PL80571B1 - Adhesive compositions containing (1) an organic solvent (aliphatic hydrocarbon), (2) 100 parts of rubber consisting of (a) 10-100% of a diene or polyisobutylene[DE1900195A1] - Google Patents

Abstract

Adhesive compositions containing (1) an organic solvent (aliphatic hydrocarbon), (2) 100 parts of rubber consisting of (a) 10-100% of a diene or polyisobutylene rubber having an average molecular wt. of at least 30,000 and containing 0.005-0. 12 COOH equivalent per 100 g. (a carboxylated butadiene/styrene copolymer), and (b) 0-90% of a rubbery addition polymer deroid of COOH groups, (3) 0.1-80% of a solvent-soluble, COOH-reactive, resin compound of a metal of Group IZ, IIA, IIB or IVA of Derring's Periodic Table (Zn rosinate), and (4) 50-450 parts of a solubilising resin (phenolic resin) soluble in the organic solvent and compatible with the rubber. The adhesive have good cohesive strength and heat-resistance, and are easily applied by trowelling. [DE1900195A1]

Description

Patent holder: Pfizer Inc., New York (United States of America) Process for the preparation of new acylpenicillins The subject of the invention is a process for the preparation of new penicillins of the general formula I, wherein M is a hydrogen, sodium or potassium atom or a lower trialkylamino group, Rx is a thienyl, furyl, pyridyl group or a phenyl radical, optionally containing a substituent such as a lower alkyl radical, a chlorine or bromine atom, a lower alkoxy or alkylamino group or a trifluoromethyl group, and X' is a group of the formula —OR2 or —SR7, wherein R2 in the formula —OR2 is a hydrogen or sodium atom, a phenyl radical, optionally containing at least one of the substituents such as a chlorine, bromine or fluorine atom, a lower alkyl radical, a lower alkoxy, alkanoyl or a carboalkoxy group, a nitro group or a lower dialkylamino group, a furyl group, a quinolyl group, a methylquinolyl group, a phenazinyl group, a 9,10-anthraquinonyl group, a phenanthrenequinonyl group, anthracenyl group, a phenanthryl group, a 1,3-benzodioxylyl group, a 3-(2-methyl-4-pyronyl) group, a 3-(4-pyronyl) group, a N-methylpyridyl group, a group of the general formula 2, in which Y2 represents a group —CH=CH—O—, —CH=CH—S—, —CH2—CH2—S—, —CH=N—CH==CH—, —CH=CH—CH=CH—, —C(O)—CH=CH— —C(O)— or —C(O)—C(O)—CH-=CH—, or R2 represents a group of the general formula 3, in which Z' is a lower alkylene radical —(CH2)3— or —(CH2)4— optionally substituted with methyl radicals, chlorine or bromine atoms, or R2 is a benzyl radical optionally containing a substituent such as a chlorine or bromine atom, a lower alkyl radical, a lower alkoxy, alkanoyl, carboalkoxy or dialkylamino group, a nitro group, or R2 is a phthalimidomethyl, benzhydryl, trifluoromethylphenyl or cholesteryl group, an alkenyl or alkynyl radical of at most 8 carbon atoms, a cycloalkyl radical, a substituted lower cycloalkyl radical of 3-7 carbon atoms in the ring, a dialkyl group, cyclo[4,4,0]decyl, thujulic, fenchyl, isophenchyl, 7-adamantyl, 2-pyrrolidonemethyl, 4-imidazolylmethyl, 1-indanylmethyl, 2-indanylmethyl, lower (2,2-dialkyl-1,3-dioxolon-4-yl)methyl, furylmethyl, pridylmethyl, acetylindanyl, optionally substituted with a methyl radical or a chlorine or bromine atom, acetyltetrahydronaphthyl group and substituted derivatives thereof, in which the substituent is a methyl radical, chlorine or bromine or R2 is an alkyl radical or a lower alkyl radical containing at least one substituent such as chlorine, bromine, fluorine, a nitro, a lower alkoxy, alkanoyl or carboalkoxy group, a cyano group, a lower alkylmercapto, alkylsulfinyl or alkylsulfonyl group, a group of the formula —CH2—CH2—NR5R6, —CH2—CH2—CH2—NR5R6, —CH2—CH(CH3)—NR5R6, in which formulae the group —NR5R6 denotes a lower alkanoylimino, dialkylamino, alkylamilinoamino or a lower alkyleneacetidine, alkyleneaziridine, alkylenepyrrolidine, alkylenepiperidine, alkylenethiomorpholino, alkylene-N-alkylpiperazine, alkylenepyrrole group, alkyleneimidazole, alkylene-2-imidazoline, alkylene-2,5-dimethylpyrrolidine, alkylene-1,4,5,6-tetrahydropyrimidine, alkylene-4-methylpiperidine or alkylene-2,6-dimethylpiperidine, wherein the lower alkyl radicals in these groups contain 1-4 carbon atoms and the lower alkylene radicals contain 1-3 carbon atoms, and R7 in the formula -SR7 denotes a hydrogen or sodium atom, a phenyl radical, optionally containing 1-3 substituents, of which at least one is a chlorine, bromine or fluorine atom, a lower alkyl radical, a lower alkoxy group or a trifluoromethyl group, wherein in the phenyl ring only one of the ortho positions to The thio group is substituted and the lower alkyl radicals contain 1-4 carbon atoms. The process according to the invention consists in acylating a compound of the general formula IV, wherein M has the meaning given above, at the nitrogen atom with a compound of the general formula V, wherein R' and X' have the meaning given above. Known methods for introducing α-carboxy-arylacetyl groups into amino compounds, such as 6-aminopenicillanic acid, involve the use of simple or mixed acid anhydrides or arylmalonic acid halides. Such acylation reactions, however, must be carried out with extreme caution, and special care must be taken during the isolation of the product in order to prevent decomposition of the carboxyl group and to obtain a good yield of the product. The acylating agents "used in the process according to the invention react with amines quickly, even at low temperatures, and no by-products are formed during the reaction. The arylcarboxyketene or arylcarbotriolketene esters of formula 5 used in the invention are very well suited for the acylation of amines to obtain α-carbothio- and α-carboxyarylacetylamines and are particularly valuable agents for the acylation of 6-aminopenicillanic acid. Many penicillin esters of formula 1 obtained in the process according to the invention show better absorption when administered orally than those compounds used in the form of the corresponding free acid or alkali metal salt. This makes these compounds suitable for the effective use of α-carbothio- and α-carboxyarylpenicillins. Furthermore, many compounds of formula 1 and 2 are particularly suitable for the acylation of 6-aminopenicillanic acid. Formula 1, although inactive or of relatively low activity against gram-negative organisms, metabolizes to the parent acid, e.g., α-carboxybenzylpenicillin, after parenteral administration to an animal or human. Metabolic conversion of such esters to the parent acid occurs at a rate that provides an effective and prolonged concentration of the parent acid in the animal's body. Thanks to this, these esters act as stored sources of the parent acid. Particularly useful in this respect are compounds with an ester group of the formula —COOCH2 CH2Yi, where Y1 is a basic group such as a lower dialkylamino group, a pyrrole group, a pyrrolidino group, a piperidino group, a phthalimido group, an imidazoline group, and a diisopropylamino group. those in which the ester group (—COOR2) contains a tertiary carbon atom, such as tertiary butyl, triphenylmethyl and 2-naphthyl. The acylation of 6-aminopenicillanic acid is carried out at a temperature of about -70°C to about 50°C, preferably at a temperature of 0°C to 30°C. The reaction time is generally from a few minutes to about 5 hours. A reaction-inert solvent such as ethyl acetate, dioxane, tetrahydrofuran, methyl isobutyl ketone, chloroform or methylene chloride generally facilitates stirring and control of the reaction. It has been found particularly convenient to first prepare the arylcarboxy- or aryl-ester. carbothiol ketene of formula V and, without isolating it, use the reaction mixture directly for acylation of the amine. In such a case, an organic base is used, i.e., a tertiary amine, such as triethylamine or another trialkylamine, preferably a lower trialkylamine, which binds the hydrogen chloride evolved during the preparation of the ketene ester. In practice, 6-aminopenicillanic acid is used in the form of its triethylamine salt. For this reason, methylene chloride is the preferred solvent because the triethylamine salt dissolves readily in it. Salts such as the sodium or potassium salt of 6-aminopenicillanic acid can also be used, but the triethylamine salt is preferred because of its greater solubility. An excess of the amine to be acylated can naturally serve to bind the acid, but this is generally not advisable not only for economic reasons but also to prevent possible ammonolysis of the ester group. The reaction is preferably carried out under a nitrogen atmosphere. The N-acylation reaction can also be carried out in a neutral or alkaline aqueous solution, taking into account that the rate of reaction of arylcarboxy- or arylcarbothiolketene esters with neutral or alkaline aqueous solution is slower than the rate of reaction with the amino group. The reaction is carried out at a temperature of 0-50°C, preferably 0-20°C. In order to enable the reaction to be carried out at low temperatures, it is advantageous to use a mixture of solvents, e.g., water and a water-miscible organic solvent such as dioxane or tetrahydrofuran. The resulting ketone ester is preferably used in solution in the same inert solvent and added to an aqueous solution of 6-aminopenicillanic acid. The resulting products are isolated by known methods. For example, a typical method consists in evaporating the reaction mixture to dryness under reduced pressure, dissolving the residue in citrate buffer (pH = 5.5) and extracting the product with chloroform. The chloroform extracts are washed with citrate (pH 5.5), dried over anhydrous sodium sulfate, and evaporated to dryness. Another method, advantageous for isolating acylation products sparingly soluble in methylene chloride or chloroform, involves using n-butanol as the extracting agent instead of chloroform. The product remaining after removal of the n-butanol solvent by evaporation is triturated with ether to obtain an amorphous solid. According to another method, a saturated solution of sodium or potassium hydrogen carbonate is used instead of the citrate buffer, which gives the sodium or potassium salt of the acylation product. To obtain a solid product, the salt is triturated with ether. Another procedure is to add the residue remaining after removal of the volatile compounds from the reaction mixture to water at a pH of 2.3-2.9, preferably about 2.7, and the acylation product in the form of the free acid is extracted from the acidic solution with chloroform, ether, m-butanol or another suitable solvent. The chloroform, ether or n-butanol extract is then washed with an aqueous acid solution at a pH of 2.3-2.9, and the product is isolated by lyophilization or by conversion into a solvent-insoluble salt by neutralization with an n-butanol solution of sodium or potassium 2-ethylhexanoate. The obtained esters are converted by known methods into the corresponding acids: for example, when R2 in formula OR2 is a benzyl or substituted benzyl group, the group is removed by catalytic hydrogenation in a reaction-inert solvent such as water, ethanol, dioxane, at a pH of about 5 to about 9 under near atmospheric pressure at ambient temperature. Preferred catalysts are platinum, rhodium, nickel, and palladium. When R2 is a group other than a benzyl radical, optionally substituted, the group is removed by mild acid treatment or enzymatically by treatment with an esterase, such as homogenized liver. To obtain the free acid form of penicillins, the most preferred ester groups are those in which R2 is a benzyl group. triphenylmethyl, tertiary butyl, and p-diisopropylaminoethyl. These groups are readily removed by mild acid treatment and satisfactory yields of penicillin acid are obtained. The compounds obtained by the process of the invention are valuable products, effective in treating a variety of gram-positive and gram-negative infections in animals and humans. For this purpose, these compounds can be used alone or mixed with other antibiotics. These compounds can be used directly or in combination with pharmaceutical carriers, in accordance with pharmaceutical practice. They can therefore be administered orally in the form of tablets containing additives such as starch, lactose, certain types of clay, etc., or in capsules—alone or mixed with such They can also be administered orally in the form of elixirs or suspensions, which may contain flavoring, flavoring, or coloring agents, or parenterally, e.g., intramuscularly or subcutaneously. For parenteral administration, sterile aqueous solutions are the preferred drug form. The medium in these solutions may be, in addition to water, isotonic saline, isotonic dextrose solution, Ringer's solution. For injection, non-aqueous vehicles such as fatty oils of vegetable origin (cotton seed oil, peanut oil, corn oil, sesame oil) and other non-aqueous vehicles that do not reduce the therapeutic effect of the preparation and are not toxic in the used form can also be used. volume or amount ^Meerol, r propylene glycol, sorbitol). In addition, the formulations include compositions suitable for the preparation of solutions before use. Such compositions may contain liquid diluents, e.g., propylene glycol, diethyl carbonate, glycerol, sorbitol, etc., buffering agents, and local anesthetics and inorganic salts to achieve the desired pharmacological properties. Oral and parenteral dose levels of the compounds described above are in the order of up to 200 mg/kg and 100 mg/kg of body weight, respectively. The antibacterial spectra of numerous tt-karr esters of boxoxybenzyl ipenicillins against Staphylococcus aureus and Escherichia coli are given below. Tests were conducted under standard conditions, in whose broth medium containing various concentrations of the compounds under test was inoculated with a specific organism, and the minimum rate of development (MIC), i.e., the development of organisms that is no longer detectable, was observed and recorded. Compounds with the lower substituents (R2) were tested. These compounds were tested in the form of their sodium or potassium salts. Tests were carried out with benzylpenicillin (K salt) against S. aureus and Es- Table I — in vitro spectra of R2 \^^^^ : J ' 1-'naphthy 1 5H(1,3-benzodioxolyl) 2-naphthy 1: 6-quinolyl 3-(2-methyl-4-pyronyl) H phenyl o-methylphenyl m-.methylphenyl p-methylphenyl o-ethylphenyl o-isopropylphenyl o-formylphenyl o-acetylphenyl p-acetylphenyl • « 1 o-nitrophenyl 2,3-dimethylphenyl 3,4-dimethylphenyl 2,3-dimethoxyphenyl 2-chloro-5-methylphenyl 4-chloro-3-methylphenyl 2-chloro-3,5-dimethylphenyl 2-chloro-3,4-dimethylphenyl 2-chloro-4,5-dimethylphenyl 4-chloro-2,3-dimethylphenyl 4-chloro-2,5-dimethylphenyl 4-chloro-2,6-dimethylphenyl 2,4-dichloro-6-methylphenyl 2,4-dichloro-3,5-dimethylphenyl 1 S. aureus | 2 0.39 3.12 1.56 1.56 0.78 1.25 3.12 0.78 [ 0.78 0.39 0.39 0.39 1.56 50 25 25 0.78 0.78 1.56 3.12 1.56 1.56 1.56 0.39 0.19 0.19 0.19 0.39 1.56 1 3 E. coli 1 3 6.25 1 25 12.5 1 50 50 3.12- 26 123 J 6.25 ' 6.25 1 - 25 12.5 25 200 200 200 50 25 50 3.12 1.56 1.56 3.12 0.39 0.19 0.39 0.19 0.39 3.12 17 80 571 8 continued from Table I 1 1 4,5-dichloro-2,3-dimethylphenyl 4-chloro-2-nitrophenyl 1-(1,2,3,4-tetrahydronaphthyl) 2-(1,4-naphthoquinonyl) 4-indanyl 5-indanyl 5-quinolyl x 8-quinonyl methyl ethyl 1 n-propyl f n-butyl [sec. butyl 2-methylpropyl hexyl octyl decyl tetradecyl 2-cyanoethyl 2-methoxyethyl 2-acetoxyethyl 1n(1-carboethoxy)ethyl 2-ethoxy)- n-propyl 2-chloroethyl 2,2,2-trichloroethyl 2,2,2,-trifluoroethyl 2-(2-trifluoromethyl)-propyl 1-ethoxy-2,2-trifluoroethyl 1-ethoxy-2,2,2-trichloroethyl 1-isopyropoxy-2,2,2-trichloroethyl 1-butoxy-2,2,2-trichloroethyl carboethoxyethoxymethyl dicarboethoxyethoxymethyl 1-(2,3-dibutyryloxy)-propyl 3-ketobutyl 1,1-dimethylaminoethyl 2-nitrobutyl 2-dimethylaminoethyl 2-dimethylaminoethyl 2-dimethylaminoethyl 2-dimethylaminopropyl ...ethyl 2-dimethylaminopropyl 2-dimethylaminoethyl 2-dimethylaminoethyl 2-dimethylaminopropyl 2-dimethylaminoethyl 2-dimethylaminoethyl 2-dimethylaminopropyl 2-dimethylaminoethyl 2-dimethylaminoethyl 2-dimethylaminoethyl 2-dimethylaminoethyl 2-dimethylaminopropyl 2-dimethylaminoethyl 2-dimethylaminoethyl 2-dimethylaminoethyl 2-dimethylaminoethyl 2- 3-di-(n-propyl)-amino-2-propyl 2-pyrrolidinoethyl 2-(2-imidazoline)-ethyl 2-(2,5-dimethylpyrrolidino)-ethyl 2-(4-methylpiperidino)-ethyl 3-(pyrrolidino)-propyl 3-piperidipropyl 3-morpholinopropyl 3-pyrrolidino-2-propyl 3-piperidino-2-propyl 2-aziridinoethyl 2-pyrrolidino-1-propyl 2-alpha-ethidinoethyl » 2-piperidino-1-propyl 2-(2-dimethylpiperidino)-ethyl 2-morpholino-1-propyl 2-di(nH-propylamino)-1-propyl 2-(N-methylamilino)-ethyl 3-di(n-propylamino)propyl 3-dimethylamino-2-propyl 3-morpholino-2-propyl isopropyl tert. butyl crotyl 2-imidazoleethyl (2,2-dimethyl-1,3-dioxo- lon-4-yl)-methyl 2 ¦ 0.04 25 0.39 12.5 0.39 0.39 1.50 1.56 0.625 1.25 6.25 50 3.12 3.12 200 200 200 200 1.9 3.12 3.12 100 1.66 50 100 1.56 0.78 0.78 0.78 1.56 0.39 25 1.56 500 50 200 100 1.56 0.78 0.78 1.56 0.78 0.78 0.39 0.78 1.56 1.56 0.19 0.19 1.56 1.56 0.39 0.39 50 0.78 3.12 0.78 1.56 . 3.12 1.56 0.39 0.19 1.56 1.56 6.25 1.56 1.56 0.39 3 1 0.09 200 12.5 200 6.25 6.25 50 50 50 100 200 200 200 100 —* 200 200 200 6.25 100 200 200 200 200 200 25 200 50 12.5 100 50 100 50 200 200 20 200 50 1 12.5 | 6.25 100 12.5 25. 3.12 6.25 50 ; 12.5 6.25 12.5 12.5 6.25 3.12 1.56 -— . 6.25 100 6.25 12.5 60 6.25 100 12.5 25 6.25 200 100 200 50 50 from Table I 1 1 , benzhydryl 2-carboethoxyethyl 4-quinolyl 2-(4-methylquinolyl) 1-butynyl-4-triphenylmethyl phthalimidomethyl 2-pyridylmethyl 4-pyridylmethyl pyrrolidonemethyl propargyl 4-imidazolylmethyl p-methoxyphenyl p-methoxyphenyl (NEP salt)(a) 6-chloro-2-methylphenyl 6-chloro-2-methylphenyl (NEP salt) 4-chloro-2-methylphenyl 4-chloro-2-methylphenyl (NEP salt) 4-chloro-3,5-dimethylphenyl 4-chloro-3,5-dimethylphenyl (NEP salt) 4-chloro-2,3,5-trimethylphenyl 1,1-dimethyl-2,2,2-trifluoroethyl m-fluorophenyl 4-chloro-2,6-dinitrophenyl 6-chloro-2,4-dinitrophenyl 2,5-dimethylphenyl 2,5-dimethylphenyl (NEP salt) 3,5-dimethylphenyl | 3,5-dimethylphenyl* (NEP salt) and 2,4-dimethylphenyl 2,4-dimethylphenyl (NEP salt) 2,6-dimethylphenyl 2,6-d.dimethylphenyl (NEP salt) m-ethylphenyl m-ethylphenyl (NEP salt) methoxyphenyl p-ethoxyphenyl 4,6-dibromo-2-,methylphenyl 2,6-dibromophenyl 2-methoxy-4-methylphenyl 2-methoxy-4-methylphenyl (NEP salt) 4-chloro-2,3-diethylphenyl 2-methyl-3-methoxyphenyl 2-methyl-3-methoxyphenyl (NEP salt) 4H(a,a-dimethylbenzyl)- -phenyl 5-ethyl-3-methylphenyl 4-(1-indanyl)-phenyl 2,4-(dicyclopenphen-2-yl)-phenyl p-fluorophenyl p-carbomethoxyphenyl p-carb-n-propoxyphenyl 2-(5,6,7,8-tetrahydronaphthyl) 2-(5,6,7,8-tetrahydronaphthyl) {NEP salt) p-carbonoctyldoxyphenyl m-dimethylaminophenyl p-dimethylaminophenyl o-ipropylphenyl p-propylphenyl 2,4-dibromophenyl 2-i(N-methylanilino)-ethyl 7-adamantanyl 2-isopropoxyethyl 2-piperidinoethyl 2-Morphinoethyl 3-(N-methoxyanilino)-2-propyl (NEP salt) 3-(N-ethylanilino)-2-propyl 1 (NEP salt) ' 2 - 0.78 100 3.12 3.12 3.12 1.56 0.78 1.56 0.39 0.19 0.78 1.56 0.19 0.39 0.39 0.04 0.78 0.09 1.56 - 0.39 0.045 0.19 0.78 1.56 3.12 0.39 0.04 0.78 0.09 0.09 0.04 0.39 0.01 1.56 0.39 3.12 3.12 0.19 3.12 0.39 0.04 0.19 0.39 0.09 0.78 0.39 0.78 0.005 1.56 0.78 0.78 0.39 0.04 0.39 0.78 1.56 0.19 0.39 1.16 0.19 0.09 1.56 0.78 1.56 0.09 0.09 3 12.5 200 200 100 200 25 12.5 25 25 25 25 100 12.5 3.12 25 6.25 50 3.12 25 3.12 6.25 50 ' 12.5 200 200 6.25 3.12 6.25 3.12 3.12 3.12 25 12.5 3.12 3.12 25 12.5 I 6.25 25 12.5 3.12 25 12.5 6.25 25 12.5 50 12.5 50 12.5 12.5 3.12 1.56 50 12.5 12.5 25 12.5 25 25 50 200 3.12 6.25 25 25 18© 57* In Ir; and 2-,(N-ethylanilino)-ethyl (NEP salt) l-methoxy-2,2,2-trichloroethyl dicarbamethoxyethoxymethyl | o-ethoxyphenyl (NEP salt) 2-n-butoxyethyl 2-isopropoxyethyl m-acetylphenyl 2-isopropylmercaptoethyl 5-4-indanyl (TEA salt)(b and 5-indanyl (morpholine salt) cont. of Table I ' 2 !" | 3 | i ^ ¦ 100 6.25 116 0.39 IM 6.25 3.12 0.05 0.05 | ]2£ . 20Q 50 6.25 | 50 1 200 12.5 200 6.25 1.56 | cont. of Table II of chlorophyll a-carbathiolpenicillin esters showed the corresponding values of 0.156100. In vitro spectra of chlorophyll a-carbathiolpenicillin esters The values are given below: 1 R7 phenyl p-chlorophenyl o-isopropylphenyl for R1 = p-chlorophenyl and R2 = 2-naphthyl | (b)TEA = triethylamine | Saureus 6.25 3.12 6.25 1.56 E. coli 25 . 25 100 200 | Table II presents data from in vivo studies conducted in mice with numerous compounds obtained by the method of the invention (PO denotes oral administration, SQ — subcutaneous administration). The values given are obtained under standardized conditions. The procedure consists in inducing an acute experimental E. coli 266 infection in mice by intraperitoneal inoculation of the mice with a standardized (10~e) culture of E. coli 266. as a 5% suspension in pig stomach mucosa. The compounds under test, in the form of their sodium or potassium salts, are administered to infected mice in multiple doses, with the first dose given 0.5 hour after inoculation and subsequent doses given 4, 24, and 48 hours later. The percentage of mice remaining alive is then determined. The LD100 of E. coli 266 (the lowest concentration required to cause 100% mouse mortality) is 10-7. Control animals receive Table II Data from in vivo studies on mice infected with E. coli 266 1 1-carboethoxyethoxyethyl dicarboethoxyethoxymethyl 1-isopropoxy-2,2,2-trichloroethyl l-butoxy-2,2,2-tri- chloroethyl 1-naphthyl % Survival PO mg/kg 200 2 0 30 20 10 30 100 3 20 0 20 20 20 SQ mg/kg | 200 4 0 60 40 0 30 100 | 5 10 40 30 10 1 o 1 15 30 25 40 45 50 55 60 65 1 2-naphthyl 5-indanyl 5-4-indanyl (TEA salt) 4-indanyl 5^€hinoMl; ? e^hijnoHl 5-(1,3-benzodioxolyl m-methylphenyl pemethylphenyl; o^methylienyl ethylphenyl or isopropylphenyl 2,3-dimethylphenyl 3,4-dimethylphenyl 4-methoxyphenyl 2,6-dimethoxyphenyl m-fluorophenyl 2-trichloro-6-methylphenyl 4-chlora-2H-methylphenyl 2-chloro*5-methylphenyl 4-chlorQ*5-methylphenyl 4-chloro-3-methylphenyl 2-chloro-3,4-dimethylphenyl 4-chloro-3,5-dimethylphenyl 4-chloro-2,3-dimethylphenyl 4-chloro-2,6-dimethylphenyl 2-chloro-4,5-dimethylphenyl 4-chloro-2,5-dimethylphenyl 2,4-dichloro-6-methylphenyl 2,4-dichloro-3,5- 4-dimethylphenyl 4-chloro-2,3,5-trimethylphenyl 4-chloro-2,6-dinitrophenyl phenyl 2-dimethylaminoethyl 2-diethylaminoethyl 2-di-{n-propyl)-aminoethyl 2-di-(isopropyl)-aminoethyl 2-di-(n-butyl)-aminoethyl 3-dimethylaminopropyl 3-di(n-propyl)-amino-2-propyl 2-pyrrolidinoethyl 2n(2-imidazolino)-ethyl 2-piperidinoethyl 2-morpholinoethyl 2-(2,5-dimethylpyrrolidino)-ethyl 2-(4-methylpiperidino)-ethyl 3-(prodrolidino)-propyl 3-piperidinopropyl 3-morpholinopropyl 3-pyrrolidino-2-propyl 3-piperidino-2-propyl 2-pyrrolidino-1H-propyl 2-azetidinoethyl 2-piperidino-1-propyl 2-(2,6-dimethylpiperidino)-ethyl 2-dimorphino-1-propyl 2-di(n-propylamino)-1-propyl 2-(N-methylanilino)- 40 100 100 80 10 20 30 70 30 30 20 90 80 80 20 10 70 30 40 0 70 70 20 60 90 10 20 10 50 60 10 0 0 D 20 20 10 0 10 0 30 0 0 0 0 0 10 10 10 10 0 60 70 50 0 20 20 30 20 0 10 60 10 30 10 0 20 10 0 0 10 20 10 60 10 20 0 10 10 50 0 0 0 0 10 0 10 0 10 0 10 0 0 30 10 50 70 100 40 50 10 30 80 20 Ó 10 50 80 50 40 0 50 40 20 30 60 60 30 60 90 30 70 10 10 70 80 20 10 IOW It) 90 40 90 30 70 80 40 80 30 60 60 80 100 80 70 90 80 0 80 100 40 90•n 80 571 12 1; -• 1 -ethyl . - 3-di-(n-propylamino)-propyl 3-dimethylamino-2- -propyl 3-improlino-2-propyl 2-formamidoethyl H 2-chloroethyl 2-imidazoloethyl p-acetylphenyl 2-a-cetoxyethyl (2,2-dimethyl-1,3-trioxolon-4-yl)- methyl benzhydryl acetoylpimethyl 2-tritripbutyl; 2-(1,4-naphthoquinoline) 2-(4-methylquinoline) phthalimidomethyl 2,3-dimethoxyphenyl 2-pyridylmethyl 4-pyridylmethyl 2-formylphenyl 3-(2-methylethyl)-4-pyronyl) propargyl 1-ethoxy-2,2,2-trichloroethyl 4-imidazolylmethyl 5-indanyl(NEP salt) o-isopropylphenyl o-ethylphenyl(NEP salt) (1,2,3-triscarboethoxy)- -2-propyl 1-yl-d-dimethyl-2,2,2- -trifluoroethyl 2,2,2-trifluoroethyl 6-chloro-2,4-dinitrophenyl 2,5-dimethylphenyl ., 3,5-dimethylphenyl 2,4-dimethylphenyl 2,6-dimethylphenyl m-ethylphenyl m-ethoxyphenyl p-ethoxyphenyl 4,6-dibromo-2-methylphenyl 2,6-dibromophenyl 2-methoxy-4-methylphenyl 2-methyl-2-methoxyphenyl 5-ethyl-3-methylphenyl (1-indainyl)-phenyl 2,4-(dicyclopent-2-enyl)-phenyl p-fluorophenyl p-carbomethoxyphenyl p-carbo-n-propoxy-phenyl 2-(5,6,7,8-tetrahydronaphthyl) 2-(5,6,7,8-tetrahydronaphthyl)(NEP salt) p-carbo-n-octyloxy-phenyl -dimethylamino- phenyl p-dimethylamino- phenyl p-propylphenyl 2,4-dibromophenyl 2-(N-methylanilino)- 1-ethyl 2 ., 40 0 0 0 20 — 10 0 0 0 0 0 10 10 0 0 20 10 0 0 0 0 70 20 100 80 20 0 20 10 0 80 80 90 20 90 0 60 0 0 100 30 40 20 70 0 0 0 100 20 60 70 80 60 70 3 0 0 0 10 0 0 0 0 0 0 0 0 0 0 0 10 0 0 0 0 0 0 0 10 70 50 10 10 0 0 0 70 60 20 0 60 0 10 0 10 50 0 0 10 10 0 0 0 60 42 0 50 0 20 30 40 cont. tat ': and ... 80 80 20 70 20 -^ 10 40 10 0 30 50 0 0 20 3Q 30 0 10 40 80 30 100 70 30 100 40 10 10 60 20 30 90 80 80 70 100 10 70 10 60 100 40 30 10 60 60 80 60 50 40 70 80 80 50 50 licy II 5 '10 90 20 20 10 70 0 0 0 10 ¦ io ¦ 10 10 0 0 0 0 20 0 20 0 U 30 20 10 100 20 0 0 - 20 ' 0 0 60 | 30 | 50 50 70 0 50 0 40 50 30 10 20 30 10 20 20 30 ' 19 0 40 80 80 30 0 10 15 25 45 50 1 1 ' 3-(N-methylanilino)-2-propyl (salt NEP) 3H(N-ethylanilino)-2- . -propyl (NEP salt) 2-(N-ethylanilino)- -ethyl 1-methoxy-2,2,2-trichloroethyl dicarbomethoxyethoxymethyl o-ethoxyphenyl 2-n-butoxyethyl 1 2-isopropoxyethyl m-acetylphenyl 2-isopropylmercaptoethyl 5-indanyl imorpholine salt 2 0 0 90 0 10 0 100 3 135 100 60 10 0 25 0 0 0 0 70 continued from table 11 4 0 • 40 70 40 60 20 100 5 1 87 50 50 0 20 37 6' 30 20 0 100 of the infecting agent in amounts of 10-5, 10-6 and 10-7 as a test for possible change in virulence. The following data refer to the compound of formula 1, in which R1 is a phenyl radical and X* is a group of formula SR7, in which R7 has the meanings given below. Studies on mice infected with E. coli 266 R7 and phenyl p-chlorophenyl o-isopropylphenyl (a) 150 mg/kg (b) 75 mg/kg (c) 50 mg/kg % remaining alive PO/mg/kg 200 2 0 0 10 100 3 0 20 0 SQ/mg/kg 200 4 60 60 30 100 5 20 0 Table III gives the results of tests for a number of compounds of formula I using the infrared spectral analysis method and the chromatographic method, where the symbol X denotes that the solution of the compound was tested in chloroform, while the remaining compounds were tested in potassium bromide tablets. The chromatographic systems used in the tests were as follows: (a) chloroform : 95% ethanol : formic acid (2:1:2) (b) benzene : acetic acid : water (2:2:1) (c) butanol : water : acetic acid (5:4:1) (d) lysoamyl acetate : sodium acetate (0.1 mol, pH 4.5) (e) pyridine : toluene : water (5:20:10; McIvaines buffer, pH 3.0) Table III Test results in infrared and chromatographic studies Hf 1 isopropyl tert. butyl 2-cyanoethyl * 2-methoxyethyl 2-chloroethyl kn-1-yl 2-imidazoloethyl p-acetylphenyl * 2-acetoxyethyl * 2-acetylphenyl 2-piperidinoethyl * 1,2-dimethyl-1,3-dioxolo(n-4-yl)-methyl benzhydryl * 2-dimethylaminoethyl * 2-pyrrolidinoethyl * 2,2,2-trichloroethyl * 3-oxobutylacetonylmethyl 2-nitrobutyl 2-carboethoxyethyl * 1,1-dimethylacetonyl * 2-diethylaminoethyl 2-pyridylmethyl 1 o-nitrophenyl * 4-chloro-2-nitrophenyl * 4-pyridylmethyl 3-dimethylaminopropyl 2-naphthyl pyrrolidonemethyl 2-di-n-propylaminoethyl 2-di-n-butylaminoethyl 2-diisopropylaminoethyl 2-(2,5-dimethylpyrrolidino)-ethyl 2-formylphenyl * 3-(2-methyl-4-pyronyl)-propargyl 2-aziridinoethyl 1-ethoxy-2,2,2-trichloroethyl 3-diHn-propylamino- 2-propyl 2-,{4-1-methylpiperidino)-ethyl 3-pyrrolidino-2-pyrropyl 3-piperidino-2-pyropyl 3-pyrilidine-2-pyropyl 3-pyrilidine-propyl * 1-(2,3-dibutyryl*-oxy)-propyl 4-imidazolylmethyl * 5-(1,3-benzodioxolyl) * 5-(1,3-benzodioxolyl) (NEP salt) 5-indanyl * (potassium salt) 5-indanyl * 5-indanyl * (TEA salt) 5-indanyl (morpholine salt) 5-indanyl * (NEP salt) 6-quinolyl * 5-quinolyl 4-quinolyl * 2-(1,4-naphthoquinolyl) 2-(4-methylquinolyl) 1-butyn-4-yl 3-piperidinopropyl 3-morphodinopropyl LR. , 2 3.05, 5.61, 5.75, 5.92, 6.0, 6.25, 6.55—6.6 3.05, 5.61, 5.74, 5.82, 5.97, 6.07 2.98, 4.45, 5.58, 5.68, 5.73, 6.23 3.0, 5.58, 5.72, 5.78, 5.91, 3.05, 5.61, 5.73, 5.80, 5.95, 6.25 3.0, 3.2—3.26, 3.83, 3.99, 5.62, 5.72, 5.78 (inflection 5.97) 3.05, 5.63, 5.71, 5.95, 6.25 3.05, 5.61, 5.75, 5.80, 5.95, 6.00, 6.24 2.98, 5.63, 5.73, 5.95, 6.0, 6.25 3.0, 5.65, 5.76, 5.98, 6.25 3.05, 5.61, 5.71, 5.75, 5.91, 6.06, 6.25 3.05, 5.62, 5.75, 5.78, 5.95, 6.25 3.0, 5.63, 5.70, 5.75, 5.84, 5.95, 6.25 3.0, 5.66, 5.76, 5.98, 5.97 3.35, 5.5, 5.73 (overkill) 5.92, 6.25, 6.98 3.36, 4.08, 4.32, 5.13, 5.21, 5.25, 5.33, 5.37, 5.63 (inflection) 1 5.8, 5.97, 6.06, 6.25, 6.67, 6.89 3.35, 3.4, (inflection), 3.45, (inflection), 4.1, 4.3, 5.13, 5.23, 5.35, 5.45, 6.06, 6.25, 6.45, 6.78, 6.92 3.36, 5.78, 5.97, 6.25, 6.62, 6.78, 7.09 3.35, 5.14, 5.63, 5.8, 6.02, 6.26, 6.55, 6.69 3.0, 5.63, 5.78, 5.95 3.05, 5.65, 5.78, 6.0, 6.10, 6.3 3.08, 3.35, 4.33, 5.25, 5.39, 5.63, 5.97, 6.23, 6.27, 6.62, 6.78, 6.99 3.34, 5.43, 5.49, 5.67, 5.85, 5.97, 6.09, 6.21, 6.29, 6.56, 6.80, 6.89 7.1 2.97, 5.58—5.70, 5.92, 6.55 2.87, 5.6, 5.72, 5.92, 5.98, 6.5 (br) 3.05, 5.65, 5.71, 5.77, 5.97, 6.15, 6.25 3.0, 4.18, 6.0, 5.73, 5.97, 6.19, 6.25 3.0, 5.66—5.79, 5.97, 6.25, 2.95, 3.35, 4.1, 5.7, 5.86, 5.95, 6.2, 6.65, 6.8, 7.15 2.9, 3.35, 5.7, 4.0, 5.65, 5.7, 6.05, 6.27, 6.7, 6.83, 6.95, 7.15, 7.25 2.98—3.00, 5.68 (Br), 5.83, 6.01, 6.25 3.0 (Br, W), 5.66, 5.73, 5.80, 6.0, 6.25 3.0 (Br, W), 5.66, 5.72, 5.99, 6.27 3.05, (Br, W) 5.63, 3.75, 5.97, 6.25 2.95, 3.35, 4.05, 5.73, 5.95, 6.0, 6.2, 6.75, 6.85, 7.2 2.7, 2.95, 3.35, 4.05, 4.25, 5.6, 5.75, 5.95, 6.2, 6.75, 6.85, 7.2 2.95, 3.45, 5.6, 5.9, 6.15, 6.6, 6.7, 6.8 3.36, 3.51, 5.63, 5.97, 6.21, 6.63, 6.71, 6.78, 7.14 2.95, 3.35, 5.55, 5.7, 5.9, 6.2, 6.7, 6.8, 6.9, 7.15 2.95, 3.35, 5.62, 5.95, 6.20, 6.72, 6.85, 7.15 2.95, 3.4, 3.45, 4.1 (W), 5.6, 5.73, 5.9, (inflection), 5.95, 6.2, 6.72, 6.85, 7.25 2.95, 4.5, 5.6, 5.7, 5.92, 6.18 2.95, 3.35, 4.0, 5.55 (inflection) 5.65, 5.95, 6.10, 6.20, 6.60, 6.75, 7.25 2.95, 3.05, 3.35, 5.60, 5.80, 5.95, 6.07, 6.25, 6.68, 6.85, 7.35 2.9, 3.35, 5.7, 6.0, 6.25, 6.3, 6.50, 6.80, 7.1 2.92, 4 (Br, W), 5.6, 5.7, 5.75, 5.87, 5.92, 6.17, 6.5 Rf 3 0.2(a) 0.45(b) 0.6(b 0.9(b 0 0.35 0.3(b) 0.8(b 0.05(b) 0.45(b) 0.95 0 0 0.6 0.6 0.6(b) 0.6(b) 0.6(b) 0 0.9(b) 0.&(b 0(b) 0.6(b) 0.95(b) 0.05(b) 0(b) 0(b) 0(b) 0.85(b) 0(b) 0(b) 0(b) 0.75(b) 0.7 0(O 0.9 1.0(c 0.75(b) 0.75(b) 1.0(c) Q(b) Q(b)80 571 15 16 continued from Table III 3-morpholino-2-propyl 3-dimethylamino-2-propyl 2-pyrrolidino-1-propyl 2-azetidinoethyl triphenylmethyl * 1-ethoxy-2,2,3-trifluoroethyl' phthalimidomethyl * 2,3-dimethoxyphenyl * 3-di-n-propylamino-propyl * m-tolyl * o-isopropylphenyl * o-isopropylpheny 1 (potassium salt) 1-naphthyl* 4-indanyl * 4-indanyl (NEP salt) p-tolyl * o-ethylphenyl * o-ethylphenyl (NEP salt) o-tolyl * o-tolyl * (NEP salt) (1,2,3-tricarboethoxy)-2- -propyl 2-piperidino-1-propyl 2-(2,6-dimethylpiperidino)-ethyl 2-morpholino-1-propyl 2-di-n-propylamino- -1-propyl 2-(N-methylanilino)-ethyl 3,4-dimethylphenyl 3,4-dimethylphenyl (NEP salt) 2,3-dimethylphenyl 2,3-dimethylphenyl (NEP salt) p-methoxyphenyl * p-imethoxyphenyl * (NEP salt) 6-chloro-2-methyl-phenyl * 6-chloro-2-methylphenyl (NEP salt) 4-chloro-2-methylphenyl * 4-chloro-2-methylphenyl (NEP salt) 2-chloro-3,4-dimethyl-phenyl * 2-chloro-5-methylphenyl * 2-chloro-5-methylphenyl (NEP salt) 4-chloro-3,5-dimethylphenyl 4-chloro-3,5-dimethyl-phenyl * 4-chloro-3,5-dimethyl-phenyl (NEP salt) 4-chloro-2,3-dimethyl-phenyl * 4-chloro-2,3-dimethyl-phenyl (NEP salt) 4-chloro-2,6-dimethyl-phenyl * 2-chloro-4,5-dimethyl-phenyl * 2,4-dichloro-6-methylphenyl * 2,4-dichloro-3,5-dimethylphenyl * 4-chloro-2,3,5-trimethylphenyl * 1-n-ibutoxy-2,2,2-trichloroethyl dicarboethoxyethoxymethyl carboethoxyethoxymethyl m-fluorophenyl 2.9, 5.6 (W), 5.12, 5.92, 6.05, 6.22 2.9, 5.57,5.70,5.85,5.92,6.2, 6.6 3.05, (Br), 5.66—5.75 (Br), 5.81, 5.95, 6.23 2.95, 3.35, 5.1, 5.5, 5.7, 5.9, 6.1, 6.25, 6.5, 6.65, 6.85, 7.15 2.95, 3.35, 5.55, 5.9, 6.2, 6.54, 6.85, 7.15 2.95, 3.35, 5.55, 5.70, 5.90, 6.20, 6.60, 6.80, 7.15 2.95, 3.35, 3.50, 5.65, 5.9, 6.2, 6.25, 6.65, 6.70, 7.15 3.5 (br), 5.63, 5.77, 5.97, 6.20 3.05, 5.65, 5.72, 5.97, 6.22, 6.32 3.05, 5.65, 5.75, 5.97, 6.27, 6.65 3.0, 5.65, 5.72, 5.93, 6.23 2.95, 3.35, 5.55, 5.70, 5.90, 6.20, 6.30, 6.65, 6.80, 7.15 2.95, 3.35, 5.55, 5.70, 5.90, 6.20, 6.27, 6.67, 6.80, 7.15 2.95, 3.10, 3.35, 5.60, 5.90, 6.17, 6.45, 6.75, 7.15 2.95, 3.35, 5.59, 5.70, 5.9, 6.20, 6.65, 6.85, 7.15 2.95, 3.35, 5.60, 5.72, 5.92, 6.24, 6.55, 6.70, 6.85, 7.15 2.97, 4.5 (Br), 5.6, 5.7, 5.93, 6.20 2.95, 3.35, 5.60, 5.70, 5.92, 6.20, 6.30, 6.68, 6.85, 7.15 2.95, 3.35, 4.5 (Br), 5.6, 5.69, 5.92, 6.15 3.0, (Br), 5.65, 5.8, 6.0, 6.2, 6.28 . 2.92, 5.6, 5.68, 5.82, 5.95, 6.2 2.9, 5.6, 5.7, 5.87, 5.93, 6.20 2.9—2.95, 5.62, 5.70, 5.85, 5.97, 6.23 2.95, 4 (Br), 5.62, 5.72, 5.9, (inflection), 5.95, 6.20 2.97, 4.0 (Br), 5.6, 5.72, 5.87, (inflection), 5.95, 6.23 3.0, 5.62, 5.7 (inflection), 5.9, 5.195, 6.24 2.90, 3.10, 3.35, 4.20, 5.60, 5.90, 6.20, 6.42, 6.65, 6.85, 7.15 2.95, 5.6 (Br), 5.87, 5.95, 6.23 2.95, 3.10, 3.35, 5.62, 5.90, 6.20, 6.45, 6.65, 6.77, 6.85, 7.15 - 2.95, 3.35, 3.50, 4.10, 5.60, 5.70, 5.9, 6.20, 6.65, 6.85, 6.92, 7.15 3.0, 4.5 (Br), 5.65, 5.75, 5.95, 6.22 2.95, 3.35, 5.55, 5.90, 6.20, 6.65, 6.80, 7.15 2.95, 3.15, 3.40, 4.45, 5.65, 5.92, 6.23, 6.45, 6.67, 6.85, 7.15 2.95, 3.35, 5.69, 5.90, 6.10, 6.20, 6.45, 6.72, 6.92, 7.2 2.90, 4.2 (Br), 5.62, 5.92, 6.13, 6.20, 6.40 2.95, 3.35, 5.55, 5.9, 6.23, 6.65, 6.77, 6.80, 7.15 2.95, 3.35, 5.60, 5.9, 6.25, 6.45, 6.70, 6.90, 7.15 2.95, 4.2 (Br), 5.62, 5.97, 6.27, 6.40 2.95, 3.35, 5.60, 5.90, 6.20, 6.65, 6.85, 7.15 2.95, 3.35, 5.60, 5.90, 6.10, 6.20, 6.50, 6.80, 7.15 2.95, 3.15, 3.35, 4.25, 5.65, 5.95, 6.25, 6.40, 6.48, 6.65, 6.77, 6.88 7.15 2.95, 3.35, 5.60, 5.9, 6.20, 6.65, 6.80, 7.15 2.95, 3.10, 3.40, 5.65, 5.90, 6.20, 6.45, 6.65, 6.85, 7.15 2.95, 3.37, 5.60, 5.90, 6.23, 6.30, 6.65, 6.80, 7.20 2.95, 3.37, 5.60, 5.90, 6.25, 6.45, 6.68, 6.87, 7.20 ,2.95, 3.37, 5.60, 5.90, 6.25, 6.45, 6.65, 6.65, 6.82, 7.15 2.95, 3.37, 5.60, 5.95, 6.25, 6.65, 6.85, 9.2 2.95, 3.40, 5.62, 5.93, 6.10, 6.20, 6.65, 6.85, 7.2 3.0 (Br), 0.63, 5.70, 5.88, (inflection), 5.95, 6.2380 571 17 18 cont. Table III 1 4-chloro-2,6-dinitrophenyl 6-chloro-2,4-dinitrophenyl 2,5-dimethylphenyl 2,5-dimethylphenyl (NEP salt) 3,5-dimethylphenyl * 3,5-dimethylphenyl (NEP salt) 2,4-dimethylphenyl 2,4-dimethylphenyl * (NEP salt) 2,6-dimethylphenyl 2,6-dimethylphenyl (NEP salt) m-ethylphenyl m-ethylphenyl (NEP salt) m-ethoxyphenyl p-ethoxyphenyl 4,6-dibromo-2-methylphenyl 2,6-dibromophenyl 2-methoxy-4-methylphenyl * 2-methoxy-4-methylphenyl (NEP salt) 4-chloro-2,3-diethylphenyl* 2-methyl-3-methoxyphenyl * 2-methyl-3-methoxyphenyl (NEP salt) 4-(a,a-dimethylbenzyl)- -phenyl * 5-ethyl-3-methylphenyl * 4- 2,4-(dicyclopenten-2-yl)- -phenyl * p-fluorophenyl * p-carbomethoxy p-carbo-n-propoxyphenyl * 2-(5,6,7,8-tetrahydro- naphthyl) * 2-(5,6,7,8-tetrahydro- naphthyl * (NEP salt) p-carbo-n-octyloxyphenyl * m-dimethylaminophenyl * p-dimethylaminophenyl o-propylphenyl * p-propylphenyl * 2,4-dimbromophenyl * p-tert. butylphenyl 2-(N-methylanilinoethyl) * 2-(N-methylanilino)-ethyl (NEP salt) 3-(N-methylanilino)- -2-propyl * (NEP salt) 3-i(N-ethylanilino)- -2-propyl * (NEP salt) 2-(N-ethylanilino)-ethyl (NEP salt) 1-methoxy-2,2,2-trichloroethyl dicarbomethoxymethyl o-ethoxyphenyl 2-n-butioxyethyl 2-isopropoxyethyl * m-acetylphenyl * 2-ethoxyethyl * 8-quinolyl * 2-isopropylmercaptoethyl 5-quinolyl methyl ethyl n-hexyl n-octyl n-decyl I ! 2 3.0 (Br), 5.61, 5.66, 5.95, 6.12, 6.19, 6.23 3.0 (Br), 5.62, 5.97, 6.0, 6.25 3.0, 5.63, 5.71, 5.90, 5.95, 6.17 2.95, 4.5 (Br), 5.6, 5.7, 5.92, 6.3 2.98, 5.63, 5.73, 5.91, 6.16, 6.25 2.90, 3.10, 3.35, 4.15, 5.60, 5.95, 6.15, 6.25, 6.65, 6.85, 7.15 2.95, 5.62, 5.72, 5.91, 5.95, 6.22 2.97, 4.3 (Br), 5.6, 5.7, 5.93, 6.17 2 95, 5.63, 5.73, 5.91, 6.22 2.95, 3.10, 3.35, 5.32, 5.65, 5.95, 6.20, 6.45, 6.70, 6.90, 7.15 2.95, 5.63, 5.71, 5.91, 5.96, 6.22 3.0, 4.5, 5.65, 5.74, 5.96, 6.23 3.0, 5.63, 5.71, 5.91, 5.95, 6.21, 6.26 2.95, 5.63, (Br), 5.71, 5.91, 5.95, 6.15, 6.25 3.0, 5.63, 5.70, 5.92, 5.97, 6.25 3.0, 5.63, 5.66, 5.95, (Br), 6.25 2.97, 3.40, 5.60, 5.70 (overkill) 5.92, 6.23, 6.65, 6.83, 7.20 2.95, 3.15, 3.40, 5.65, 5.90, 6.25, 6.47, 6.62, 6.68, 7.15 2.95, 3.35, 5.60, 5.90, 6.10, 6.23, 6.50, 6.80, 7.20 2.97, 3.40, 5.62, 5.70 (overkill), 5.92, 6.20, 6.30, 6.80, 6.95, 7.15 2.95, 3.10, 3.40, 5.65, 5.90, 6.20, 6.27, 6.45, 6.65, 6.77, 6.85, 7.15 2.95, 3.35, 5.60, 5.70, (overkill), 6.92, 6.23, 6.65, 6.90, 7.15 2.97, 3.40, 5.60, 5.70 (overkill), 5.92, 6.15, 6.27, 6.65, 6.85, 7.15 2.95, 3.35, 5.60, 5.70, 5.90, 6.20, 6.45, 6.65, 6.85, 7.15 2.95, 3.37, 5.58, 5.70, 5.92, 6.23, 6.65, 6.85, 7.15 2.95, 3.35, 5.10, 5.61, 5.65, (overkill), 5.90, 6.23, 6.45, 6.65, 6.85, 7.20 2.95, 3.35, 5.60, 5.75, 6.25 6.65, 6.92, 7.15 2.95, 3.25, 5.60, 5.80, 6.20, 6.65, 6.80, 7.15 2.95, 3.40, 5.60, 5.73, 5.93, 6.18, 6.70, 6.90, 7.15 2.85, 3.05, 3.35, 5.60, 5.90, 6.15, 6.40, 6.62, 6.85, 7.10 2.95, 3.35, 5.60, 5.80, 5.92, 6.10, 6.20, 6.65, 6.82, 7.02 3.0 (Br), 5.63, 5.73, 5.95, 6.22 3.0, 5.63, 5.75, 5.97 (Br), 6.22 3.35, 5.6, 5.85, 5.95, 6.10, 6.20, 6.35, 6.65, 6.87, 7.15 2.95, 3.37, 5.60, 5.70, 5.90, 6.20, 6.65, 6.85, 7.20 2.95, 3.40, 3.50, 5.60, 5.80, 6.10, 6.25, 6.65, 6.80, 7.10 3.0 (Br), 5.63, 5.78, 5.9—6.1 (Br) 6.25 2.98, 4.5 (Br), 5.62, 5.76, 5.95, 6.25 3.0 (Br), 4.1 (Br), NH3 —, 5.65, 5.84, 6.0, 6.25 3.0, 5.63, 5.97, 5.81, 6.25 2.98, 4.4—4.5 (Br) NH3—, 5.62, 5.77, 5.90, 6.25 2.95, 3.10, 3.35, 5.60, 5.90, 6.20, 6.45, 6.65, 6.75, 6.90, 7.15 3.01, 5.61, 5.7—5.8, 5.95, 7.7, (Br) 8.1 (Br), 8.85 2.98, 5.59, 5.74, 5.92, 7.3 (Br), 8.7, 8.85 3.0, 5.60, 7.56, 5.95, 6.24, 8.89 2.95, 3.35, 4.05, 5.65, 5.95, 6.1, 6.2, 6.3, 6.65, 6.77, 7.25 3.05 (Br/W), 5.60 5.64, 5.79, 5.95, 6.25 3/05, (Br, W), 5.61, 5.73, 5.81, 5.92 3.05 (Br, W), 5.61, 5.77, 5.80, 5.95 3.05, 5.61, 5.80, 5.94 3 0.95 ¦ ¦¦¦¦¦ 0.95^ ¦ 1 0.9(d) 1 0.95 . 0.95(d) 0.95(d)- 0.9(d) 0.95(d) 1 0.8 0.95(d) 0.95(d) 0.95(d) 0.95(d) 0.9(d) 0.9(d) 0.9(d) 0.95(d) 0.95(d) 0.95(d) 0.95(d) 0.95(u' 0.95 0.95(d) 0.95(d) 0.9(d) 0.95(d) 0.95(d) 0.95(d) 0.9(d) 0.85(d) 0.95(d) 0.95(d) | 0.8(d) 0.75 0.6(b) 0.6(b) 0.75(b) 1.0 |8fr571 19 cont. from Table III 1..... £ . . 1' tetradecyl phenyl phenyl*" n-butyl sec.: butyl n-propyl isobutyl o-isopropylphenyl 2-piperidinoethyl | 2-morpholinoethyl Bi p-chlorophenyl R2 1 2 i 3.05, 5.61, 5/75; 5.79y 5.95, 6.07 ,:' 3.05, 5.63, 5.70 {Bfrfr 5.95; £6.27< ' 2.95, 3.35, 4.45 (Br), 5.95, 5.67, 5.90, 6.17 3.0, (Br, W), 5.63, 5.75, 5.83, 5.97, 6.25 3.0, (Br, W), 5.63, 5.81, (Br), 5.97, 6.25 3.0, (Br, W), 5.63, 5.81 (Br), 5.97, 6.08, 6.25 :- , 3.38, 5.63, 5.78, 5.97, 6.25, 6.62 3.38, 5.63, 5.78, 5.97, 6.25, 6.62 2.95, 4.25 (Br), 5.62, 5.8, 5.85, 5.93, 6.2 " 2-maphtyl R7 (compounds in which X* is SR7) phenyl p-cycloprophenyl 2.95, 3.35, 4.05, 5.05, 5.25, 5.5, S.85, 6.2, 6.7, 6.8, 6.85, 7.15, 7.25 2.95, 3.35, 4.05, 5.25, 5.6, 5.9, 6.25, 6.35, 6.65, 6.75, 6.85, 7.15 3 r ! 0.95(b) y - --.: (K8< • 0.95 V '. - •:•• 1.0(c) ' :ro.8cb) 0.8 . < ¦ 0.75 ' Q- 0.95(d) -.'¦ 0.95(c :X).95(C •¦¦¦!¦(¦'¦ 0.85(b! 0.8 The compounds of formula 5, in which Rx and X* have the meanings given above, used in the process according to the invention for the acylation of 6-aminopenicillanic acid derivatives of formula 4, in which M has the meaning given above, are prepared, for example, in the following way: that an arylmaloic acid of the general formula (VI), wherein R1 has the meaning given above, is reacted with a halogenating agent to obtain a compound of the general formula (VI), wherein R1 has the meaning given above and X is a halogen atom, is then reacted with a compound X'-OH, wherein X' has the meaning given above. Preferably, compounds of the formulas P(X)5, P(X)3, PO(X)3 or SQ(X)2 are used as halogenating agents, wherein X has the meaning given above. The halogenation reaction is carried out at a temperature of 0-50°C. The dihalide obtained is decomposed by heating to a temperature of 80-100°C, wherein an arylchlorohydrocarbonylketene of the formula (VI), wherein R1 and X have the meaning given above, is obtained. This compound is reacted at a temperature of -70°C to 30°C with an alcohol or thiophenol of the formula X'-OH, wherein X' has the meaning given above, to give an arylcarboxyketene or arylcarbothiolketene ester of the formula V, wherein R1 and X' have the meaning given above. This reaction probably proceeds first with the ketene group, forming an intermediate compound of the formula V or V, wherein X, R1, R2 and R7 have the meaning given above, after which this compound undergoes rearrangement with the liberation of a hydrogen halide, forming an ester of the formula V, wherein R1 and X' have the meaning given above. The invention is further explained in the examples given below. Example I: 0.1 mole An arylhalocarbonylketene of formula 7, wherein R1 and X have the meanings given above, is dissolved in methylene chloride, using 5-10 ml of solvent per g of ketene, and 0.1 mole of an alcohol of formula X'H, wherein X' has the meaning given above, is added to the solution. The mixture is kept under nitrogen, protected from moisture, and stirred at a temperature from -70°C to -20°C for 1/3 -3 30 hours, after which the infrared spectrum of the mixture is examined to determine the disappearance of ketene. A solution of 0.1 mole of the triethylamine salt of 6-aminopenicillanic acid in 50 ml of methylene chloride is then added and stirred at a temperature from -70°C to -20°C for 1/3 -3 30 hours. 10 minutes, then the cooling bath is removed and the mixture is allowed to warm to room temperature. The product is isolated by one of the methods given below. Method A. The reaction mixture is evaporated to dryness under reduced pressure and the residue is dissolved in citrate buffer solution (pH 5.5). The product is extracted from the buffer solution with chloroform. The chloroform extract is washed with citrate buffer solution (pH 5.5), then dried over anhydrous sodium sulfate and evaporated to dryness. The sodium salt of the compound of formula 1 is obtained. Method B. The procedure is as in Method A, but n-butanol is used instead of chloroform as the extracting solvent. The product obtained after evaporation of n-butanol is triturated with ether to obtain an amorphous solid. Method C. This method is a variation of method A. A saturated aqueous solution of sodium or potassium bicarbonate is used instead of the citrate buffer solution. The sodium or potassium salt of the penicillin compound of formula I is obtained. This method is generally used to recover penicillin compounds which are sparingly soluble in methylene chloride or chloroform. Method D. The reaction mixture is extracted twice with a saturated aqueous solution of sodium or potassium bicarbonate, washed with water, dried and evaporated to dryness. The sodium or potassium salt is obtained, which triturated with ether, unless the product is solid. Method E. This method is a variation of method D and is used for compounds of formula I that are sparingly soluble in methylene chloride. A solution of sodium or potassium bicarbonate (method D) is extracted with m-butanol, the butanol extract is dried and evaporated to dryness. Method F. This method is used to isolate compounds of formula I in the form of the free acid. The residue after evaporating the reaction mixture to dryness is dissolved in an aqueous solution of an acid, e.g., hydrochloric acid, at pH 2.7, and the product is extracted with n-butanol. The butanol extract is washed with an aqueous solution of an acid (pH 2.7) and then lyophilized. Method F-1. Butanol extract from method F The mixture is neutralized with an n-butanol solution of potassium 2-ethylpentanoate and the potassium salt of penicillin of formula I is precipitated. Example II. Sodium and potassium salts of compounds of formula I obtained as described in 2-imidazoleethyl 5-indanyl 5-indanyl 5-indanyl o-isopropylphenyl 4-indanyl o-ethylphenyl o-tolyl 3,4-dimethylphenyl 2,3-dimethylphenyl 6-chloro-2-methylphenyl 4-chloro-2-methylphenyl 2-chloro-5-methylphenyl 4-chloro-3,5-dimethylphenyl 4-chloro-2,3-dimethylphenyl 2,5-dimethylphenyl 3,5-dimethylphenyl 2,4-dimethylphenyl 2,6-dimethylphenyl m-ethylphenyl 2-methoxy-4-methylphenyl 2-methyl-3-methoxyphenyl 2-(N-methylanilinoethyl) 3-(N-methylanilino)-2-propyl 3-(N-ethylanilino)-2-propyl 2-(N-ethylanilinophenyl) o-ethoxyphenyl Example IV. The benzyl esters and substituted benzyl esters obtained as described in Example I are converted into the corresponding acids by catalytic hydrogenation at room temperature. The general method consists in hydrogenating the benzyl ester in water in the presence of a suspension of previously 10% hydrogenated palladium on charcoal until hydrogen uptake ceases. For each 0.05 mole of benzyl ester, 5.7 g of catalyst are used and 1000 ml of water. When hydrogenation is complete, the mixture of Example I is converted to the corresponding acids by carefully neutralizing the aqueous solutions of the salts with aqueous phosphoric acid and then extracting the acid with methyl isobutyl ketone. The methyl isobutyl ketone solutions are washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to obtain the free acids of formula I. Example III. The free acids obtained in the manner described in Examples I and II are converted to their salts: calcium, magnesium, ammonium, procaine, N,N'-dibenzylethylenediamine, N-ethylpiperidine, dibenzylamine, 1-ephenamine, triethylamine, N-benzyl-p-phenethylamine, N,N'-bis(dehydroabietyl)ethylenediamine and benzhydrylamine, by reacting solutions of the free acids with an equivalent of the appropriate base. The salts are isolated by lyophilization. Table IV gives the melting points of the obtained compounds of formula I, where Rx denotes a phenyl radical and X' denotes a group of the formula —OR2, and the meanings of the symbols R2 and M are also given in this table. The reaction mixture is filtered off, the filtrate is adjusted to pH 7.5 with sodium or potassium bicarbonate and then evaporated to dryness under reduced pressure at a temperature below 40°C. The obtained products are purified on a cellulose chromatography column, eluted with a mixture of butanolethanol and water, and isolated from the eluate by evaporation of the solvent. Example V. A solution of 0.5 g of the triethylamine salt of α-[carbo(5-indanyloxy)l-benzylpenicillin in 5 ml of a saturated aqueous hydrogen solution. Table IV M 2 H morpholine N-ethylpiperidine triethylamine potassium N-ethylpiperidine N-ethylpiperidine N-ethylpiperidine N-ethylpiperidine N-ethylpiperidine N-ethylpiperidine N-ethylpiperidine N-ethylpiperidine N-ethylpiperidine N-ethylpiperidine N-ethylpiperidine N-ethylpiperidine N-ethylpiperidine N-ethylpiperidine N-ethylpiperidine N-ethylpiperidine N-ethylpiperidine N-ethylpiperidine N-ethylpiperidine N-ethylpiperidine Melting point (°C) 3 110 (dec) 116—-117 139^141 141—143 193 (decomposition) 136^139 140 (decomposition) 104—145 (decomposition) 145—147 151—153 150—.151 149_151 144—145 (decomposition) 140—142 144^147 144_150 (decomposition) 147—149 142—149 (decomposition) 150—151 132—«137 150—152 150^152 69— 77 86— 92 86— 97 69— 77 138—142 *2 1 M 2 Melting point (°C) 3 10 Dli dc :y] dc dc r\C dc ac dc dc dc dc dc dc dc dc dc dc dc dc dc dc dc dc dc dc M'SH 23 24 sodium carbonate is stirred at room temperature. Samples are taken at 10-minute, 30-minute, and then half-hour intervals and examined by paper chromatography in the isoamyl acetate-citric acid-diphosphate buffer system (pH 4.5) and by bioautography (Badllus subtilis). Samples are also extracted with chloroform (3 x 3 ml), the combined extracts are concentrated, and the concentrated and exhausted aqueous sample are examined by paper chromatography and bioautography. ' fester, which Initially giving a single spot (Rf 0.91) on paper chromatogram, it suddenly appears in equilibrium as two epimers, as confirmed by the appearance of two spots in the chromatogram at Rf 0.81 and 0.91. Hydrolysis of the ester is essentially complete within 2 hours, as confirmed by the presence of the ester in the chromatogram and the presence of α-carboxybenzylpenicillin along with a small amount of benzylpenicillin. In a similar manner, α-[carbo(5-indanyloxy)]-benzylpenicillin sodium salt; α-[carbo(1-β-ethoxy-2,2,2-trichloroethoxy)]-benzylpenicillin sodium salt; α-(carboallyloxy)-benzylpenicillin sodium salt; α-(Carbocyclohexyloxy)benzylpenicillin and α-(Carbophenylthio)benzylpenicillin are converted to the corresponding acids. Example VI. A solution of 0.5 g of the sodium salt of α-[carbo(2-di-n-propyl)aminoethoxy]benzylpenicillin in 5 ml of water is left at room temperature for 24 hours. The pH is adjusted to 7.0-7.2 by adding sodium bicarbonate. The solution is then dried by triturating the residue with ethanol. The disodium salt is obtained. By this method, the sodium salts of the following penicillin esters are converted to their corresponding disodium salts: α-[carbo-(5-indanyloxy)]-benzylpenicillin, α-[carbo-(dicarboethoxyethoxymethoxy)]-benzylpenicillin, α-(carbopropargyloxy)-benzylpenicillin, α-[carbo-(2-bicyclo-[4,4,0]-decyloxy)]-benzylpenicillin and α-(carbophenylthio)-benzylpenicillin. Example VII. To a solution of 0.1 g of the sodium salt of α-carbo[(2-N-methylanilino)-ethoxy]-benzylpenicillin in 5 ml of chloroform was added 5 ml of citrate buffer solution (pH 5.5) and the resulting mixture was shaken thoroughly for 75 minutes. The aqueous layer was monitored every 15 minutes by chromatography. paper, using an isoamyl acetate: citrate-phosphate buffer (pH 4.5) and bioautography (Bacillus subtilis). Within 15 minutes, α-carboxybenzylpenicillin is present in the aqueous phase along with the starting ester in significant amounts. After 60 minutes, no ester is detected in the aqueous phase. α-carboxybenzylpenicillin is obtained as the main product, while small amounts of the decomposition product benzylpenicillin are also found in the aqueous phase. α-carboxybenzylpenicillin is isolated by lyophilization, and the crude product is purified by chromatography. PL PL PL PL PL PL PL PL PL