NO763546L - - Google Patents

Description

The invention relates to new acyl derivatives, namely those of 6-aminopenicillanic acid of the formula

where T means a C2-5 alkyl or alkenyl residue or cyclopropylmethyl, cyclobutylmethyl or cyclopentyl residue, and A means furyl, tetrahydrofuryl, pyrrolyl, pyrrolidinyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-thiadiazolyl, imidazolyl , pyrazolyl, pyridyl, 1-oxidopyridyl, tetrahydropyranyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, quinolyl or iso-quinolyl, and where the residues A can be substituted with halogen, oxo, hydroxy, amino, C-^-^-alkyl, c^ C1-3-Alkoxy, C1-3-Alkoxycarbonyl and/or C1-3Alkanoylamino,

as well as pharmaceutically usable salts and hydrated forms thereof.

As halogen substituents, fluorine, chlorine and bromine in particular come into consideration.

C atoms. An alkyl or alkenyl group in the substituent T can be straight-chain or branched. Examples of such groups

is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, 3-methylbutyl, neopentyl henh. vinyl, allyl, methallyl, butenyl and pentenyl.

Preferred groups of the compounds according to the invention are

those in which A means 3-pyridyl, 2-methyl-4-pyridyl, 3-isoxazolyl, 4-oxazolyl, 2-oxo-2-pyrrolidinyl, pyrazinyl, tetrahydro-2-furyl, 2-acetamido-4-thiazolyl, 1 ,5-dimethyl-3-pyrazolyl, tetrahydro-4-pyranyl, 1,2,3-thiadiazol-4-yl, 2-furyl or 4-pyridyl.

Further preferred groups of the compounds according to the invention are those. where T means an alkyl or alkenyl group with 4 or 5 C atoms. Preferred compounds are also those indicated in the tables further below. Particularly preferred is the compound of formula I, where A means 2-furyl and T 2-methylpropyl, i.e. [1-(2-furoyloxy)-3-methylbutylpenicillin, especially the R-form and its salts.

For the salt formation, the bases that were already used for other penicillins can be used. Examples of pharmaceutically usable salts are alkali metal salts, such as the sodium and potassium salts;

the ammonium salt; alkaline earth metal salts, such as the calcium salt, as well as salts with organic bases, such as amines, e.g. N-ethyl-piperidine, procaine, dibenzylamine, N,N'-dibenzylether-ethylenediamine or with mono-, di- or trialkylamines.

Salts of compounds of formula I can also be hydrated. The hydration can take place in the course of the preparation or successively, as a consequence of the hygroscopic properties of a first anhydrous salt of a compound of formula I.

The compounds of formula I and their salts can exist as optically pure isomers and as diastereomer mixtures.

The compounds of formula I and their salts can be prepared on

in a manner known per se by reacting 6-aminopenicillanic acid, whose carboxyl group is in protected form, with an acid of the general formula

where A and T have the above meaning,

or with a reactive functional derivative thereof, after which the protecting group is cleaved off and the reaction product is transferred, if desired, into a salt.

The carboxyl group of 6-aminopenicillanic acid can e.g. is protected by conversion to an easily cleavable ester, e.g. benzyl or a silyl ester, e.g. the trimethylsilyl ester, or by salt formation with an inorganic or tertiary organic base, such as triethylamine.

As reactive functional derivatives of acids with formula II occur, e.g. halides, ie chlorides, bromides and fluorides; azides; anhydrides (especially anhydrides mixed with stronger acids); reactive esters, e.g. N-Hydroxy-succinimide ester; and amides, e.g. imidazolides.

The reaction of 6-aminopenicillanic acid with a compound of formula II or a reactive functional derivative thereof can be carried out according to the usual methods in peptide chemistry. Thus, e.g. the free acids of formula II are condensed with the aforementioned esters of 6-aminopenicillanic acid by means of a carbodiimide, such as dicyclohexylcarbodiimide, in an inert solvent, such as acetic ester, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide and then cleavage of the ester group. Instead of carbodiimides, oxazolium salts can also be used as condensation agents, e.g. N-ethyl-5-phenyl-isoxazolium-3<1->sulfonate.

According to another embodiment, a salt of 6-aminopenicillanic acid is reacted, e.g. a trialkylammonium salt, with a reactive functional derivative of an acid of formula II, and as mentioned above in an inert (e.g. one of the above) solvents.

The reaction of the protected 6-aminopenicillanic acid with a compound of formula II or a reactive functional derivative thereof can conveniently be carried out at temperatures between approx. + 5°C and - 40°C, for example at approx. 0°C.

After sales have been made, the protection group is split off. IN

if the protecting group means a benzyl group (benzyl ester) then this can be cleaved off by means of catalytic hydrogenation, e.g. by means of a noble metal catalyst, e.g. palladium coal. When the protecting group is a silyl group (silyl ester), this group can be removed particularly easily by treating the reaction product with water. When, moreover, the carboxyl group of the 6-aminopenicillanic acid is protected by salt formation (e.g. with triethylamine), the removal of this salt-forming protective group takes place by treatment with acid at a relatively low temperature, for example at about 0° to about 10° C. As an acid, for example hydrochloric acid, sulfuric acid, phosphoric acid or citric acid can be used.

The acids of formula II can be used in optically uniform form or also as racemates. R-enantiomers are preferably used.

Compounds of formula II and their reactive functional derivatives are new compounds according to the present invention. According to the invention, they can be produced by using a combination with the general formula

where A and T have the above meaning and where

B means a protected carboxyl group,

. transfers the group B in the free carboxyl group.

The protected carboxyl group B can be an easily cleavable ester group, e.g. the benzyl or tert.butyl ester group.

In the case of the benzyl ester, the transfer of the protected carboxyl group B to the free carboxyl group can take place by catalytic hydrogenation using a noble metal catalyst, e.g. palladium charcoal, and in the case of the tert.butyl ester by treatment with an acid, e.g. with a mineral acid, such as hydrochloric acid, or with trifluoroacetic acid.

The actual conversion of the thus obtained acids of formula II into functional derivatives, e.g. halides, azides, anhydrides, esters and amides can take place according to methods known per se.

Compounds of formula III can be obtained in a known manner by

that one protects the carboxyl group of a compound of formula

e.g. by forming the benzyl ester or tert.butyl ester, and reacting the resulting compound with a compound of formula A-COOH, e.g. in the production of benzene sulfochloride.

Compounds of formula I, their salts and their hydrates are antibiotic, particularly bactericidally active. They have a broad spectrum of action against gram-positive and gram-negative micro-organisms. Their stability against stomach acid can also be mentioned as advantageous properties. The compounds can be used as therapeutic and disinfectant agents. Current single-dose rings for adults are 200 - lOOO mg. The oral administration of the compounds according to the invention is particularly preferred.

The antimicrobial activity of the compounds according to the invention appears in the following table. The minimum inhibitory concentration in vitro was assessed after duplicate dilution experiments in nutrient broth.

Pharmaceutical preparations may contain the compounds of formula I, their salts and hydrated forms thereof in admixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral, especially oral, percutaneous or parenteral administration. f. e.g. water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragées, dry ampoules, capsules, in semi-solid form, e.g. as ointments 5 or in liquid form, e.g. as solutions suspensions or emulsions. If necessary, they are sterilized and/

/v or contains auxiliary substances, such as preservatives, stabilisers, wetting or emulsifying agents, salts for change

■ of the osmotic pressure or.puffers. They may also contain other therapeutically valuable substances.

EXAMPLE 1. '* - ';22.6 g (R)- 2-(2 - fluorooxy)-isocaproic acid, 80 ml abs. benzene and 36 ml of thionyl chloride are heated. 2 .,'5 hours, evaporated and dried. 24.5 g of R-(2-furoyloxy)-isocaproic acid chloride is obtained. This is dissolved in 70 ml of methylene chloride and added dropwise at 0 with stirring into a solution of 21.6 g of aminopenicillanic acid in a mixture of 150 ml of methylene chloride and 23 ml of triethylamine. The reaction mixture is allowed to stand for 20 hours at 0°, after which it is evaporated under reduced pressure at 20°. The residue is dissolved in 150 ml of ice water and extracted twice with 50 ml of ether each time. The aqueous phase is adjusted at 0 o to pH 2 with 3-n sulfuric acid and extracted three times with 80 ml of ethyl acetate each time. The ethyl acetate solution is washed three times with each time 20 ml of ice-cold 5% sodium chloride solution, after which it is dried with magnesium sulfate and evaporated under reduced pressure at 20 . The remainder is dissolved in 300 ml abs. ether, filter and add 50 ml of 2-,n sodium 2-ethyl caproate in ethyl acetate. The precipitated | (R)-1-(2-furoyloxy)-3-methylbutyl|penicillin sodium is filtered off with suction, washed with abs. ether and low-boiling petroleum ether, and after drying is recrystallized in water/isopropanol. Temp. 182 - 183° (decomposition). ;[aj^<5>+221.5° (c = 2.0 in water). The (R)-2-(2-furoyloxy)-isocaproic acid used here as starting material can be obtained as follows: 55.5 g of (R)-2-(2-furoyloxy)-isocaproic acid benzyl ester is hydrated in 400 ml of alcohol after addition of 5 g of palladium carbon1 (5%), until the theoretical amount of hydrogen is taken up. The catalyst is suctioned off and the filtrate is evaporated under reduced pressure at 40°. The remaining oil is dissolved in 250 ml of 8% sodium bicarbonate solution and washed twice with 80 ml of ether each time. The bicarbonate solution is adjusted to pH 2 with concentrated hydrochloric acid and extracted three times with 100 ml of ethyl acetate each time. The ethyl acetate solution is washed twice with 50 ml of water each time, dried with magnesium sulphate and evaporated under reduced pressure at 45°. The (R)-2-(2-furoyloxy)-acid remaining as an oil in sokapron is dried for 2 hours, at 0.4 mmHg and 40°. | o = +<7,>0°;(c .= 4 .0 in alcohol) . The (R)-2-(2-furoyloxy)-isocaproic acid benzyl ester is in turn obtained in the following way: In a three-necked flask equipped with a stirrer, thermometer and reflux skirts with calcium chloride, dissolve 264 g of (R)- 2-hydroxy-isocaproic acid in 1.8 1 absolute dioxane, after which 285 ml of triethylamine and 236 ml of benzyl chloride are added in turn, after which the mixture is heated for 20 hours with stirring in an oil bath to an internal temperature of 100°. After. cooling, the triethylamine hydrochloride obtained is filtered off and washed with 500 ml of ethyl acetate. The filtrate is evaporated under reduced pressure at 50°, and the remaining . The oil is dissolved in 800 ml ethyl acetate and washed twice each time with 150 ml -3-n hydrochloric acid, twice each time. 100 ml of 5% sodium chloride solution, twice with each time 150 ml of 10% potassium bicarbonate solution and twice with each time 100 ml of 5% sodium chloride solution. After each of these washings, it is washed with 200 ml of ethyl acetate. The ethyl acetate solution is dried over magnesium sulfate and evaporated under reduced pressure at 50 oC. The crude product thus obtained is distilled at 0.3 mmHg (112 - 115°C). (R)-2-Hydroxy-isocaproic acid benzyl ester is obtained, [cx]q<5>= +18.0° (c = l in methanol)-, n^3 = 1.498.. ;To a solution of 23.6 g of furan -2-carboxylic acid in. 100 ml of pyridine are added dropwise at 25° with stirring over the course of 20 minutes. 27 ml of benzene sulphochloride. Then stir for 30 minutes at ;25°. 44.4 g of (R)-2-hydroxy-isocaproic acid benzyl ester are then added dropwise while stirring. The solution is either heated for 2 hours to 60° or stirred for 20 hours at 25°. Pyridine is distilled off under reduced pressure at 30 - 50°. The residue is dissolved while adding ice in 600 ml of 3-n hydrochloric acid and extracted twice with 250 ml of ethyl acetate each time. The ethyl acetate solution is washed with 100 ml of 3-n hydrochloric acid, twice with each time 100 ml of water, two cyo. each time with 100 ml of 5% sodium bicarbonate solution and twice with each time 100 ml of water and dried with magnesium sulphate. Ethyl acetate is distilled off under reduced pressure at 40°, and the remaining oil is dried for 60 minutes under reduced pressure at 60°. R-2-(2-furoyloxy)-iso-capric acid benzyl ester is obtained, +9.0° (c 4.0 in alcohol). EXAMPLE 2 23.7 g R-2-(isonicotinoyloxy)-isocaproic acid, 80 ml abs. benzene and 36 ml of thionyl chloride are heated for 2 hours, and after evaporation, evaporation and drying are carried out three times with each time 30 ml abs. benzene under reduced pressure at 45°. 25.6 g of R-α-(isonicotinoyloxy)-isocaproic acid chloride hydrochloride are obtained. This is dissolved in 80 ml of chloroform and dropped into a solution consisting of 21.6 g of 6-aminopenicillanic acid in a mixture of 150 ml of chloroform and 42 ml of triethylamine. The reaction mixture is allowed to stand for 20 hours at 0°, after which it is evaporated under reduced pressure at 20°. ;The residue is dissolved in 200 ml of ice water and extracted twice with each. times 70 ml of ethyl acetate. The aqueous phase is adjusted to pH ;2.5 at 0° with citric acid and extracted three times with 100 ml of ethyl acetate each time. The ethyl acetate solution is washed three times with each time 30 ml of ice-cold 5% sodium chloride solution, dried with magnesium sulfate and evaporated under reduced pressure at 20°. The residue is dissolved in 100 ml of ethyl acetate, and 50 ml of 2-n sodium 2-ethyl caproate solution in ethyl acetate and 200 ml of abs. ether. The precipitated | (R)-1-(isonicotinoyloxy)-3-methylbutyl | - penicillin sodium is suctioned off, washed with abs. ether and low-boiling petroleum ether, and recrystallized after drying in water/isopropanol. Snipe. 197 - 198° (decomposition).. | o = +227°; (c = 1.0 in water) . ;The R-2-(isonicotinoyloxy)-isocaproic acid used as starting material, m.p. 138 - 139°, | o = +22.3° can be obtained via benzyl esters analogously to that stated in example 1 for the preparation of the starting material. EXAMPLE 3 9.2 g of 6-aminopenicillanic acid is stirred in 100 ml of abs., chloroform at 0° for 1 hour with 12.0 ml of triethylamine. Meanwhile, to a solution of 10.4 g of (R)-2-1 (S)-pyroglutamoyloxy|-isocaproic acid and 6.0 ml of triethylamine in 100 ml of abs. chloroform at -10° 5.2 g of pivaloyl chloride, after which one stirs for 20 minutes at -10°. The mixture is then cooled to -40°, the above-mentioned 6-aminopenicillanic acid solution is added and the whole is finally allowed to stand for 16 hours at 0°. At a solution temperature of 20° it is then evaporated under reduced pressure, after which the product is taken up in water and extracted twice with ethyl acetate. After washing the ethyl acetate extract with water and saturated sodium chloride solution and drying over sodium sulphate, it is evaporated in vacuum at 20° bath temperature to 80 ml, after which this solution is stirred into 800 ml of petroleum ether. After decanting, this procedure is repeated, whereby chloroform is used instead of ethyl acetate. The decantation residue is taken up in 100 ml of acetone, to which is added 20 ml of 2-M sodium 2-ethyl caproate in ethyl acetate. It is then precipitated with petroleum ether and decanted. (R)-3-methyl-1-[(S)-pyroglutamoyloxybutyl|-penicillin sodium crystallizes in methanol/isopropyl ether. Temp. 180 (decomposition), I « |D - +187.0° ;(c = 1.0 in water) . ;It hereby used as starting material (R)— 2 — | The (S)-pyroglutamoyl-oxyI-isocaproic acid can be obtained in the following way: 14.2 g of (S)-pyroglutamic acid are suspended in 60 ml of dimethylformamide and brought into solution with 15.4 ml of triethylamine. Under inert conditions and stirring, 52 ml of a 5.2 molar solution of phosgene in toluene is added at -60° over the course of 20 minutes, after which a precooled solution of 22.2 g of (R)-2-hydroxyisocaproic acid benzyl ester in 80 ml of pyridine; This is then allowed to stand for 16 hours at 2 - 4°, after which it is dried under reduced pressure and with the aid of a dry, cold receiving container. The residue is taken up in ether and washed three times with 1-1 hydrochloric acid, water, 10% potassium bicarbonate and water, dried over sodium sulphate and evaporated under reduced pressure. The residue containing (R)-2-1 (S)-pyroglutamoyloxy|-i sokaprOnsy rebenzyl ester is hydrated in glacial acetic acid/water (95:5) with 5% palladium charcoal until no more hydrogen is taken up. The catalyst is then filtered off and evaporated under reduced pressure. After crystallization of the residue in ethyl acetate/petroleum ether, .11 g of (R)-2-;[' (S)-pyroglutamoyloxy I-isocaproic acid with m.p. 148 - 150°; (after conversion at 80°); |o| J = +20.4 (c = 1.0 in methanol). ;EXAMPLE 4;Analogous to example 1, one obtains with (R)-2-(5-bromo-2-furoyl-oxy)-isocaproic acid | | (RS)-1-(5-bromo-2-furoyl)oxy|-3-methyl-butyl | penicillin sodium; m.p. 205 - 206° (decomposition). [ a +189° (c = 1 in water). The (R)-2-(5-bromo-2-furoyl-oxy)-isocaproic acid used here as starting material can be obtained via its tert-butyl ester analogously to the indications in example 14 for the preparation of the starting material. ;EXAMPLE 5;Analogous to example 1, one obtains with (R)-2-(2,6-dimethoxy-isonicotinoyloxy)-isocaproic acid | (R)-1-[2,6-dimethoxyisonicotinoyl)oxy]-3-methylbutyl J-penicillin sodium; m.p. from 170° ;(cleavage) |u|25= +157° (c = 2 in water). ;D ;o 2 5 The starting material used here, m.p. 79 - 81 , | television | = +12.2° (c = 2 in ether), can be obtained over the corresponding benzyl ester analogously to the indications obtained in example 1 for the preparation of the starting material. ;EXAMPLE 6;Analogous to example 1, one obtains with (R)-2-(5-methyl-2-furoyloxy)-isocaproic acid I (R)-3-methyl-1-|5-methyl-2-furoyl)-oxy Jbutyl |periici 11 in-sodium , m.p. 204 o (cleavage) | a |2 5 +211.3° (c = 1 in water). The (R)-2-(5-methyl-2-furoyloxy)-isocaproic acid used here as starting material can be obtained via the benzyl ester analogously to the indications obtained in example 1 when preparing the starting material. EXAMPLE 7 Analogous to example 1, one obtains with (R)-2-(2-benzofuroyloxy)-isocaproic acid | (R)-1-| 2-benzofuroyloxy|-3-methylbutyl|penicillin sodium; m.p. 197° |"Iq^ ~ +183.3° (c' -li water). ;The (R)-2-(2-benzofuroyl-oxy)-i socaproic acid used here as starting material can be obtained via its benzyl ester analogously to the specifications for the preparation of the starting material given in example 1. ;EXAMPLE 8;Analogous to example 1, one obtains .with (R)-2-(3-methyl-5-isoxazolyl-carbonyloxy)-i socapronic acid | (R)-1-| ( 3-methyl-5-i soxazolyl)-carbonyloxy |-3-methylbutyl |penicillin sodium; mp 185°C (dec) [ a = +214.3° (c = 2 in water)' .. ;The (R)-2-(3-methyl-5-isoxazolyl-carbonyloxy)-isocaproic acid used here as starting material, mp 5-9 - 62 o , | , a |. D 25<=>+13° (c = 2 in ethanol) can be obtained via its benzyl ester analogously to the indications for the preparation of the starting material given in example 1. ;EXAMPLE 9;Analogous to example 1 is obtained with (RS)-2-(3-f uroyloxy)-isocaproic acid | (RS)-1-(3-furoyloxy)-3-methylbutyl|-penicillin-sodium; mp 208° (decomposition) |o= +210.6° (c = 0.5 in water). ;The hereby starting material used e (RS)-2-(3-furoyloxy)-isocaproic acid, m.p. 85 - 87°, can be obtained via its benzyl ester analogously to the indications given in example 1 for the preparation of the starting material. ;EXAMPLE 10;Analogous example 1 is obtained with (S)-2-(2-furoyloxy)-isocaproic acid [(S)-1-(2-furoyloxy)-3-methylbutyl|penicillin sodium; m.p. from 150° (decomposition) [ o |^ = +216° (c = 2 in water). ;The (S)-2-(2-furoyloxy)-isocaproic acid used here as starting material, | o: | " -7° (c = 4 in ethanol), can be obtained via its benzyl ester analogously to the instructions given in example 1 for the preparation of the starting material. ;EXE MPEL 11; Analogous to example 1 is obtained with (R)-2-| , 2 , 3,6-tetrahydro-2,6-dioxo-4-pyrimidinyl)carbonyloxy|-isocaproic acid | (R)-3-methyl-1-[f (1,2,3,6-tetrahydro-2,6 -dioxo-4-pyrimidinyl)-carbonyl |oxy I butyl |penicillin sodium urn; m.p. from 220° (decomposition) ;2 5 o ;f a |D = +162.5 (c = 1 in water). ;It hereby as starting material used (R)— 2 — [ | 1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinyl|carbonyloxy|-isocaproic acid, mp ;94 - 96°C, \ lx ' = +15.5° (c = 2 in methanol), can be obtained via its benzyl ester, analogously to the indications given in example 1 for the preparation of the starting material. EXAMPLE 12 Analogously to example 1, one obtains with (R)-2- ( 1-methyl-4-imidazolyl-carbonyloxy)isocaproic acid (R)-3-methyl-1-[(1-methylimidazol-4-yl)carbonyl[oxy|butyl|penicillin sodium] mp 150°; .(splitting) J o | 2 5 =-+182, 8 o (c = .1 i e ethanol). The (R)-2-(1-methyl-4-imidazolylcarbonyloxy)-isocaproic acid used here as starting material can be obtained via its benzyl ester analogously to the indication given in example 1 for the preparation of the starting material. ;EXEM PEL 13;Analogous example 1 is obtained with (R)-2-(-4-i soquinoly 1 carbonyl-oxy)-isocaproic acid I (R)-1-1 (4-isoquinolylcarbonyl)oxy I-3-methylbutyl. [penicillin sodium: m.p. 136 o n :| 2' 5 +' 192.7 (c = 1 in ethanol). The (R-)-2-(4-isoquinolyl-carbonyloxy)-isocaproic acid used here as starting material can be obtained via its benzyl ester analogously to the indications given in example 1 for the preparation of the starting material. ;s EXAMPLE 14; Analogous to example 1 is obtained with (R)-2-(1,2,3-thiadiazol-4-yl-carbonyloxy)-isocaproic acid | (R)-3-methyl-1-[ (1,2,3-thiadiazol-4-ylcarbonyl)oxy|butyl (penicillin-sodium-, m.p. 210° .(decomposition) ;[a|^<5>= +240.2 (c = 1 in water). The (R)-2-(1,2,3-thiadiazol-4-yl-carb,onyloxy)-isocaproic acid used here as starting material can be obtained as follows: 13.0 g of 1,2,3-thiadiazole-4-carboxylic acid is suspended in 100 ml of pyridine and, at 25 - 35°, 12.8 ml of benzene sulphochloride are added dropwise and with stirring over the course of 20 minutes. The stirring is done for half an hour at room temperature , whereby a clear solution is obtained. Under further stirring, 17.9 g of (R) - cv-hydroxy i sovaleri anacid-tert-.-butyl ester are added under inert conditions and over the course of 20 minutes, whereby the temperature increases to approx. 40°. After stirring for 2 hours at 60°, it is evaporated under reduced pressure, after which it is suspended in 200 ml of ethyl acetate with subsequent suction. The precipitate is washed twice with ethyl acetate, and the combined filtrates are washed three times quickly with ice-cold dilute hydrochloric acid , once with ice water and wood times with a 10% potassium bicarbonate solution, after which it is dried over sodium sulphate and evaporated under reduced pressure. The residue containing (R)-2-(1,2,3-thiadiazol-4-yl-carbonyloxy)-i socaproic acid tert-butyl ester. pour over with 100 ml of trifluoroacetic acid, and after 1/2 hour evaporate under reduced pressure, after which the whole is taken up in ether and extracted to exhaustion with 10% potassium bicarbonate. The combined bicarbonate extracts are acidified to Congo red and extracted three times with ethyl acetate. After washing, drying and evaporation of the solvent, 19 g of pure crystallized oil remain. In isopropanol, 12 g of (R-)-2-(1,2,3-thiadiazol-4-yl-carbonyloxy)-isocaproic acid is obtained with m.p. ;104 - 105°, f a |p<5>+20.0° (c 1 in methanol). ;EXAMPLE 15;Analogous example .1 is obtained with (R)-2-(tetrahydropyran-4-ylcarbonyloxy)-isocaproic acid | (R)-3-methyl-1-| | tetrahydropyran-4-yl)carbonyl! |oxy |butyl |penicillin-sodium-, m.p. 183 (decomposition) a]<25>= +218.5° (c =1 in water). The (R)-2-(tetrahydropyran-;4-ylcarbonyloxy)-isocaproic acid used here as starting material can be obtained via its benzyl ester analogously to the indications given in example 2 2 for the preparation of the starting material. ;EXAMPLE 16;Analogous example 1 is obtained with (R)-2-(1,5-dimethyl-3-pyrazolylcarbonyloxy)-isocaproic acid | (R) — 1 - [ [ (1,5-dimethylpyrazol-3-yl)carbonyl|oxy|-3-methylbutyl|penicillin sodium: m.p. ; 205 (cleavage). |a| =.+196.7° (c ' = 1 in water). The starting material used here can be obtained as follows: 19.2 g of 1,5-dimethylpyrazole-3-carboxylic acid is heated with 80 ml of thionyl chloride for 20 minutes under reflux; after which excess thionyl chloride is removed under reduced pressure. It is evaporated a further two times with toluene under reduced pressure, after which the residue is taken up in 100 ml of toluene, and added dropwise at 0° with stirring to 22.4 g of (R)-cx-hydroxyi socaproic acid tert-butyl ester in 80 ml of pyridine. After stirring for 2 hours at room temperature, it is evaporated under reduced pressure, after which it is taken up in ether and washed with water and 10% potassium bicarbonate resp. three times each. After drying and evaporation of the solvent, a crystalline residue under petroleum ether of 25.5 g, m.p. 69 - 71°. This residue containing (R)-2-(1^-dimethylpyrazole-S^yl-carbonyloxy)-i socapronic acid-tert. Butylester is allowed to stand for 30 minutes at room temperature with 50 ml of trifluoroacetic acid, and after evaporation in vacuum dissolved in ether and extracted to exhaustion with 10% potassium bicarbonate. After acidification, the bicarbonate extracts to kongorod are extracted with ether, and the ether is evaporated under reduced pressure after washing and drying. The remaining residue is recrystallized in ethyl acetate: 16 g of (R)-2-(.1,5-dimethylpyrazol-3-ylcarbonyloxy)-isocaproic acid; m.p. 155 - 161° I (<<l>D<=>+13.1° ;(c =1.0 in methanol). ;EXAMPLE 17;Analogous example 3 is obtained with (R)-2- (2 -acetamido-4-thiazolyl-carbonyloxy) in socaproic acid | (R) — 1 — ( | (2-acetami.do-4-thiazolyl) - carbonyl|oxy|-3-methylbutyl|penicillin-Sodium; m.p. 220° ; (decomposition), | a |^5 = +151.5° (c = 1 in water). ;The starting material used here can be obtained as follows: 14.4 g of 2-acetamido-4-thiazolecarboxylic acid. suspended in 200 ml of dimethylformamide, is brought into solution with 11.9 ml of triethylamine. At -60° and vigorous stirring, 38.1 ml of a 2.86 molar solution of phosgene in toluene is slowly added, and then a to about -50° of pre-cooled solution of 14.6 g of (R)-2-hydroxyisocaproic acid tert-butyl ester in 50 ml of pyridine at once After the reaction mixture has assumed room temperature, it is evaporated under reduced pressure, after which the residue is taken up in ether and washed three times with 10% potassium bicarbonate solution, concentrated and evaporated under reduced pressure. 26 g of crystalline remains k mass, which contains (R)-2-(2-acetamido-4-thiazolecarbonyloxy)-i socaproic acid-tert. butyl ester .- This mass is allowed to stand for 30 minutes at room temperature with 100 ml of trifluoroacetic acid. After removing the solvent under reduced pressure, take up in ether and extract to exhaustion with a 10% potassium bicarbonate solution. After acidifying the aqueous solution to pH 3, it is extracted three times with ethyl acetate, and the extract is evaporated after washing with water and drying over sodium sulfate under reduced pressure. (R)-2-(2-acetamido-4-thiazolecarbonyloxy)-isocaproic acid thereby remains as a non-crystalline resin. ;EXEMP EL 18;Analogous example 1 is obtained with (R)-2-1 (RS)-tetrahydro-2-furoyloxyI-isocaproic acid | (R)-3-methyl-1-| | (RS)-tetrahydro-2-furoyl oxy|butyl|penici 1 lin-sodium; m.p. 170 - 185° (decomposition). ;[a|<25>= +200° (c = 1 in water). ;JD;It hereby used (R)-2-| as starting material (RS)-(tetrahydro-2-furoyloxyI-isocaproic acid, |a= -7° (c =4 in ethanol),' can be obtained via its benzyl ester analogously to the indications given in example 1 for the preparation of the starting material- ;EXAMPLE 19;Analogous example 1 is obtained with (RS)-2-(2-furoyloxy)-valeric acid | (RS)-1-(2-furoyloxy)-butyl|penicillin sodium; m.p. 165 - 170° (decomposition), | o. = +209° (c = 1 in water). ;The (RS)-2-(2-f uroyloxy) -;- valeric acid used here as starting material, m.p. 53 - 56°C can be obtained via its benzyl ester analogously to those in instructions for the production of the starting material given in example 35. ;EXAMPLE 20;Analogous example 1 is obtained with (RS)-2-(1,6-dihydro-6-oxonico-tinoyloxy)-isocaproic acid [(RS)-1-|(1,6 -dihydro-6-oxonicotinyl) oxo^-3-methylbutyl |penicillin-sodium, m.p. 200° (decomposition) -, [ cx ]^=<+>191° (c = in water) ;'It hereby as starting material used (RS)-2-(1,6-dihydro-6-oxonicotinyloxy)-i socaproic acid, m.p. 167 - 170°C, can be obtained via its benzyl ester analogue gt the specifications given in example 35 for the production of the starting material. ;EXAMPLE 21;Analogous to example 3, one obtains with (R)-2-(pyrazinylcarbonyloxy)-isocaproic acid | (R)-3-methyl-1-| (pyrazinylcarbonyl)oxy|butyl|penicillin potassium; m.p. 150°(cleavage), [ u|^ = +186.5° ;(c in water) . ;The (R)-2-(pyrazinylcarbonyloxy)-i socaproic acid used here as starting material can be obtained via its tert-butyl ester analogously to the indications given in example 17 for the preparation of the starting material.. ;EXAMPLE 2 2 ;Analogous to example 1 is obtained with (R)-2-(nicotinoyloxy)-isocaproic acid-N-oxide | (R)-3-methyl-1-| (1-oxidonicotinoyl)oxy|-butyl Ipenicillin sodium; m.p. 175° (spal tni ng. ) , ' |_ a | =<+>168.3(c=1 in water). -hydrochloride is dissolved in 150 ml of pyridine and 50 ml of dimethylformamide, and while stirring, at a maximum of 15°, 22.2 g of (R)-2-hydroxyisovaleric acid benzyl ester is added | prepared by reaction of (R)-2-hydroxy-isovaleric acid and benzyl chloride; analogously to that indicated in example 1 |. -After two hours of stirring at room temperature, evaporate under reduced pressure. The rest is recorded. ;. in ether, washed three times with water and extracted six times; with ice-cold 3-n hydrochloric acid. The hydrochloric acid phases are immediately drummed into saturated potassium bicarbonate solution, and the base thus liberated is extracted three times with ether. After washing and drying, it is evaporated under reduced pressure, whereby a resin containing (R)-2-(nicotinoyloxy) is obtained -isocaproic acid benzyl ester (27 g).. This is hydrated in 200 ml of ethanol with 2 g of 5% palladium charcoal until two equivalents of hydrogen are taken up. After filtration and evaporation, take up in 10% potassium bicarbonate, then wash twice with ether and adjust the pH to 3 with citric acid. After extraction with ether, washing, drying and evaporation of the extract, a crystalline oil is obtained. In acetic ester/petroleum ether, 14 g of (R)-2-(nicotinoyloxy)-isocaproic acid with m.p. 101 - 103° I « Ij^ = +18.8° (c = 1.0 in methanol). % hydrogen peroxide at 70 - 80°. After further addition of 8 ml of 30% hydrogen peroxide, the whole thing is allowed to stand overnight at this temperature. Evaporate carefully under reduced pressure, and evaporate twice with 50 ml of water each time. whereby one is not allowed to evaporate to dryness. The residue is taken up in chloroform, washed four times with water, dried and evaporated under reduced pressure. 19 g of (R)-2-nicotinoyloxy-i socapronic acid N-oxide crystallizes from ethyl acetate with m.p. 132 - 134° a \^ = +20.8° (c = 1.0 in methanol)'. ;EXAMPLE 2 3;Analogous example. 3 is obtained with (R)-2-(4-chloropicolinoyloxy)-isocaproic acid | (R)-1-(&-chloropicolinol)-oxy|-3-methylbutyl|-penicillin sodium; m.p. 140° (decomposition) I (x Ijj<=>+146.7° ;(c = 1 in water) . ;It hereby used as starting material (R)-2-(4-chloropicolinoyloxy^isocaproic acid, m.p. 120 - 122 °C can be obtained via its tert.butyl ester analogously to the indications given in example 17 for the preparation of the starting material. ;EXAMPLE 24;Analogously to example 1 is obtained with (R)-2-(2,6-dichloroisonicotinoyl-oxy)-isocaproic acid | (R)-1-|(2,6-dichloroisonicotinoyl)oxy)-3-methylbutyl|penicillin-sodium; mp from 162° (decomposition), ;2 5 ;I a |D +164.6 (c 2 i water). The (R)-2-(2,6-dichloroisonicotinyloxy)-isocaproic acid used here as starting material, m.p. 79 - 81°C (decomposition), can be obtained via its tert.butyl ester analogously the indications given in example 16 for the preparation of the starting material. ;EXAMPLE 2 5;Analogous to example 1, one obtains with (R)-2-(4-oxazolylcarbonyl-oxy)-isocaproic acid | (R)-1-| (4-oxazolylcarbonyl )oxy |-3-methylbutyl|penicillin-sodium; mp 173 o (decomposition), | a|D2 5 +150.8° (c = 1 in ethanol).. ;D a (R)-2-(4-oxazolyl-carbonyloxy)-isocaproic acid used here as starting material can be obtained via its benzyl ester analogously to the indications given in example 1 for the preparation of the starting material. ;EXAMPLE 26;Analogous example 1 is obtained with (R)-2-, (2-methylisonicotinoyl-oxy)-isocaproic acid I (R)-3-methyl-1-1 (2-methylisonicotinoyl)-oxybutyl |penicillin-sodium- , m.p. 195 - 200° (decomposition) , ;I a |p = +188° (c = 1. in water). The (R)-2-('2-methyliso-nicotinoyloxy)-isocaproic acid used here as starting material can be obtained via its benzyl ester analogously to the indications given in example 22 for the preparation of the starting material. EXAMPLE 2 7 Analogously to example 1, (R)-2-(3-isoxazolylcarbonyl-oxy)-isocaproic acid is obtained in (R)-1-| (3-isoxazolylcarbonyl)oxy1-3-methylbutyl1-penicillin sodium, m.p. 188 (cleavage), |a| - +209.6° (c = 1 ethanol). ;The (R)-2-(3-isoxazolyl-carbonyloxy)-isocaproic acid used here as starting material can be obtained via its benzyl ester analogously to the instructions given in example 1 for the preparation of the starting material. EXAMPLE 2 8 Analogous to example 1 is obtained with ( R)-2-(3-indolylcarbonyloxy)-isocaproic acid |(R)-1-|(indol-3-yl-carbonyl)oxy |-3-methylbutyl I ;25 penicillin sodium; mp 175 (decomposition), [ o | = +131.2 ;(c =1 in ethanol) 1 ;The (R)-2-(3-indolyl-carbonyloxy)-4-socacproic acid used here as starting material can be obtained via its benzyl ester analogously to the indications given in example 1 for the production of the starting material. ;EXAMPLE 29;Arialogous example 2 is obtained with (S)-2-(isonicotinoyloxy)-isocaproic acid hydrochloride. 177 o (cleavage), | a| 2 5= +225; (c = 2 in water)'. The starting material used here is obtained by treating (S)-2-(isonicotinoyloxy)-isocaproic acid with thionyl chloride. . Sew clean on its side / m.p. 138 - 139°C, | o;\^ = +22.3° (c = 2 in ethanol) / one obtains via its benzyl ester analogously to the indications given in the example for the preparation of the starting material. ;EXAMPLE 30;Analogous example 2 is obtained with (RS)-2-(2,6-dimethyliso-nicotinoyloxy)-isocaproic acid hydrochloride I (RS)-1-| (2,6-dimethyl--, i i i25 i sonicotinoyl)oxy|-3-methylbutyl |penicillin sodium; | a \ +159° (c = 2 in water) . ;The starting material used here is obtained by treating (RS)-2-(2,6-dimethylisonicotinoyloxy)-isocaproic acid with thionyl chloride. The acid on the other hand / m.p. 95 - 96 C / ; one obtains with its benzyl ester, analogously to the indications given in example 35 for the preparation of the starting material. ;EXAMPLE 31;Analogous example 1 is obtained with (R)-2-(cinchoninoyloxy)-isocaproic acid | (R)-1-cinchoninoyloxy)-3-tylbutyl[-penicillin sodium; m.p. 143° (decomposition), |a |25 = +208.7° (c = 1 in ethanol). The (R)-2-(cinchoninoyloxy)-isocaproic acid used here as starting material is obtained via its benzyl ester analogously to the indications given in example 1 for the preparation of the starting material. ;EXAMPLE 3 2;Analogous example 1 is obtained with (R)-2-(7-chlorocinchoninoyloxy)-isocaproic acid |(R)-1-| (7-Chlorocinchoninoyl)oxy[-3-methylbutyl]penicillin sodium; m.p. 135 (cleavage), f t>. | = +196.4 ;(c = 1 in ethanol) . The (R)-2-(7-chlorocinchoninoyl-oxy)-isocaproic acid used here as starting material can be obtained via its benzyl ester analogously to the indications given in example 1 for the preparation of the starting material. EXAMPLE 33 Analogous to example 1, with (R)-2-(2-chloronicotinoyloxy)-isocaproic acid .[ (R)-1-1 (2-chloronicotinoyl)<-oxyI-3-methylbutyl>|<-> penicillin-potassium; m.p. 120 o (cleavage), | 1cv ,| 25 = +167.3o (c = 1 in water) . ;The hereby used as starting material (R.)-2-(2-chloronicotinoyl-oxy)-isocaproic acid / m.p. 64 - 67°C, | |^~<*>= +17.5° .(c

1 in methanol) / can be obtained via its tert. butyl ester analogue

the specifications given in example 16 for the production of the starting material.

EXAMPLE 34

Analogous to example 1, one obtains with (R)-2-(chinaldoyloxy)-isocaproic acid | (R (-3-methyl-1-(chinaldoyloxy)-butyl|-penicillin-sodium; m.p.' 170° (dec.), | a |25 = +119.3° (c = 1 in ethanol). It hereby (R)-2-(chinaldoyloxy)-isocaproic acid used as starting material can be obtained via its benzyl ester analogously to the indications given in example 22 for the preparation of the starting material.

EXAMPLE 35

Analogous to example 1, one obtains with (RS)-2-(isonicotinoyloxy)-isocaproic acid .[ (RS)-1-(isonicotinoyloxy)-3-methylbutyl | -

'25 o

penicillin sodium; |a | = +197.5 . (c = 2 in, water).

The starting material used here can be obtained as following:.

To a solution of 12.8 g of isonicotinic acid in a mixture of 60 ml of dimethylformamide and 14.8 ml of triethylamine is added dropwise at 60°

with stirring and in the course of 15 minutes 29.5 g of (RS) -ct-bromo-isocaproic acid benzyl ester. The reaction mixture is stirred for 5 hours at 90°. The triethylamine hydrobromide is suctioned off and the filtrate evaporated under reduced pressure at 60°. The residue is dissolved in 100 ml of ethyl acetate, filtered and the filtrate is washed three times with each time 15 ml of l-n-potassium bicarbonate solution and twice with each time 20 ml of water. The ethyl acetate solution is dried with magnesium sulfate and evaporated under reduced pressure at -45°. The RS-2-(isonicotinoyloxy)isocaproic acid benzyl ester is obtained as an oil.

For purification, this ester is dissolved in 10 ml of ethyl acetate, mixed with a solution of 19 g of p-toluenesulfonic acid in 35 ml of ethyl acetate and crystallized over the course of 2 hours at 0°. The (RS)-2-(isonicotinoyloxy)-isocaproic acid benzyl ester p-toluenesulfonate is filtered off with suction, washed with 100 ml of ether and dried under reduced pressure at 60; m.p. 136°. The p-toluenesulfonate is dissolved in 30 ml of water, adjusted to pH 9 with potassium carbonate and extracted twice with 50 ml of ethyl acetate each time. The ethyl acetate solution is washed twice with 10 ml of water each time, dried with magnesium sulphate and evaporated under reduced pressure at 40°. The oil gives after'crystallization

in low-boiling petroleum ether (RS)-2-(isonicotinoyloxy)-isocaproic acid benzyl ester with m.p. 49 - 50°•

8.2 g of (RS)-2-(isonicotinoyloxy)-isocaproic acid benzyl ester is hydrogenated in 50 ml of alcohol after adding 800 ml of palladium charcoal (5% strength) until the theoretical amount of hydrogen has been taken up. The catalyst was filtered off and the filtrate was evaporated under reduced pressure at 45 . The oil is dissolved in an excess of sodium bicarbonate solution, extracted twice with 20 ml each time. the etherbg bicarbonate solution is adjusted with 3-n hydrochloric acid to pH 2.5.

The acidic solution is extracted twice with .70 ml of ethyl acetate each time. After washing twice with each time 20 ml of 5% sodium chloride solution, the ethyl acetate solution is dried with mag-. nesium sulfate, evaporated under reduced pressure at 45°, and the remaining oil crystallized in ether-petroleum ether. One obtains (RS)-2-(isonicotinoyloxy)-isocaproic acid with m.p. 98 - 100°.

EXAMPLE. 36

Analogous example 2 is obtained with (RS)-2-(isonicotinoyloxy)-valeric acid | (RS)-1-(isonicotinoyloxy)-butyl|-penicillin sodium; -| a I 25 = +222° (c = 2 in water).

The (RS)-2-(isonicotinoyloxy)-valeric acid (m.p. 152 - 153°C) used here as starting material can be obtained via its benzyl ester analogously to the indications given in example 35 for the preparation of the starting material.

OAK SAMPLE 3 7

Analogous to example 1, (R)-2-(nicotinoyloxy)-isocaproic acid is obtained [(R)-1-(nicotinoyloxy)-3-methylbutyl |penicillin potassium; m.p. 195° (cleavage), | o =-+210.4° (c = 1 in water).

The (R)-2-(nicotinoyloxy)-isocaproic acid used here as starting material can be obtained, via its benzyl ester, analogously to the indications given in example 22 for the preparation of the starting material.

EXAMPLE 38

.Analogous example 1 is obtained with (R)-2-(2-thienoyloxy)-i socapronic acid | (R)-3-methyl-1-(2-thienoyloxy)butyl|-penicillin sodium; [ a|D = +103 ' (c = in water) .

The (R)-2-(2-thienoyloxy)-isocaproic acid used here as starting material I I <v | D 2 5 = +13.7 o'<•'(c = 2 in ethanol)| can be obtained via its tert. butyl ester analogously to the indications given in example 16 for the production of the starting material.

OAK SEMPE L 39

Analogous to example 3, with 2-(2-pyrrolylcarbonyloxy)-isocaproic acid f 3-methyl-1-| ■ (pyrrol-2-ylcarbonyl)-oxy|-butyl|-penicillin sodium as diastereomer mixture with m.p. 208°

(cleavage) | a \^ = +187.5° (c = 1 in ethanol).

The 2-(2-pyrrolylcarbonyl-poxy)-isocaproic acid used here as a starting material can be obtained via its benzyl ester analogously to the indications given in example 35 for the preparation of the starting material.

EXAMPLE 40

Analogous to example 1, one obtains with (R)-2-(1-bxido-isonicotinoyloxy)-isocaproic acid | 3-methyl-1-| (1-Oxido-isonicotino^1)oxy|-butyl|penicillin sodium; m.p. 195° (cleavage), ] u:| = +187°

(c = 2 in water) .

. 'It hereby used as starting material (R)-2-(1-oxido-isonicotinoyloxy)-i socapronic acid [m.p. 168 -169°, | etc. | = +4.2°

(c = 2 in ethanol) | one obtains via its benzyl ester, analogously to the instructions given in example 22 for the preparation of the starting material.

EXAMPLE 41

Analogously to example 3, one obtains with (R)-2-(2,4-dimethyl.-5-pyrimidinylcarbonyloxy)-isocaproic acid [ (R)-1-| (2,4-dimethyl-5-pyrimidinyl-25 ■ o carbonyl)oxy1-3-methylbutyl1-penicillin sodium; in | a\ i 2=+22' 5

(c = 1 in water), m.p. 185° (cleavage).

The (R)-2-(2,4-dimethyl-5-pyrimidinylcarbonyloxy)-isocaproic acid used here as starting material, an oily substance, can be obtained via its benzyl ester analogously to the indication given in example 1 for the preparation of the starting material.

EXAMPLE 4 2

Analogously, example 3 is obtained with (R)-2-(5-pyrimidinylcarbonyloxy)isocaproic acid I (R)-1-| (5-pyrimidinylcarbonyl)oxy 1-3-methylbutyl|penicillin sodium; IwlD 2 5 +237 o (c = 1 in ethanol), m.p. 205° (decomposition)..

Hereby, using (R)-2-(5-pyrirru,dinyl-carbonyloxy)-i socaproic acid, an oily substance, can be obtained

via its benzyl ester analogously to the indication given in example 1

for the production of the starting material.

EXAMPLE 4 3 Analogous to example 3, one obtains with (R)-2-(2-methoxycarbonyl-nicotinoyloxy)-isocaproic acid | (R)-1-(2-Methoxycarbonyl-nicotinoyloxy)-3-methylbutyl|penicillin sodium; which melts above 145° during cleavage; | tv| = +195 (c = 1 in water) .

Hereby, (R)-2-(2-methoxycar-

o 25 bonyl-nicotinoyloxy)-in socaproic acid (m.p. 63 - 65 C, | cx | = + 27.1 • (c = 1 in methanol) | can be obtained via its benzyl ester analogously to the indications given in example 3 for the preparation of the starting material .

OAK SAMPLE 44

Analogous to example 1, one obtains with (R)-2-(5-methoxymethyl-2-furoyloxy)-isocaproic acid [(R)-1-(5-methoxymethyl-2-furoyloxy)-3-methylbutyl|penicillin sodium; m.p. 173 o C (s- splitting); | i cx |D 25 +203° (c = 1 in water).

The (R)-2-(5-methoxymethyl-2-furoyloxy)-isocaproic acid (m.p. 73 - 74°C) used here as starting material can be obtained via its benzyl ester analogously to the indications given in example 1

for the production of the starting material.

EXAMPLE 45

Analogous to example 1, one obtains with (R)-2-| (S)-5-oxotetrahydro-2-furoyloxy|-isocaproic acid | (R)-3-methyl-1-(|S|-5-oxotetrahydro-2-furoyloxy)butylpenicillin sodium; m.p. 216°€ (cleavage);

I a \^ ' = +235° (c 1 in water) .

The (R)-2-1 (S)-5-oxotetra-

h+y2d3r,4 oo -2-(c fur= oy0l,o5 ki syd|-ioiksoskanåp)r| onershyroe lde|r smppa. n 1v1. i5 a - - de1n16 s . bCe; ' nz|yol|D e2 5 ster■ analogously to the indication given in example -.22 for the production of the starting material.

EXAMPLE EL 4 6

Analogous to that in example 1, one obtains with (R) — 2—| (R)-5-bisotetrahydro-2-furoyloxy)-isocaproic acid | (R)-3-methyl-1-(|R| -5-oxo-tetrahydro-2-furoyloxy ) butyl | penicillin sodium; m.p. 215°C

(cleavage), | a:| 2 5 =.+196 o (c = 1 in water).

It hereby used as starting material (R)-2-1 (R)-5-oxotetra-hydro-2-furoyloxy |-i socaproic acid, an oily substance,

is obtained via its benzyl ester analogously to those in example 22

stated specifications for the production of the starting material.

EXAMPLE 4 7

A gelatin stick capsule with the following content is produced in the usual way:

EXAMPLE 4 8

It is produced on. usually, way a lyophilisate. with the following composition calculated for 2 ml ready-to-spray solution:

This lyophilisate is filled in an ampoule; such an ampoule contains the lyophilized active substance for 2.2. ml ready-to-spray solution. For the production of 2.2 ml of solution ready for spraying, add 2 ml of water to the lyof in the seed.,

Claims (1)

1. Connections, .karakta\ - i s o r t. by. the formula where T means a C 2 -5 alkyl or oicenyl residue or cyclopropylmethyl or cyclobutyl Itnetyl residue or cyclopentyl residue oq A bet.yr tu ryi, tetrahydrofuryl, pyrrolyl. pyrrolidinyl, ti.eny.1 . oxazoly] , in r; ok km/.ol y.l . t iazolyl.. 1,2,3-ti adiuzo]yl , imidazoly], pyrazo l.yl, pyridyl, 1-oxidor>yr idyl, ■ tet r ei hyd r opyr ony 1.. py riinidi nyl. pyrazinyl. . benzofuranyl, indolyl, cliinolyl . i sar: hi noi yl oq "where the radical A can be substituted with halogen, ok so, hydroxy, amino, C 3-alkyl. C 3-3-alkyloxy, -nlkoxycarbonyl and/or C-3-alkanoylamino, as well as salts and hydrated forms. . 2..Compounds according to claim 1, characterized v c. d al; A means 3-pyridyl.. 2-ir.eth.yl-4-pyridyl, 3-isoxenzolyl. 4-oxazoly]. 2-oxo-2-pyrrolidinyl,' pyrazinyl, tetrahydro-- 2-furyl. 2-c.icelaini.do-4-thi azolyl, '1,5-dimethyl-3-pyrazoly 1 . Lel.r ahydro-4-pyt. any 1. 1.. 2 . 3-thi.a.diazol-4-yl, 2-furyl or 4-pyridyl, as well as salts and hydrated forms thereof. in Compounds according to claim 1 or 2, characterized in that T is an alkyl or alkenyl group with 4 or 5 C atoms, as well as salts and hydrated forms thereof. 4. Compounds according to claim 1, 2 or 3, characterized in that T means isobutyl, as well as salts and hydrated forms thereof. 5. A compound according to one of claims 1-3, characterized in that A means 2-furyl and T isobutyl, as well as salts and hydrated forms thereof. 6. Compounds according to one of claims 1 - 5, characterized in that the acyl residue exhibits R-configuration. 7. [(R)-1-(2-furoyloxy)-3-methylbutylpenicillin sodium. 8. Preparations with antibiotic properties, characterized in that they exhibit a content of an acyl derivative of formula I according to the definition in claim 1 or a pharmaceutical. cosmetically useful salt thereof or a hydrate. 9. Preparation according to claim 8, characterized in that it contains [(R)-1-(2-furoyloxy)-3-methylbutyl]-penicillin or a pharmaceutically usable salt thereof or a hydrate.