DE1966203C3 - 2,3-Dioxo-4- (R ', R ") - aminomethylpyrrolidines and process for their preparation - Google Patents
2,3-Dioxo-4- (R ', R ") - aminomethylpyrrolidines and process for their preparationInfo
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- DE1966203C3 DE1966203C3 DE1966203A DE1966203A DE1966203C3 DE 1966203 C3 DE1966203 C3 DE 1966203C3 DE 1966203 A DE1966203 A DE 1966203A DE 1966203 A DE1966203 A DE 1966203A DE 1966203 C3 DE1966203 C3 DE 1966203C3
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- 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
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- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
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Description
in der R' und R" Alkyl- oder Aralkylreste darstellen oder zusammen einen Morpholinrest bilden.in which R 'and R "represent alkyl or aralkyl radicals or together form a morpholine residue.
2. Verfahren zur Herstellung der Verbindungen gemäß Anspruch 1, dadurch gekennzeichnet, daß man den 2I3-Dioxo-pyTTolidin-4-carbonsäurebenzyIester der Enolformei2. A process for the preparation of the compounds according to claim 1, characterized in that the 2 I 3-dioxo-pyTTolidin-4-carbonsäurebenzyIester the Enolformei
COO—CH,- CH5 COO-CH, -CH 5
HO IHO I
/-N-H/ -N-H
einer katalytischen Hydrierung unterwirft, wonach man das entsprechende 4-CarboxyIderivat der For- jo mel subjecting to catalytic hydrogenation, followed by the corresponding 4-CarboxyIderivat the research jo mel
COOH
HO COOH
HO
N-HN-H
erhält, das man einer Aminomethylierung nach w Mannich unterwirft und das entsprechende Aminomethylpiyrrolidin isoliert.obtained, which is subjected to an aminomethylation according to w Mannich and the corresponding aminomethylpiyrrolidine is isolated.
Die Erfindung betrifft 2r3-Dioxo-4-(R',R")-aminomethylpyrrolidine der allgemeinen FormelThe invention relates to 2 r 3-dioxo-4- (R ', R ") - aminomethylpyrrolidines of the general formula
HOHO
CH2-NCH 2 -N
R'R '
R"R "
— NU- NU
den 2,3-Dioxo-pyrrolidin-4-carbonsäure-benzylester der Enolformeithe 2,3-dioxo-pyrrolidine-4-carboxylic acid benzyl ester of Enolformei
HOHO
COO-CH, —COO-CH, -
N-HN-H
einer katalytischen Hydrierung unterwirft, wonach man das entsprechende 4-Carboxylderivat der Formelsubjected to a catalytic hydrogenation, after which one the corresponding 4-carboxyl derivative of the formula
COOHCOOH
HO I J HO I J
I—H I- H
erhält, das man einer Aminomethylierung nach Mannich unterwirft und das entsprechende Aminomethyl-pyrrolidin isoliertobtained, which is subjected to an aminomethylation according to Mannich and the corresponding aminomethyl-pyrrolidine is isolated
Das erfindungsgemäße Verfahren, wie es oben definiert wurde, umfaßt insbesondere eine bemerkenswerte, nicht naheliegende Phase:The method according to the invention, as defined above, comprises in particular a notable, non-obvious phase:
Die Hydrogenolyse des 2,3-Dioxo-pynOlidin-4-carbonsäurebenzylesters der Enolformei durch katalytische Hydrierung, die die 3,4-Doppelbindung bestehen läßt, wobei dieser Hydrogenolyse eine Decarboxylierung im Milieu der Aminomethylierung folgt.The hydrogenolysis of the 2,3-dioxo-pynolidine-4-carboxylic acid benzyl ester of the enol formei by catalytic hydrogenation, which consist of the 3,4 double bond leaves, this hydrogenolysis being followed by decarboxylation in the aminomethylation environment.
Man beachte, daß im Falle eines in 1-Stellung befindlichen Wasserstoffatoms die einfache Eliminierung der Carboxylgruppe, die für die Schaffung einer aktivierten Methylengruppe (daher alkylierbar) in der 4-Stellung nützlich ist, bisher nicht durchgeführt werden konnte, ohne die heterocyclische Verkettung zu zerbrechen [vergi. Southwick et coll, J. Org. 21, 1086 (1956)}Note that in the case of a hydrogen atom in the 1-position, the simple elimination of the Carboxyl group responsible for creating an activated methylene group (therefore alkylatable) in the 4-position is useful, could not be carried out before without breaking the heterocyclic linkage [forget. Southwick et coll, J. Org. 21, 1086 (1956)}
Die beim erfindungsgemäßen Verfahren einzusetzenden Ausgangsstoffe werden gemäß Patent 19 32 504 hergestellt, indem man eine Aminosäure der FormelThe starting materials to be used in the process according to the invention are according to Patent 19 32 504 made by taking an amino acid of the formula
mit Benzylalkohol in Gegenwart einer Säure der allgemeinen Formel HX umsetzt, in der X ein Halogen-, Schwefelsäure- oder Sulfonsäure-Anion darstellt, das erhaltene Estersalz der allgemeinen Formelwith benzyl alcohol in the presence of an acid of the general formula HX, in which X is a halogen, Represents sulfuric acid or sulfonic acid anion, the resulting ester salt of the general formula
mit einein Oxalsäurealkyl- oder -aralkylester kondensiert, wobei man den gewünschten 2,3-Dioxo-pyrrolidin-,-, 4-carbonsäure-benzylester der Enolformeicondensed with an oxalic acid alkyl or aralkyl ester, whereby the desired 2,3-dioxopyrrolidine -, -, 4-carboxylic acid benzyl ester of the enol formei
in der R' und R" Alkyl- oder Aralkylreste darstellen oder zusammen einen Morpholinrest bilden.in which R 'and R "represent alkyl or aralkyl radicals or together form a morpholine radical.
Diese Verbindungen eignen sich zur vorteilhaften Herstellung von neuen Cephaiosporinvorprodukteri gemäB Patent 19 32 504, die dann zu den neuen Cephalosporinendprodiikten gemäß Patent 19 32 505 führen. Wie dort ausgeführt, besitzen diese Cephalosporintlcriviiie interessante anlibiotische Eigenschaften.These compounds are suitable for the advantageous production of new cephaiosporin precursors according to Patent 19 32 504, which then lead to the new cephalosporin end products according to Patent 19 32 505. As stated there, these cephalosporin cultures have interesting anlibiotic properties.
Das erfindungsgemäße Verfahren zur Herstellung der 2.3-Dioxo-4 (R',R")-aminomethyl-pyrrolidine der angegcgcbcncn Formel ist dadurch gekennzeichnet, daß man HO The process according to the invention for the preparation of the 2,3-dioxo-4 (R ', R ") - aminomethyl-pyrrolidines of the formula given is characterized in that HO
y/y /
COO-CH2-C11H5 COO-CH 2 -C 11 H 5
N HN H
erhält.receives.
Eine bevorzugte Ausführungsform des erfindungsgemäßen Verfahrens kann im einzelnen durch die folgenden Punkte gekennzeichnet werden:A preferred embodiment of the method according to the invention can be implemented in detail by the following Points are marked:
Die Hydrogenolyse des 23-Dioxo-pyrrolidin-4-carbonsäurebenzylesters
der Enolformel wird in Gegenwart eines Hydrierkatalysators auf der Basis von Palladium oder Platin durchgeführt
Die Aminomethylierung des Produktes der Hydrogenolyse wird durch Einwirkung von Formaldehyd
und dem Hydrochlorid des gewählten Amins durchgeführt, wobei man in chlorwasserstoffsaurem
Milieu arbeitet Als Beispiele für Amine seien Morpholin, Dimethylamin oder Diethylamin genannt
The hydrogenolysis of the 23-dioxopyrrolidine-4-carboxylic acid benzyl ester of the enol formula is carried out in the presence of a hydrogenation catalyst based on palladium or platinum
The aminomethylation of the hydrogenolysis product is carried out by the action of formaldehyde and the hydrochloride of the selected amine, working in a hydrochloric acid medium. Examples of amines are morpholine, dimethylamine or diethylamine
Das folgende Beispiel erläutert die Erfindung:The following example explains the invention:
1. Stufe
23-Dioxo-pyrroIidin-4-carbonsäure1st stage
23-Dioxo-pyrroline-4-carboxylic acid
a) Herstellung des Hydrierkatalysatorsa) Preparation of the hydrogenation catalyst
Man rührt unirr Wasserstoffatmosphäre eine Suspension von 0,8 g Tierkohle in 4 ecm einer wäßrigen 2%igen Palladiumchloridlösung. Nach der Sättigung des Katalysators saugt man ihn unter Luftausschluß ab und spült mehrmals mit wasserfreiem Dimethylformamid.A suspension is stirred in a hydrogen atmosphere of 0.8 g of animal charcoal in 4 ecm of an aqueous 2% strength Palladium chloride solution. After the catalyst is saturated, it is suctioned off with exclusion of air and rinsed several times with anhydrous dimethylformamide.
b) Hydrierungb) hydrogenation
Man löst 9,32 g 2,3-Dioxo-pyiTondin-4-carbonsäurebenzylester in 50 ecm wasserfreiem Dimethylformamid, fügt den oben hergestellten Katalysator hinzu. Man setzt das Ganze unter Wasserstoffatmosphäre, rührt dann und kühlt von Zeit zu Zeit, um jegliche spürbare Temperaturerhöhung zu vermeiden. Man filtriert, fügt 500 ecm Isopropyläther zum Filtrat, saugt ω und trocknet9.32 g of benzyl 2,3-dioxo-pyiTondin-4-carboxylate are dissolved in 50 ecm anhydrous dimethylformamide, add the catalyst prepared above. One sets the whole thing under a hydrogen atmosphere, then stirs and cools from time to time to avoid any noticeable increase in temperature to avoid. It is filtered, 500 ecm of isopropyl ether is added to the filtrate, suction and drying are carried out
Man erhält 4,618 g(96%) Produkt, das man so, wie es ist, für die weitere Synthese verwendet t Jr die Analyse löst J5 man es in 6 Volumina Dimethylsulfoxyd und 4 Volumina Methanol. Man filtriert und fügt erneut 4 Volumina Methanol hinzu. Es bildet sich ein weißer Niederschlag, den man absaugt und trocknet Ausbeute bei der Reinigung: 60%. -to4.618 g (96%) of product are obtained, which is used for further synthesis t Jr the analysis solves J5 it in 6 volumes of dimethyl sulfoxide and 4 volumes of methanol. It is filtered and another 4 volumes are added Add methanol. A white precipitate forms, which is filtered off with suction and dried Cleaning: 60%. -to
Das Produkt liegt in Form weißer Kristalle vor, die wegen Decarboxylierung wenig stabil sind. Es ist löslich in Dimethylsulfoxyd und Dimethylformamid, unlöslich in Isopropyläther und Wasser.The product is in the form of white crystals, which are not very stable due to decarboxylation. It is soluble in Dimethyl sulfoxide and dimethyl formamide, insoluble in isopropyl ether and water.
IR-Spektrum (in Nujol): "*'IR spectrum (in Nujol): "* '
Absorption im Bereich von assoziiertem OH/NH Komplexe und starke Absorption im Carboxylbereich: Schulter 1708 cm-' max. 1677 cm-'.Absorption in the area of associated OH / NH complexes and strong absorption in the carboxyl area: Shoulder 1708 cm- 'max. 1677 cm-'.
Analyse C5H5O«N: '"Analysis C 5 H 5 O «N: '"
Berechnet: C 4136, H 3,52, N 9,79%,
gefunden: C 41,7, H 3,8, N 9,9%.Calculated: C 4136, H 3.52, N 9.79%,
found: C 41.7, H 3.8, N 9.9%.
Soweit bekannt, ist diese Verbindung in der Literatur ■» nicht beschrieben.As far as is known, this connection is in the literature ■ » not described.
2. Stufe2nd stage
Hydrochlorid des 2,3-Dioxo-4-morpholino-methylpyrrolidins 2,3-Dioxo-4-morpholino-methylpyrrolidine hydrochloride
t>ot> o
mitwith
" = CH2CH2-O-CH2-CH2 "= CH 2 CH 2 -O-CH 2 -CH 2
Man fügt 2 Tropfen In-Chlorwusserstoffsäure zu IO ecm einer Morpholin-hydrochloridlösung, die durch Neutralisation von 8,71 g Morpholin mit konzentrierter Chlorwasserstoffsäure und Zugabe von 50 ecm Wasser hergestellt worden war. Man fügt 2 ecm 30%igen Formaldehyd hinzu und trägt dann 2,83 g 2,3-Dioxopyrrolidin-4-carbonsäure ein. Die Reaktionsmjschung wird unter Rühren 30 Stunden lang auf 60 bis 65° C erhitzt Man dampft zur Trockne ein und kristallisiert den Rückstand in Äthanol um. Man erhält2^86 g Produkt das direkt für die weitere Synthese brauchbar ist2 drops of in-hydrochloric acid are added IO ecm of a morpholine hydrochloride solution, which by Neutralization of 8.71 g of morpholine with concentrated Hydrochloric acid and adding 50 ecm of water. Add 2 ecm 30% Formaldehyde is added and then carries 2.83 g of 2,3-dioxopyrrolidine-4-carboxylic acid a. The reaction mixture is heated to 60 to 65 ° C. for 30 hours with stirring It is evaporated to dryness and the residue is recrystallized from ethanol. 2 ^ 86 g of product are obtained can be used directly for further synthesis
Zwecks Analyse löst man das Produkt in 1 Volumen heißen Wassers und fügt 3 Volumina Äthanol hinzu. Man stellt in Eis, saugt ab und erhält mit einer Ausbeute von 80% ein Produkt das in Form weißer Kristalle vorliegt wenig löslich in Äthanol und Äther, löslich in Wasser.For analysis, the product is dissolved in 1 volume of hot water and 3 volumes of ethanol are added. Man Puts in ice, sucks off and receives a product in the form of white crystals with a yield of 80% Slightly soluble in ethanol and ether, soluble in water.
Analyse C9H15O3N2Cl = 234,7:Analysis C 9 H 15 O 3 N 2 Cl = 234.7:
Berechnet: C 46,06, H 6,44, N 1134, Cl 15,11%;
gefunden: C 45,8, H 6,4, N 11,8, Cl 15,2%.Calculated: C 46.06, H 6.44, N 1134, Cl 15.11%;
found: C 45.8, H 6.4, N 11.8, Cl 15.2%.
IR-Spektrum in Nujol:IR spectrum in Nujol:
Absorptionsbanden bei 3210cm-' und 3,6 bis 4,1 μ Triplett im CarbonylbereichAbsorption bands at 3210 cm- 'and 3.6 to 4.1 μ Triplet in the carbonyl range
1711 cm-1 1711 cm- 1
1691cm-'1691cm- '
1664 cm '·1664 cm '
Soweit bekannt, ist diese Verbindung in der Literatur nicht beschrieben.As far as is known, this compound is not described in the literature.
Das Hydrochlorid des 23-Dioxo-4-morphoIinomethyl-pyrrolidins kann auch ausgehend von 23-Dioxo-pyrrolidin-4-carkcinsäure-benzylester ohne Isolierung der zwischendurch auftretenden freien Säure auf folgende Weise erhalten werden:The hydrochloride of 23-dioxo-4-morphoIinomethyl-pyrrolidins can also be made from 23-dioxo-pyrrolidine-4-carkcinsic acid benzyl ester can be obtained in the following manner without isolating the free acid which occurs in between:
Man trägt 3033 g 23-Dioxo-pyrrolidin-4-carbonsäure-benzylester in 300 ecm Dioxan mit 10% Wasser ein, erhitzt leicht, um das Produkt zu lösen, fügt 3 g Tierkohle und 1 ecm einer wäßrigen 20%igen Palladiumchloridlösung hinzu, man setzt unter Wasserstoffatmosphäre und rührt sehr energisch. In 1 Stunde und 40 Minuten werden 2700 ecm Wasserstoff absorbiert (theoretisches Volumen: 2912 ecm). Man kühlt ab, spült mit Stickstoff und leitet dann 130 ecm der wie folgt, zusammengesetzten Mischung ein:3033 g of 23-dioxopyrrolidine-4-carboxylic acid benzyl ester are carried in 300 ecm of dioxane with 10% water, heated slightly to dissolve the product, add 3 g Animal charcoal and 1 ecm of an aqueous 20% palladium chloride solution are added, and the mixture is set under a hydrogen atmosphere and stirs very vigorously. In 1 hour and 40 minutes, 2700 ecm of hydrogen are absorbed (theoretical Volume: 2912 ecm). It is cooled, flushed with nitrogen and then passed 130 ecm of the compound as follows Mixture one:
Morpholin 43,5 gMorpholine 43.5 g
Wasser 100 ecmWater 100 ecm
Konzentrierte Chlorwasserstoffsäure 40 ecmConcentrated hydrochloric acid 40 ecm
1 n-Chlorwasserstoffsäure 15 ecm1 n-hydrochloric acid 15 ecm
Formaldehyd 50 ecmFormaldehyde 50 ecm
Wasser zur Ergänzung auf 500 ecmWater to supplement to 500 ecm
Man erhitzt die Reaktionsmischung auf ungefähr 50° C und fängt innerhalb 1 Stunde 2325 ecm Kohlendioxydgas auf. Theoretisch müßte so viel Kohlendioxyd entwickelt werden, wie anfangs in der Reaktion Wasserstoff absorbiert wurde. Man erwartet daher höchstens die Entwicklung von 2700 ecm Kohlendioxydgas. Man rührt leicht einige Minuten, filtriert und dampft im Vakuum zur Trockne ein. Der Rückstand kann so, wie er ist, für die weitere Synthese verwendet werden.The reaction mixture is heated to about 50 ° C. and 2325 ecm of carbon dioxide gas is captured within 1 hour on. Theoretically, as much carbon dioxide should be evolved as hydrogen is initially absorbed in the reaction became. One therefore expects at most the development of 2700 ecm of carbon dioxide gas. One stirs lightly a few minutes, filtered and evaporated to dryness in vacuo. The residue can be as it is for them further synthesis can be used.
Zwecks Analyse teigt man das erhaltene Produkt mit Äthanol an, spült mit Äther, trocknet und erhält mit einer Ausbeute von 63,5% ein Produkt, das mit dem oben beschriebenen identisch ist.For the purpose of analysis, the product obtained is made into a paste with ethanol, rinsed with ether, dried and obtained with a 63.5% yield of a product identical to that described above.
Herstellung des AusgangsmaterialsProduction of the starting material
Stufe ALevel a
p-Toluolsulfonat des j9-Alaninbenzylesters
In eine Apparatur.die mit einem Wasserabscheider für
dieazeotrope Entfernung von in der Reaktion gebildetem
Wasser versehen ist, erhitzt man die folgende Mischung 5 Stunden lang am Rückfluß:p-Toluenesulfonate of the j9-alanine benzyl ester
The following mixture is refluxed for 5 hours in an apparatus equipped with a water separator for the azeotropic removal of water formed in the reaction:
/3-Alanin 89 g/ 3-alanine 89 g
p-Toluolsulfonsäure-monohydrat 210 gp-toluenesulfonic acid monohydrate 210 g
Benzylalkohol 450 ecmBenzyl alcohol 450 ecm
Tetrachlorkohlenstoff 500 ecmCarbon tetrachloride 500 ecm
Während dieser Zeit wurden ungefähr 45 ecm Wasser abgeschieden. Die Reaktionsflüssigkeit wird anschließend durch Destillation im Vakuum auf ein kleines Volumen eingeengt; man kühlt ab und kristallisiert das gebildete Produkt in Äther. Man stellt in Eis, saugt ab, ι ο trocknet und gewinnt 350 g (entspricht einer quantitativen Ausbeute) Kristalle, F.= 142°C.During this time approximately 45 ecm of water was separated out. The reaction liquid then becomes concentrated to a small volume by distillation in vacuo; one cools down and crystallizes that formed product in ether. It is placed in ice, suctioned off, ι ο dried and recovered 350 g (corresponds to a quantitative Yield) crystals, mp = 142 ° C.
Das erhaltene Produkt ist identisch mit dem von Nobuo Yzumiya et coll, Nippon Kagaku Zasshi 78,662 (1957) beschriebenen. πThe product obtained is identical to that of Nobuo Yzumiya et coll, Nippon Kagaku Zasshi 78,662 (1957). π
Stufe B
2,3-Dioxo-pyrrolidin-4-carbonsäure-benzyIesterLevel B.
2,3-Dioxo-pyrrolidine-4-carboxylic acid benzyl ester
Man trägt 225 g Kalium-tert-butylat in 900 ecm wasserfreies Benzol ein. fügt ΰΟΟ ecm Benzylalkohol hinzu, kühlt die Mischung in einem Eis/Methanol-Bad ab und gibt, ohne 30°C zu überschreiten, 351 g p-Toluolsulfonat des Ji-AIaninbenzylesters hinzu.One carries 225 g of potassium tert-butoxide in 900 ecm anhydrous benzene. adds ΰΟΟ ecm benzyl alcohol added, the mixture cools in an ice / methanol bath and gives, without exceeding 30 ° C., 351 g of p-toluenesulfonate of the Ji-alanine benzyl ester.
Andererseits löst man 300 g Oxalsäure-benzylester in 600 ecm heißem Benzol, läßt auf Raumtemperatur zurückkommen und neutralisiert die schwache Azidität der Lösung durch Zugabe von 0,4 ecm Triäthylamin. Diese Lösung gibt man zu der oben gebildeten Mischung und hält immer im Kühlbad. Man erwärmt wieder so auf Raumtemperatur und erhitzt 5 Stunden lang zum Rückfluß.On the other hand, 300 g of benzyl oxalate are dissolved in 600 ecm of hot benzene, allowed to return to room temperature and the weak acidity of the solution is neutralized by adding 0.4 ecm of triethylamine. This solution is added to the mixture formed above and is always kept in the cooling bath. The mixture is heated again so to room temperature and heated for 5 hours to reflux.
Man verjagt das Benzol im Vakuum, fügt nacheinander zuerst 2 1 Wasser.das 15 ecm Essigsäure enthält,dann 1,5 I Isopropyläther und schließlich 110 ecm konzentrierte Chiorwasserstoffsäure hinzu (bis man einen pH von 1 erhält). Man stellt unter Rühren 2V2 Stunden lang in Eis. Man saugt ab, wäscht mit Wasser, mit Isopropyläther und kristallisiert durch Auflösen in Dimethylformamid und Ausfällen mit Wasser um. Man erhält 130,5 g (56%) Produkt, R= 186° C, löslich in Alkoholen, Äther und Aceton, unlöslich in Benzol und Wasser.The benzene is expelled in a vacuum, first 2 liters of water containing 15 ecm of acetic acid are added one after the other, then 1.5 liters Isopropyl ether and finally 110 ecm concentrated Add hydrochloric acid (until pH 1 is obtained). It is placed in ice for 2½ hours with stirring. It is filtered off with suction, washed with water, with isopropyl ether and crystallized by dissolving in dimethylformamide and precipitates with water. 130.5 g (56%) are obtained Product, R = 186 ° C, soluble in alcohols, ether and acetone, insoluble in benzene and water.
Analyse Ci2HnO4N =233,24:Analysis Ci 2 H n O 4 N = 233.24:
Berechnet: C 61,8, H 4,76, N 6,01%;
gefunden: C 62, H 5,1, N 6,3%.Calculated: C 61.8, H 4.76, N 6.01%;
found: C 62, H 5.1, N 6.3%.
IR-Spektrum:IR spectrum:
Zwei Maxima im Carbonylgebiet 1729 cm-1 und 1693 cm-'Two maxima in the carbonyl region 1729 cm- 1 and 1693 cm- '
Absorption im Gebiet von assoziiertem OH/NH
Aromatisch monosubstituiert vorhanden.Absorption in the area of associated OH / NH
Aromatically monosubstituted.
Soweit bekannt, ist diese Verbindung in der Literatur nicht beschrieben.As far as is known, this connection is in the literature not described.
VersuchsberichtTest report
Das über die erfindungsgemäßen Produkt erhältliche γ-Lactam der L( + )-6 H,7 H-cis-7-(p-aminophenyldCetamidoJ-S-aminomethyl-ceph-S-em^-carbonsäure (freie Base = Verbindung B) wurde hinsichtlich ihrer pntibakteriellen Eigenschaften mit der 7-(«-AminophenylacetamidoJ-.^-meinyl-ceph-S-em^-carbonsäure, beschrieben in der Patentanmeldung Nr. 6 71 260 in der Südafrikanischen Union, veröffentlicht 1967 und bekannt unter dem Handelsnamen »Cephalexin«, und mit der 7-(D-(x-Aminophenylacetamido)-cephalosporansäure, beschrieben in der niederländischen Patentanmeldung Nr. 67 14 442, veröffentlicht am 25 April 1968 und bekannt unter dem Handelsnamen »Cephaloglycin«, verglichen. The γ- lactam obtainable via the product according to the invention which L (+) -6 H, 7 H-cis-7- (p-aminophenyldCetamidoJ-S-aminomethyl-ceph-S-em ^ -carboxylic acid (free base = compound B) was with regard to its antibacterial properties with the 7 - ("- aminophenylacetamidoJ -. ^ - meinyl-ceph-S-em ^ -carboxylic acid, described in patent application No. 6 71 260 in the Union of South Africa, published in 1967 and known under the trade name" Cephalexin ", And compared with 7- (D- (x-aminophenylacetamido) -cephalosporanic acid, described in Dutch patent application No. 67 14 442, published April 25, 1968 and known under the trade name" Cephaloglycine ".
Antibakterielle Aktivität in vitro:Antibacterial activity in vitro:
1) Milieu »Penassay Broth« (DIFCO) bei pH1) “Penassay Broth” environment (DIFCO) at pH
Die Ergebnisse werden ausgedrückt in minimalen Hemmkonzentrationen (y/ml) nach 24The results are expressed in minimum inhibitory concentrations (y / ml) after 24
oder 48 Stunden Inkubationszeit:or 48 hours incubation time:
Verbindung B Cephalexin CephalogiyrinCompound B Cephalexin Cephalogiyrin
24 Std. 48 Std. 24 Std. 48 Std. 24 Std. 48 Std.24 hours 48 hours 24 hours 48 hours 24 hours 48 hours
Penicillino-empfindlicher 0,05 2 1 2 2 40More sensitive to penicillino 0.05 2 1 2 2 40
Staphylococcus aureusStaphylococcus aureus
Peniciüino-resistenter 0,4 2 5 5 5 40Peniciuino-resistant 0.4 2 5 5 5 40
Staphylococcus aureusStaphylococcus aureus
2) Selber Stamm wie vorstehend und selbes Milieu, jedoch 55 3) Selber Stamm wie vorstehend und selbes Milieu, jedoch unter Zusatz von 5% menschlichen Albumins: unter Zusatz von 10% menschlichen Serums:2) Same strain as above and same milieu, but 55 3) Same strain as above and same milieu, however with the addition of 5% human albumin: with the addition of 10% human serum:
Verbindung B CephalexinCompound B cephalexin
24 Std. 48 Std. 24 Std. 48 Std.24 hours 48 hours 24 hours 48 hours
Penicillinö-Penicillin
sensiblermore sensitive
StaphylococcusStaphylococcus
aureusaureus
Penicilline)·Penicillins)
resistentermore resistant
StaphylococcusStaphylococcus
aureusaureus
0,20.2
0,40.4
Verbindung B CephalexinCompound B cephalexin
24 Std. 48 Std. 24 Std. 48 Std.24 hours 48 hours 24 hours 48 hours
Pehicillinö-Pehicillin
sensiblermore sensitive
StaphylococcusStaphylococcus
aureusaureus
Penicillino-Penicillino
resistentermore resistant
StaphylococcusStaphylococcus
aureusaureus
0,20.2
0,40.4
4) Im Milieu »Houd Hervitt Broth« (DiF-CO) bei pH 7,8:4) In the "Houd Hervitt Broth" environment (DiF-CO) at pH 7.8:
Verbindung B Cephalexin CephaloglycinCompound B Cephalexin Cephaloglycine
24 Stcl. 48 Std. 24 Stil. 4« Sl(I. 24 Ski. 48 Std.24 pcs. 48 hours 24 style. 4 «Sl (I. 24 Ski. 48 hrs.
Streptococcus 0,6 1.5 I 1 5Streptococcus 0.6 1.5 I 1 5
haemolyticushaemolyticus
(klinischer Stamm)(clinical strain)
5) Milieu »Antibiotic Medium« (OXOID) bei pH 7:5) Environment »Antibiotic Medium« (OXOID) at pH 7:
Verbindung B CephaloglycinCompound B cephaloglycine
24 Std. 48 Std. 24 Std. 48 Std.24 hours 48 hours 24 hours 48 hours
Bacillus 0,02 0,02 <0,1 0.4Bacillus 0.02 0.02 <0.1 0.4
subtilissubtilis
Akute foxizität an der Maus (intraperitoneal)Acute toxicity in the mouse (intraperitoneal)
Ver- Cephalexin CephaloglycinVer Cephalexin Cephaloglycine
bindung Bbinding B
LDv, > lg/kg 0.4-1,3 g/kg") 1-1.4 g/kg"LDv,> lg / kg 0.4-1.3 g / kg ") 1-1.4 g / kg"
·) Mercklndex. 9. Auflage. Nr. 1932. Seite 248. " C. A. 73. 1970. 12 672 r·) Merck Index. 9th edition. No. 1932. page 248. "C.A. 73, 1970. 12,672 r
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR156898 | 1968-06-27 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE1966203A1 DE1966203A1 (en) | 1972-01-27 |
| DE1966203B2 DE1966203B2 (en) | 1980-02-07 |
| DE1966203C3 true DE1966203C3 (en) | 1980-10-09 |
Family
ID=8651750
Family Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19691932498 Withdrawn DE1932498A1 (en) | 1968-06-27 | 1969-06-26 | New cephalosporin derivatives and their manufacturing process |
| DE19691966204 Pending DE1966204A1 (en) | 1968-06-27 | 1969-06-26 | New 1,3-thiazine derivatives |
| DE1967030A Expired DE1967030C3 (en) | 1968-06-27 | 1969-06-26 | γ-lactams of 6H, 7H-cis-7-amino-3aminomethyl-ceph-3-em-4-carboxylic acids |
| DE1966203A Expired DE1966203C3 (en) | 1968-06-27 | 1969-06-26 | 2,3-Dioxo-4- (R ', R ") - aminomethylpyrrolidines and process for their preparation |
Family Applications Before (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19691932498 Withdrawn DE1932498A1 (en) | 1968-06-27 | 1969-06-26 | New cephalosporin derivatives and their manufacturing process |
| DE19691966204 Pending DE1966204A1 (en) | 1968-06-27 | 1969-06-26 | New 1,3-thiazine derivatives |
| DE1967030A Expired DE1967030C3 (en) | 1968-06-27 | 1969-06-26 | γ-lactams of 6H, 7H-cis-7-amino-3aminomethyl-ceph-3-em-4-carboxylic acids |
Country Status (14)
| Country | Link |
|---|---|
| JP (2) | JPS4934999B1 (en) |
| AT (2) | AT293614B (en) |
| BE (1) | BE735127A (en) |
| BR (3) | BR6910252D0 (en) |
| CH (3) | CH515276A (en) |
| DE (4) | DE1932498A1 (en) |
| ES (2) | ES368820A1 (en) |
| FR (1) | FR1584569A (en) |
| GB (5) | GB1271015A (en) |
| HU (1) | HU162644B (en) |
| IL (1) | IL32379A (en) |
| NL (2) | NL142691B (en) |
| PL (1) | PL79142B1 (en) |
| SU (2) | SU495841A3 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0277215A1 (en) * | 1986-08-19 | 1988-08-10 | Horst Forschner | Do-it-yourself garments and set of components of do-it-yourself garments |
| EA013864B1 (en) * | 2008-08-29 | 2010-08-30 | Лимонова, Анастасия Викторовна | Method of enhancement antimicrobal activity of cephalosporin antibiotics |
-
1968
- 1968-06-27 FR FR156898A patent/FR1584569A/fr not_active Expired
-
1969
- 1969-06-11 IL IL32379A patent/IL32379A/en unknown
- 1969-06-13 PL PL1969134161A patent/PL79142B1/en unknown
- 1969-06-24 CH CH968069A patent/CH515276A/en not_active IP Right Cessation
- 1969-06-24 CH CH968169A patent/CH513206A/en not_active IP Right Cessation
- 1969-06-24 CH CH14171A patent/CH522635A/en not_active IP Right Cessation
- 1969-06-25 BE BE735127D patent/BE735127A/xx unknown
- 1969-06-25 HU HURO582A patent/HU162644B/hu unknown
- 1969-06-25 SU SU1343897A patent/SU495841A3/en active
- 1969-06-25 SU SU1340776A patent/SU384232A3/ru active
- 1969-06-26 DE DE19691932498 patent/DE1932498A1/en not_active Withdrawn
- 1969-06-26 DE DE19691966204 patent/DE1966204A1/en active Pending
- 1969-06-26 NL NL696909849A patent/NL142691B/en not_active IP Right Cessation
- 1969-06-26 ES ES368820A patent/ES368820A1/en not_active Expired
- 1969-06-26 DE DE1967030A patent/DE1967030C3/en not_active Expired
- 1969-06-26 NL NL696909850A patent/NL142415B/en not_active IP Right Cessation
- 1969-06-26 DE DE1966203A patent/DE1966203C3/en not_active Expired
- 1969-06-27 AT AT618469A patent/AT293614B/en not_active IP Right Cessation
- 1969-06-27 GB GB47787/71A patent/GB1271015A/en not_active Expired
- 1969-06-27 GB GB47789/71A patent/GB1271017A/en not_active Expired
- 1969-06-27 BR BR210252/69A patent/BR6910252D0/en unknown
- 1969-06-27 GB GB32567/69A patent/GB1271013A/en not_active Expired
- 1969-06-27 GB GB47788/71A patent/GB1271016A/en not_active Expired
- 1969-06-27 JP JP44050288A patent/JPS4934999B1/ja active Pending
- 1969-06-27 GB GB47790/71A patent/GB1271018A/en not_active Expired
- 1969-06-27 AT AT618569A patent/AT293615B/en not_active IP Right Cessation
- 1969-06-27 BR BR210250/69A patent/BR6910250D0/en unknown
- 1969-06-27 BR BR210251/69A patent/BR6910251D0/en unknown
- 1969-06-27 JP JP44050289A patent/JPS5028440B1/ja active Pending
-
1971
- 1971-09-17 ES ES395175A patent/ES395175A2/en not_active Expired
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