PROCEDURE FOR THE PRODUCTION OF NEW PENICILLIN DERIVATIVES

The invention concerns a procedure for the production of a new class of Penicillinen, which possess antibacterial effectiveness and with the treatment of infections, which were caused by a wide range of gramnegativer organisms, with humans, depths and poultry are valuable. The invention concerns the production of new 6-Methoxy-a-carboxypenicilline, whose A-Carboxygruppe is verestert. In the GB-PS No. 1.339.007 are among other things in 6-Stellung substituierteAcylaminopenicilline that all mine formula H RB l j RA - N] N i 0 co2Rc (A) where RA ecyl is, RB Hydroxy, Mercapto, nitrile, Carboxy, if necessary substituted Methoxy, Äthoxy, methyl, ethyl, Methylthio or Äthylthio, Carbamoyloxy, Carbamoylthio, c1 _6 - Alkanoyloxy, Ct_6 - and represents RC hydrogen, a pharmakologisch compatible ester remainder or a cation means Alkanoylthio, Cyano, Carboxy or a derivative of the Carboxygruppe, like Carbamoyl, mentioned. In these Patentechrift is the only one, particularly mentioned A-carboxysubstituierte ecyl RA 2-Carboxyphenylacetamido. Special examples of a such Seitenkette are specified with the following groups of RB: Methyl, nitrile, Aminomethyl and 2-Carboxy-2-amino-äthoxy. It is not anything over a 6-methoxysubstituiertes penicillin with one A-carboxysubstituierten Acylseitemkette geoffenbart. It was now found that 6a-subetituierte Penicilline including 6a-Methoxypenicilline represent completely different class than usual 6a-Hydrogenpenicilline. Actually most have hievon an insignificant antibacterial effectiveness including the majority of the connections of the GB-PS No. 1,339,007. The invention creates A-esters of penicillin derivatives with a 6a-Methoxysubstituenten and a group of carboxyls in a-position of the Seiteukette. These two groups are substantial for the effectiveness, and changes also only one of these substituents cause an enormous loss of activity. This stands in sharp contrast to the 6a-Hydrogenpenicillinen and stresses that from the GB-PS No. 1.339.007 no conclusions can be drawn over the antibacterial effectiveness of this series of connections. The DE-OS 2,312,041 and 2,344,765 reveals certain kinds of “- esters of usual 6-Hydvogenpenieillinen. Since however between 6a-substituiertau Penicillinderiva EN and normal 6-Hydrogenpenicillinen does not exist relationship, it could not be before-save-said that with substitution of the 6a-Wasserstoffatoms of a-esters of these disclosure writings by a 6a-Methoxygruppe will keep the antibacterial effectiveness upright can, while with employment the entire useful effectiveness is lost to a Methoxygrnppe in place of the 6a-Wasserstoffatoms of most other Penicilline. In the Abstraet No. 368 of the “Program and A bstracts OF the 14th Intersclence Couference EN Antimicrobial Ageuts and Chemotherapy” held from the 11. until 13 September 1974 in sow Francisco, California (the USA), is only over only one 6-N [ethoxypenicillin the above formula (A) reported, i.e. on the 6a-Methoxy-6 - (2-carboxyphenylacetamido) - penicillansäur e. It va rde now gefunalen that determined new esters. a Ideinen of decrees of 6-Methoxy-a-carboxypenicillinen, including which aforementioned connection, compared with which free e - Carboxyverbindungen, an improved oral absorption exhibit. The subject of the invention is thus a procedure for the production of new Penicillinderlvaten of the general formula OCH CH: /S R. CH.I CO. NH --]. N] CH route, o \ CO R o (0 where R Phenyl or 2oder 3-Thienyl, R hydrogen is, a pharmakologisch compatible salt supplying ion or one means R into vivo hydrolyzable group of esters and! a pharmakologisch verträgliahe, into vivo hydrolyzable E stergruppe, in particular A cyloxyalkyl, how Acetoxymethyl, Trimethylacetoxymethyl, A-Acetoxyäthy! , A-Acetoxybenzyl and A-Trimethylacetoxyäthyl, furthermore Alkoxycarbonyloxyalkyl, like Äthoxycarbonyloxymethyl and A-Äthoxycarbonyloxyäthyl, furthermore Lacton, Thiolacton and Dithiolacton, - 3 - Nr.$54631 i.e. groups of esters of the general formula - CO.O - CH - Z' I I X' - C=Y' where X' and Y' oxygen or sulfur are and Z' ethylen or 1,2-Phenylen means, that if necessary by halogen, Nitro or nied. Alkoxy is substituted, or alkyl, Cycloalkyl, alkenyl, Alkinyl, aryl, Aralkyl or a hetero-cyclic group, which can be substituted all, represent. Suitable ones, a salt supplying ions fürR2 are rivet all ions, e.g. ions of aluminum, the alkali metals, like sodium or potassium, the alkaline earth metals, like calcium or magnesium, as well as ions of ammonium or substituiertemAmmon|over, e.g. such of nied. Alkyl amines, like tri ethyl amine, low-molecular hydroxyalkyl amines, like 2-Hydroxyäthylamin, until (2-hydroxyäthyl) - amine or trichloroethylene (2 - hydroxyäthyl) - amine, Cycloalkylaminen, like Bieyelohexylamin, or ions of Proeain, Dibenzylamin, N, N-Dibenzyläthylendiamin, 1-Ephenamin, N-Äthylpiperidin, N-benzyle - phenäthylamin, Dihydroabietylamin, N, N' until dehydro abietyläthylendiamin or ions of bases of the Pyridintyps, like Pyridin, Collidin or Chinolin, or ions of other amines, those for the formation of salts with Benzylpenicillinen uses Purden. Into vivo hydrolyzable, pharmakologisch compatible ester remainders for R2 are such, which hydrolyze in the human body under formation of the master acid. Suitable examples are, as indicated for g 1, Acyloxyalkyl, like Acetoxymethyl, Trimethylacetoxymethyl, - Acetoxyäthyl, “- Acetoxybenzyl and - Trimethylacetoxyä hyl, furthermore Alkoxycarbonyloxyalkyl, like Äthoxycarbonyloxymethyl and - Äthoxycarbonyl0xyäthyl, furthermore Lacton, Thiolacton and Ditbiolacton, i.e. it ergruppen the general formula - CO.O. - CHZ' I I X' - C=Y' where X' and Y' oxygen or sulfur are and Z' ethylen or 1, 2-Phenylen meant, that if necessary by halogen, Nitro or nied. Alkoxy is substituted. Preferential ester remainders are the Phthalidund 5, 6-Dimethoxyphthalideeter. Beyond that Rl, as mentioned, can be alkyl, Cycloalkyl, alkenyl, Alkinyl, aryl, Aralkyl or a hetero-cyclic group, which can be substituted. Examples are: a) Alkyl, in particular nied. Alkyl, like methyl, ethyl, nund ISO Propyl, n, sec. - tert, isound. Butyl or Pentyl; b) substituted nied. Alkyl with at least one of the following substituents: Chlorine, bromine, fluorine, Nitro, I itril, 1-Indanyl, 2-Indanyl, Furyl, Pyridyl, 4-Imidazolyl, Phthalimido, Azetidhuo, A zkridino, Pyrrolidono, Plperldino, Morpholino, Thiomorpholino, Pyrrolo, Imidazolo, 2-Imidazolino, 2,5-Dlmethylpyrrolidino, 1.4, 5, 6-Tetrahydropyrimidino, 4-Methylpiperidino, 2, 6-Dimethylpiperidino, Carbo (nied. alkoxy), nied. Alkanoyl, n [OD. Alkoxy, nied. Alkylmercapto, nied. Alkylsulfinyl, nied. Alkyleulfonyl, n (nied. Alkyl) - piperazino, Alkylamino, Dialkylamino, Alkanoylamino or Alkylanilino, what latter by chlorine, bromine, nied. Alkyl or nied. Alkoxy to be substituted can; c) Cycloalkyl or through nied. Alkyl substituted Cycloalkyl with 3 to 7 C-flavours in the Cycloalkylteil and [2, 2-Di (nied. alkyl) - l, 3-dioxolon-4-yl] - methyl; d) Alkenyl with up to 8 C-flavours; e) Alkinyl with up to 8 C-flavours; f) Aryl, like Phenyl or substituted Phenyl, where at least one substituent chlorine, bromine, fluorine, Nitro, nied. Alkyl, nied. Alkoxy, nied. Alkanoyl, Carbo (nied. alkoxy) or Di (nied. ) - alkylamino is, or a group of the general formula J _j where Y one of the following groupings means: - CH=CH - O -, - CH=CH S, CH2 - CH2 - S -, - CH=N - CH=CH -, - CH=CH - CH=CH -, - CO - CH=CH - CO - or - CO - CO - CH=CH -, or a group of the general formula is, where Z nied. Alkyls is, like tri trimethylen or Tetramethylen and of them substituted derivatives, whereby the substituent is methyl, chlorine or bromine; g) Aralkyl, like benzyle or substituted benzyle, whereby as substituent chlorine, bromine, fluorine, Nitro, nied. Alkyl, nied. Alkoxy, nied. Alkanoyl, Carbo (nied. ) - alkoxy or Di (nied. ) - alkylamino in consideration kornmen; h) heterocyelische groups, like Furyl, Chinolyl, methyl-substituted Chinolyl, Phenazinyl, 1, 3-Benzodioxolyl, 3 (2-Methyl-4-pyronyl), 3 (4-Pyronyl) or n (NIethylpyridyl); j) other hydrocarbon remainders, how alicyclisches Indanyl methyl-substituted or its chlorine, more bromoder derivatives, furthermore alicyclisches Tetrahydronaphthy! or its chlorine, bromoder methyl-substituted derivatives, as well as Benzohydroyl, Trityl, Cholesteryl or Bicyclo [4.4, 0] decyl. For Ri are preferential nied. Alkyl, benzyle, Phthalidyl, Indanyl, Phenyl, mono, dlund trichloroethylene (nied. ) - alkyl-substituted Phenyl, like o, decay p-Methylphenyl, Äthylphenyl, noder ISO Propylphenyl, n, sec. - tert, more isooder. Bntylphenyl. Special connections available in accordance with the invention are: 6 - Methoxy-6f! - (D, L-2-phenoxycarbunyl-thien2' yl-aQetamido) - penicillansäur e, 6 “- Methoxy-6fl (2 ' - phenoxycarbunyl-thien-3-yl-acetamido) - penicillansäur e, 6fl [D, L-2 (Isobutyloxyearbonyl) - thien-3-yl-acetamido] - 6a-methoxy-penicillansäure, 6 f! - [D, L-2 (Indan-5-yloxyoarbonyl) - thien3-yl-acetamido] - 6a-methoxypenicillansäur e, 6a-Methoxy-SB [D, L-2 (4-methylphenoxycarbonyl) - thien-3-yI-acetamido] - penicillansäur e, 6 œ - Methoxy-6f! - [D, L-2 (phthalid-3-yloxyearbonyl) - thien-3' yl-aeetamido] - penieillansäure, 6fl [D, L-2 (2-sek. Butylphenoxyearbonyl) - thien-3' yl-aeetamido] - 6a-methoxypenieillansäure, 6 f! - [D, L-2 (2-Äthylphenoxyc arbonyI) - thien3' - DL-aeetamido] - 6a - methoxypencillans äure, 6 “- Methoxy-6f! - [D, L-2 (4-isopropylphenoxycarbonyl) - thien-3' yl-acetamido] - penicillansäure, 6fl [D, L-2 (3, 4-Dimethylphenoxyearbenyl) - phenylaeetamido] - 6a-methoxypenieillansäur e, 6a-Methoxy-6f! - [D, L-2 (4-methylphenoxyearbonyl) - phenylacetamido] - penicillansäure, 6 “- Methoxy - 6 flat steel bars - (1), L-2 - phenoxyear bunylphenylaeetamido) - penie illansäur e, 6 “- Methoxy-6f! - [D, L-2 (3-methylphenoxyoarbonyl) - 2-phenylacetamido] - penioillansäure, 6 - [D, L - 2 (5-indanyloxyearbenyl) - 2-phenylacetamido] - 6a-methoxy-penioillansäure and 6fl (D, L-2-Isobutoxyearbonyl2-phenylaeetamido) - 6a-methoxy-peneillansäur e. The connections of the formula (I) by the fact it is manufactured that one a connection of the general formula SR3 CH R - CH. C0. NH. : “S CH CO2Ri // ß O CO R2 2 (n) where R, Ri and R2 the meaning indicated above possess and R nied. Alkyl or benzyle meant, with methanol in presence of a metal ion converts, and afterwards if necessary the received connection into a salt or an ester transfers. As Metallion appropriately a tellurium (III) becomes -, lead (IV) -, bismuth (V) -, mercury, lead, Kadminm, Thslliumoder Silbersalz use. Preferably the conversion is accomplished with -50 to +25°C in a solvent. The new connections working as antibiotics can be prepared for administration in arbitrary way for use in the Humanoder veterinary medicine, as this admits with other antibiotics is. They are thus used for drugs, the one connection of the formula (I) zueammen if necessary with pharmakologisch compatible substrate [EN and/or diluents contained. The drugs can be formulated for administration on arbitrary way, although oral administration is preferred. The drugs can be present in the form of tablets, caps, propellants, granulates, Pastillen or liquid preparations, like oral or sterile parenteral solutions or suspensions. Tableßen and caps to the oral Verabreiohung can be present in single dosage forms and usual Exzipientien, like bonding agents, e.g. syrup, acacia rubber, gel, Sorbit, Tragant or Polyvinylpyrroliden, fillers, e.g. lactose, sugar, mark strength, Calciumphoephat, Sorblt or Glycerin, Gleltmittel, e.g. magnesium stearate, talcum powder, PL glycol or Sillciumdioxyd, decay aid, e.g. potato strength, or compatible wetting agents, like Natriumlaurylsulfat, contain. The tablets can be coated according to the methods well-known in usual pharmaceutical practice. Oral liquid preparations can be present in the form of for example aqueous or oily suspensions, solutions, emulsions, syrups or Elixieren, or they can be handed as drying product for a redissolution with water or other suitable carriers before a Inbenutzungsnahme. Such liquid preparations know usual additives, how Suspensionshilfsmlttel, e.g. Sorbit, syrup, methyl cellulose, Ghcosesirup, gel, Hydroxyäthyleellulose, Carboxymethylcellulose, Aluminlumstearatge! or e.g. Lecithin, Sorbitanmonooleat or Akazlengummi, furthermore not aqueous carriers, which include food oils, hydrogenated Speisefette, emulsifying means, e.g. almond oil, fractionated coconut oil, oily esters, like Glycerin, propylene glycol, or ethyl alcohol, as well as Koneervierungsmittel, e.g. the Methyloder Propylester of the p-Hydroxybenzoesäure or the Sorbinsäure, and if necessary usual Geschmacksund of coloring materials, contain. Suppositorien contain usually a Suppositoriengrundmasse, e.g. cocoa butter or other Glyceride. Manufactured for the parenteral administration liquid E inzsldosierungsformen using the connection and a sterile carrier, whereby water is preferred. The connection can be present depending upon the used carrier and the applied concentration either in the carrier suspended or solved. During the production of solutions the connection can be solved in water to Injektlonezwecken and filtered under sterile conditions, before the solution in suitable containers or ampuls is abgefllllt and sealed. Preferentially auxiliary materials, like local anaesthetics, can be solved in the carrier preservatives and Puffersubstanzen. For the increase of stability the drugs can be frozen after the racking into containers and be released under decreased pressure from the water. The freezingdried powder then melted in the Glasgef eat and added a Fläschchen with water for injection purposes, in order to rekonstituieren the liquid before use. Parenteral suspensions can be manufactured essentially in the same way, however with the measure that the connection in the carrier suspends instead of in it “is solved and that the Sterilieierung does not need to be accomplished together with a filtration. The connection can be sterilized thereby that one exposes it before suspending in the sterile carrier to ethylen oxide. Vorteilhafterweiee can be worked an boundary surface-active connection or a wetting agent into the drug, around an even distribution of the connection zuerleichtern. The drugs can do 0.1 to 99 thread - %, lecture way 10 to 60 Gsw. - % active connection depending upon the administration form contain. If the drugs consist of single dosages, each unit contains preferredwhite of 50 to 500 mg active ingredient. The dosage quantity, which is used with a treatment by Erwachsensn, amounts to preferably täglich100 to 3000 mg, e.g. daily 1500 mg, depending upon the H ufigkeit and the way of the Verabrelchung. It is evidently, there the Seitenkette of the Penici! LINE of the formula (I) an effective asymmetrical carbon atom exhibits. The invention covers from there the production of all possible Epimeren of the connections of the formula (I) as well as their mixtures. The following example is to describe the invention more near, without these however on that limited its target. Example: a) öa-Methylthio6 - (D, L2-phenoxycarbenyl-2-phenyl-acetamido) - penicillansäur more ebenzylester 1, 57 g (3, 0 mMol) benzyle - 68 - amino - 6 - rnethylthiopenlclllanattoluo1-4-sulfonat are vibrated with 100 ml to ethyl acetate and 75 ml 0, 5N Bicarbonatlöeung with 0 to 5°C, until moose solved everything. Then one separates the ethyl acetate layer, extracts the aqueous Schiech twice with ever 25 ml ethyl acetate, combines the Extral e, dry her over water-free magnesium sulfate and evaporates her. 1VIau receives methylthiopenicillansäur ebenzyle ster to 6 - Amino6 “-. This ester is loosened in 60 ml Dichlormethan, which contains 0, 67 ml Pyridin, cooled in the ice bath and treated with 1, 28 g (5, 0 mMol) 2-Phenoxycarbenyl-2-phenylacetylchlorid (made of Phenylmalensäuremenophenylester is) in 20 ml Dichlormethan. The solution is agitated 2 h and evaporated then. Mau receives an oil, which is loosened in Äthylaeetat. The solution is washed to water, N-Natr successively with water, 10%iger CItronens urelösung, umbicarbenatlösung and satisfied Koahsalzlösung, dried and evaporated then. One receives an oil. After chromatography at Sllikagel one receives 1.32 g (= 74, 5% D. Th. ) derim title connection mentioned as pale-yellow 8ehaum. Dünnschichtchromatographie at sie2 with a mixture from ethyl acetate and petroleum ether of the boiling range 60 to 80°C in the relationship! : 3 as Laufmittel: Rf = 0,16. ] R-Spe rum Vmax (hot Nujol): 3300, 1780, 1740 and 1690 cm-1. NMR spectrum (CDC18): ö = 7.90 (1H, s, - ix - ICO -); 7, 0 to 7.8 (15H, m, 3 × pH); 5, 67 and 5.63 (1H, 2 × s, Cs-Preton); 5,23 (2H, s, - CO2 CH2 F); 4,95 (left-i, s, PhCH=); 4,50 and 4.47 (1H, 2 × s, C3 - proton); 2,25 and 2.22 (3H, 2 × s, - SCH3); 1, 35 and 1.30 (6I-I, 2 × s, gladly. Dimethylgruppen). b) 6a-Methoxy-6/3 (D, L-2-phenoxycarbonyl-2-phenylacetamido) - more penicillansäurebenzylester 0.523 g (0, 91 mMol) 6 “- Methylthio-6 - (D, L-2-phenoxycarbonyl-2-pbenylacetamido) - penicillansäurebenzylester and 0, 29 g mercury (II) - acetate in 4 ml methanol are agitated under nitrogen 90 min at ambient temperature. Then the Methauol under decreased pressure is vibrated removed, the arrears with ether, filtered by a filter from Dicalciumeilikat and Dicalciumaluminat and evaporated the filtrate to a strohfarbenen foam. The chromatography at silica-gel supplies 0, 270 g (52, 7% D. Th. ) at the connection specified in the title. Dünnschichtchromatographie at Sie2 with a mixture from ethyl acetate and petroleum ether of the boiling range 60 to 80oc in the relationship 1: 3 as Laufmitteh Rf = 0,14. NiV] R-spectrum (CDC1): ö = 8.12 and 8.02 (1H, 2 × s, - NHCO -); 7, 9 to 7, 0 (12H, m, 3 × pH); 5,70 (1H, s, Cs-proton); 5,25 (2H, s, - C02 CH2 F); 5,00 (1H, S., PhCH=); 4,49 (1H, s, Cs-proton); 3,50 and 3.47 (3H, 2 × s, - OCH3); 1, 33 (6H, s, in accordance with. Dimethylgrupp n). c) 6 “- Methoxy-6 - CD, L-phenoxycarbonylphenylacetamido) - penicillansäure 620 g 6 “- Methoxy-6 - (D, L-2-phenoxycarbonyl-2-phenylacetamido) - more penicillansäurebenzyloster in 20tal freshly distilled ethanol are treated with 4, 5 ml water and 0, 92 ml freshly prepared n-Natriumbicarbonatlösung. Then one adds 620 mg 10%ige palladium coal in nitrogen atmosphere and hydrogenates the mixture 1 h long. Then one filters the mixture by a filter from Dicalciumsililmt and Dicalcinmaluminat and washes the arrears with 10 ml 50%igem to aqueous ethanol. Whereupon one adds further 0, 7 g catalyst and continues the hydrogenation, until no more benzyle ester lets itself prove, like this by Dünnschichtchromatographie at Sililmgel in a mixture from chloroform, acetone and acetic acid in the relationship 50: 50: is evident to 7 as Laufmittel. The mixture is evaporated by a filter from calcium silicate and Dicalciumaluminat filtered, under decreased pressure, in order to remove ethanol, and freezingdried. One receives the desired connection as sodium salt. Dünnschichtchromatographie at sie2 with a mixture from chloroform, A concrete and acetic acid in the relationship 50: 50: 7 as Laufmittel: Rf = 5, 69. ] R-spectrum of Vmax (KBr): 3420 (broadly), 2967, 1710, 1680, 1597, 1490, 1190, 690 cm-t. The NMR spectrum shows that no benzyle ester is more present. Biological data 1st antibacterial effect the autibakterielle effectiveness of the connection available in accordance with the example is in the following table 1 in the form of Mindesthemrnkonzentrationen indicated. Table 1 A-ester of the 6-Meßhoxycarbeniclllins example RST E. eoli JT1 E. eoli JT4 E. coli JT426 Salto typhi Shig sennen HP. aeruginosa 10662 HP. aerughuosa 10662 (10-z) Serratla rnarceseens US32 Klebsiella of aero gene A Enterobacter cloacae N1 P. mirabiIls C 977 P. mirabilis 889 P. morganii P. r more ettger, i B. sublimis Staph. aureus Oxford Staph. aureus Russell Staph. aureus 1517 STR ep. faecalis B-haemolytisches Strep. CN10 standard Verd'ünnung in 5% blood agar 2nd oral absorption CHs COzH g 1 = it are measured with mice the Blutspiegel by 6-Methoxy iearcillin after oral administration of the ester. With animals, which hate certain connections received, also the urine was collected and determined biochromatographlsch whether not hydrolyzed esters are separated. The extent of the hydrolysis of the ester during the mikrobiologisohen attempt is useblut in the M and measured in Koehsalzlösung. The following methods are used: Species Verabreiohungsweg: orally 18 to 22 g heavy male CS1-Albinomäuse minimum inhibiting concentration in gg/tal 5.0,2.5 > 100 > i00 1.0,5.0,2.5,5.0,2.5,2.5 > 100 > i00 > I00 > i00 > i00 i0 Doslerung of the esters is given in a dose, dLe 100 mg/kg, related to the free Stammpeniclllansäure, contains. Attempt samples examined in form of the Stammpenicilline using ven Neisseria catarrhalis as Versuchsorganlsmus. Chromatography the urine is collected by mice, which received available the according to invention connection. The samples are noted in the Blochromatogramm. It becomes a butanol: Äthanoh water SystemimVerhältnis 4: 1: applied, and the strips are made visible on agar plates, which are inoculated with Neisseria catarrhalis. The results of the Blutspiegel with mice are indicated in table 2. Table 2 mouse No. 1 of 2 3 4 means blood PSE gel of 6-Methoxyticarcillin with mice after oral doses 3.4,5.0,3.9,3.8,2.9,3.8 of the C - Carboxyesters in a quantity of 100 mg/kg concentration ug/ml) of 6-Methoxyticarcillin in minutes of 5.4,7.0,6.1 15.9 6.1 after the administration 10.5 6.4,7.4,8.4,5.8,7.7 3, 9,4.3,5.6,2.1,3.5,3.9,120,3.0,2.9,2.0,1.4,1.7,2.2,240 0.85 O, ü3 1.4 0.80 0.78 0,87