 1615 (-COONa), 1040 (-SO^Na). (-CONH-, -N=C), 1615 (-COONa), 1040 (-SO^Na).

NMR J(D20): 2,43 (3H, singlett, NMR J(D 2 O): 2.43 (3H, singlet,

3,2 - 3,5 (4H, ), 3,84 (2H, triplett, J=4,5 c/s, , 5,1 (1H, dublett, J=4,9 c/s, , 5,20 (1H, singlett, , 5,3 (2H, I CH2-N®), 5,70 (1H, dublett, J=4,9 c/s, 7,3 - 7,6 (3H, tiofen), 9,12 (1H, singlett. 3.2 - 3.5 (4H, ), 3.84 (2H, triplet, J=4.5 c/s, , 5.1 (1H, doublet, J=4.9 c/s, , 5, 20 (1H, singlet, , 5.3 (2H, I CH2-N®), 5.70 (1H, doublet, J=4.9 c/s, 7.3 - 7.6 (3H, thiophene), 9.12 (1H, singlet.

Eksempel 9 Example 9

558 mg (2 x 10 mol) natrium-7-aminocefalo-sporanat, 790 mg (l x 10~^ mol) pyridin og 1,94 g 558 mg (2 x 10 mol) sodium 7-aminocephalosporanate, 790 mg (1 x 10~^ mol) pyridine and 1.94 g

(2 x 10~<5> mol) KSCN ble opplost i 2 ml vann og den resulterende opplosning ble satt hen ved 50°C i 8 timer. Reaksjonsopplosningen ble renset ved kolonnekromatografi ved bruk av "Amberlite XAD-2" for å oppnå pyridinium-7-aminocefalosporanat som ble opplost i 10 ml vann hvoretter opplbsningen ble omsatt med 235 mg a-sulfo-3-tienyl-acetylklorid for å oppnå natrium-N-/?-(a-sulfo-3'-tienyl-acetamido )cef-3-em-3-yl-metyl7pyridinium-4-karboksylat. Denne forbindelse var identisk med det produkt som ble oppnådd i eksempel 6, bestemt ved IR- og NMR-spektroskopi. (2 x 10~<5> mol) KSCN was dissolved in 2 ml of water and the resulting solution was placed at 50°C for 8 hours. The reaction solution was purified by column chromatography using "Amberlite XAD-2" to obtain pyridinium 7-aminocephalosporanate which was dissolved in 10 ml of water after which the solution was reacted with 235 mg of α-sulfo-3-thienyl-acetyl chloride to obtain sodium- N-/?-(α-sulfo-3'-thienyl-acetamido)cef-3-em-3-yl-methyl-7-pyridinium-4-carboxylate. This compound was identical to the product obtained in Example 6, as determined by IR and NMR spectroscopy.

Claims (1)

Analogifremgangsmåte for fremstilling av teraAnalogy method for the production of terra peutisk aktive cefalosporiner med den generelle formel Itherapeutically active cephalosporins of the general formula I der R er tienyl eller fenyl og R2 er en pyridinium-gruppe som eventuelt er substituert med -C0NH2, eller en tiazoliumgruppe som eventuelt er substituert med -CFLj og/eller -CH2CH20H, eller et farmasøytisk aksep-tabelt salt derav, karakterisert ved at (1) en sulfocefalosporansyre med den generellewhere R is thienyl or phenyl and R2 is a pyridinium group which is optionally substituted with -CONH2, or a thiazolium group which is optionally substituted with -CFLj and/or -CH2CH2OH, or a pharmaceutically acceptable salt thereof, characterized in that ( 1) a sulfocephalosporanic acid with the general formelformula der R har den ovenfor angitte betydning, eller et salt • eller en lett dekomponerbar ester derav, omsettes med en forbindelse R2 med den ovenfor angitte betydning; eller (2) en aminocefalosporansyre med den generelle formelwhere R has the above meaning, or a salt • or an easily decomposable ester thereof, is reacted with a compound R2 with the above meaning; or (2) an aminocephalosporanic acid of the general formula der Rg har den ovenfor angitte betydning, eller et salt eller en lett dekomponerbar ester derav, omsettes med en a-sulfokarboksylsyre, eller et funksjonelt derivat derav, med formelenwhere Rg has the meaning given above, or a salt or an easily decomposable ester thereof, is reacted with an α-sulfocarboxylic acid, or a functional derivative thereof, with the formula der R har den ovenfor angitte betydning,where R has the above meaning, hvoretter en eventuell estergruppe spaltes av, og, hvis onskelig, de oppnådde forbindelser omdannes til et far-masøytisk aksepterbart salt.after which any ester group is cleaved off, and, if desired, the compounds obtained are converted into a pharmaceutically acceptable salt.
NO251872A 1971-07-17 1972-07-13 ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE CEPHALOSPORINES NO142914C (en)

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US4063019A (en) 1976-03-30 1977-12-13 E. R. Squibb & Sons, Inc. [[[(2,4-Dioxo-1-imidazolidinyl)amino]carbonyl]amino]-acetylcephalosporin derivatives
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US4396620A (en) * 1981-09-08 1983-08-02 Eli Lilly And Company Cephalosporin quinolinium betaines
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