Antibiotic preparations having increased effectiveness, processes for their manufacture and method for increasing the antibiotic action of antibiotics

Claim 2

Pharmaceutical preparations with antibiotic activity comprising an antibiotically effective amount of a combination of at least one antibiotic and an amount effective to increase the activity of said antibiotic of at least one muramylpeptide of the formula (I) ##STR14## wherein X represents carbonyl or carbonyloxy, R 1 represents optionally substituted alkyl or aryl, R 2 , R 4 and R 6 represent hydrogen or lower alkyl, R 3 represents hydrogen or lower alkyl, R 5 represents hydrogen, lower alkyl, free or functionally modified hydroxy-lower alkyl, free or functionally modified mercapto-lower alkyl, optionally substituted amino-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, optionally substituted aryl or aralkyl, nitrogen-containing heterocyclyl or heterocyclyl-lower alkyl, or R 4 and R 5 together represent also alkylene having 3 or 4 carbon atoms, R 7 represents hydrogen or optionally esterified or amidated carboxyl, and one of the radicals A 1 and A 2 represents a radical of the formula ##STR15## wherein T represents NH or O, Y represents an optionally substituted alkylene group that can also be interrupted by one or two oxycarbonyl and/or iminocarbonyl groups, W represents hydrogen, and Z represents a 1,2-dihydroxyethyl or 2-hydroxyethyl group in which at least one hydroxy group is esterified by an optionally unsaturated long-chain aliphatic carboxylic acid or etherified by an optionally unsaturated long-chain aliphatic alcohol, or each of W and Z represents a hydroxymethyl group esterified by an optionally unsaturated long-chain aliphatic carboxylic acid or etherified by an optionally unsaturated long-chain aliphatic alcohol, and the other of the radicals A 1 and A 2 represents free or etherified hydroxy, free or alkylated amino, lower alkylamino or aminocarbonyl-lower alkylamino, and/or a pharmaceutically acceptable salt thereof together with a significant amount of a pharmaceutically acceptable carrier.

Claim 3

Preparations according to claim 1 that contain at least one antibiotic from the group consisting of β-lactam antibiotics, aminoglycosides, tetracyclines, macrolides, lincomycins, polyene antibiotics, polypeptide antibiotics, anthracyclines, chloramphenicols and thiamphenicols, cycloserines, fusidic acids or rifamycins.

Claim 4

Preparations according to claim 1 that contain as antibiotic a penicillin, cephalosporin, penem, nocardicin, thienamycin, a clavulanic compound, a streptomycin, neomycin, tobramycins, a kanamycin, gentamycin or sisomycin.

Claim 5

Preparations according to claim 1 that contain as antibiotic amoxycillin, ampicillin, carbenicillin, cloxacillin, cyclacillin, dicloxacillin, mecillinam, methicillin, penicillin G, penicillin V, pivampicillin, sulbenicillin, azlocillin, ticarcillin, mezlocillin, pivmecillinam, 6-(4-endoazatricyclo[5.2.2.0 2 ,6 ]undec-8-enyl)-methyleneaminopenicillanic acid, cefaclor, cefazaflur, cefazolin, cefadroxil, cefoxitin, cefuroxime, cephacetril, cephalexin, cephaloglycin, cephaloridines, cephalothin, cefamandole, cephanon, cephapirin, cefatrizine, cephradine, cefroxadin {(7β-[D-2-amino-2-(1,4-cyclohexadienyl)-acetamido]-3-methoxy-3-cephem-4-carboxylic acid}, cefsulodin, cefotaxime, cefotiam, ceftezole, cefazedon, nocardicin A, thienamycin, clavulanic acid, streptomycin, streptomycin A, neomycin B, tobramycin, dibekacin, mixtures of kanamycin A, B and C, amicacins, mixtures of gentamycin A, C 1 , C 2 or C 1a , sisomycin, netilmycin, lividomycin, ribocamycin, paromomycin, tetracycline, doxycycline, chlorotetracycline, oxytetracycline, methacycline, maridomycin, spiramycins, erythromycins, oleandomycins, lincomycins, amphothericin B and the methyl ester thereof, nystalin, colistin, gramicidin S, polymyxin B, virginiamycin, tyrothricin, viomycin, vancomycin, rifamycin S, -SV, B or semisynthetic derivatives thereof.

Claim 6

Preparations according to claim 1 that contain as antibiotic cephacetril, cefadroxil, rifampicin, cefsulodin, cefroxadin, bicozamycin or cefotiam.

Claim 7

Preparations according to one of claims 1 to 5 that contain per dosage unit between 50 and 1000 mg of antibiotic and, in the case of orally administrable preparations, between 1 mg and 50 mg of muramylpeptide or, in the case of orally administrable coated tablets that are resistant to gastric juice or in the case of injectable preparations, between 0.01 mg and 50 mg of muramylpeptide, together with a pharmaceutically acceptable carrier.

Claim 8

Preparations according to one of claims 1 to 5 wherein X represents carbonyl, R 1 represents optionally substituted alkyl having up to 18 carbon atoms or aryl having up to 30 carbon atoms, R 2 , R 3 , R 4 and R 6 represent hydrogen or lower alkyl, R 5 represents hydrogen; lower alkyl optionally substituted by hydroxy, lower alkoxy, mercapto, lower alkylmercapto, amino, lower alkylamino or by halogen; cycloalkyl or cycloalkyl-lower alkyl, wherein the cyloalkyl radical contains from 4 to 6 carbon atoms; optionally substituted phenyl or phenyl-lower alkyl; heterocycyl or heterocyclyl-lower alkyl, each having 5 or 6 ring members and containing one or two aza atoms, or R 4 and R 5 together represent also alkylene having 3 or 4 carbon atoms, R 7 represents hydrogen, and one of the radicals A 1 and A 2 represents a radical of the formula ##STR16## wherein T represents NH or O, Y represents optionally substituted alkylene that has up to 20 carbon atoms and can also be interrupted by carbonyloxy or carbonylimino, W represents hydrogen, and Z represents a 1,2-dihydroxyethyl or 2-hydroxyethyl group in which at least one hydroxy group is esterified by an optionally unsaturated long-chain aliphatic carboxylic acid having up to 30 carbon atoms or by a mycolic acid, or is etherified by an optionally unsaturated long-chain aliphatic alcohol having up to 30 carbon atoms, or each of W and Z represents a hydroxymethyl group esterified by an optionally unsaturated long-chain aliphatic carboxylic acid having up to 30 carbon atoms or by a mycolic acid or etherified by an optionally unsaturated long-chain aliphatic alcohol having up to 30 carbon atoms, and the other of the radicals A 1 and A 2 represents free or etherified hydroxy, amino, lower alkylamino or aminocarbonyl-lower alkylamino.

Claim 9

Preparations according to one of claims 1 to 5 wherein X represents carbonyl, R 1 represents lower alkyl optionally substituted by hydroxy, lower alkoxy or by halogen; or phenyl optionally substituted by hydroxy, lower alkoxy, lower alkyl or by halogen, R 2 , R 4 and R 6 represent hydrogen or methyl, R 3 represents hydrogen, methyl or ethyl, R 5 represents hydrogen; lower alkyl having from 1 to 7 carbon atoms optionally substituted by hydroxy, lower alkoxy, mercapto, lower alkylmercapto or by halogen; 4-aminobutyl; cycloalkyl or cycloalkyl-lower alkyl wherein the cycloalkyl radical contains from 4 to 6 carbon atoms and the lower alkyl radical contains from 1 to 3 carbon atoms; phenyl or phenyl-lower alkyl having from 1 to 3 carbon atoms in the lower alkyl radical and optionally substituted by hydroxy, lower alkoxy or by halogen; 4-imidazolylmethyl or 3-indolylmethyl, or R 4 and R 5 together represent also alkylene having 3 or 4 carbon atoms, R 7 represents hydrogen and one of the radicals A 1 and A 2 represents a radical of the formula ##STR17## wherein T represents NH or O, Y represents lower alkylene or a radical of the formulae --Y.sub.1 --COO--Y.sub.2 (IIIa) or --Y.sub.1 --CONH--Y.sub.2 (IIIe) in which each of Y 1 and Y 2 independently of the other represents lower alkylene that has from 1 to 7 carbon atoms and is optionally substituted by lower alkyl, W represents hydrogen and Z represents a 1,2-dihydroxyethyl or 2-hydroxyethyl group in which at least one hydroxy group is esterified by an aliphatic carboxylic acid having from 14 to 24 carbon atoms and optionally containing one or two unsaturated bonds, or by a natural or synthetic mycolic acid or etherified by an aliphatic alcohol having from 10 to 20 carbon atoms and optionally containing one to two unsaturated bonds, or each of W and Z represents a hydroxymethyl group esterified by an aliphatic carboxylic acid having from 16 to 22 carbon atoms and optionally containing one or two unsaturated bonds, or by a natural or synthetic mycolic acid or etherified by an aliphatic alcohol having from 12 to 18 carbon atoms and optionally containing one or two unsaturated bonds, and the other of the radicals A 1 and A 2 is hydroxy, lower alkoxy, amino, lower alkylamino or aminocarbonyl-lower alkylamino.

Claim 10

Preparations according to one of claims 1 to 5 wherein X represents carbonyl, R 1 represents lower alkyl or phenyl, R 2 , R 6 and R 7 represent hydrogen, R 3 and R 4 represent hydrogen or methyl, R 5 represents hydrogen, lower alkyl having from 1 to 7 carbon atoms optionally substituted by phenyl, or R 4 and R 5 together represent also trimethylene, wherein A 1 represents hydroxy, lower alkoxy, amino, lower alkylamino or aminocarbonyl-lower alkylamino and A 2 represents a radical of the formula ##STR18## wherein T represents NH or O, Y represents ethylene or a radical of the formulae ##STR19## wherein each of Y 1 and Y 2 independently of the other represents unsubstituted lower alkylene, W is hydrogen and Z is a 1,2-dihydroxyethyl or 2-hydroxyethyl group in which at least one hydroxy group is esterified by an alkanecarboxylic acid having from 16 to 20 carbon atoms and optionally containing one or two unsaturated bonds, or etherified by an alkanol having from 12 to 18 carbon atoms and optionally containing one or two unsaturated bonds, or each of W and Z represents a hydroxymethyl group esterified by an alkanecarboxylic acid having from 16 to 22 carbon atoms and optionally containing one or two unsaturated bonds, or etherified by an alkanol having from 12 to 18 carbon atoms and optionally containing one or two unsaturated bonds, and those compounds in which the meanings for A 1 and A 2 are interchanged.

Claim 11

Preparations according to one of claims 1 to 5 wherein X represents carbonyl, R 1 represents lower alkyl or phenyl, R 2 , R 4 , R 6 and R 7 represent hydrogen, R 3 represents hydrogen or methyl, R 5 represents lower alkyl having from 1 to 3 carbon atoms, A 1 represents amino and A 2 represents a radical of the formula ##STR20## wherein R d represents the acyl radical of an alkanecarboxylic acid having from 16 to 20 carbon atoms and optionally containing one or two unsaturated bonds.

Claim 12

Method for increasing the activity of antibiotics in mammals including man comprising administering to said mammals at least one antibiotic and an amount effective to increase the activity of said antibiotic of at least one muramylpeptide according to claim 1.

Claim 13

Animal feedstuffs and feedstuff additives that contain an antibiotically effective amount of a combination comprising at least one antibiotic and an amount effective to increase the activity of said antibiotic of at least one muramylpeptide according to claim 1.

Claim 14

A pharmaceutical preparation according to claim 1, that contains an effective amount of amphotericin B and the sodium salt of N-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-alanyl-2-(1',2'-dipalmitoyl-sn-glycero-3'-hydroxyphosphoryloxy)ethylamide, together with a pharmaceutically acceptable carrier.

Claim 15

Preparations according to claim 7 that contain per dosage unit between 50 and 1000 mg of antibiotic and, in the case of orally administrable preparations, between 1 mg and 50 mg of muramylpeptide or, in the case of orally administrable coated tablets that are resistant to gastric juice or in the case of injectable preparations, between 0.01 mg and 50 mg of muramylpeptide, together with a pharmaceutically acceptable carrier.

Claim 16

Preparations according to one of claims 1 to 5 wherein X represents carbonyl, R 1 represents lower alkyl optionally substituted by hydroxy, lower alkoxy or by halogen; or phenyl optionally substituted by hydroxy, lower alkoxy, lower alkyl or by halogen, R 2 , R 4 and R 6 represent hydrogen or methyl, R 3 represents hydrogen, methyl or ethyl, R 5 represents hydrogen; lower alkyl having from 1 to 7 carbon atoms optionally substituted by hydroxy, lower alkoxy, mercapto, lower alkylmercapto or by halogen; 4-aminobutyl; cycloalkyl or cycloalkyl-lower alkyl wherein the cycloalkyl radical contains from 4 to 6 carbon atoms and the lower alkyl radical contains from 1 to 3 carbon atoms; phenyl or phenyl-lower alkyl having from 1 to 3 carbon atoms in the lower alkyl radical and optionally substituted by hydroxy, lower alkoxy or by halogen; 4-imidazolylmethyl or 3-indolylmethyl, or R 4 and R 5 together represent also alkylene having 3 or 4 carbon atoms, R 7 represents hydrogen and one of the radicals A 1 and A 2 represents a radical of the formula ##STR21## wherein T represents NH or O, Y represents lower alkylene or a radical of the formulae --Y.sub.1 --COO--Y.sub.2 (IIIa) or --Y.sub.1 --CONH--Y.sub.2 (IIIe) in which each of Y 1 and Y 2 independently of the other represents lower alkylene that has from 1 to 7 carbon atoms and is optionally substituted by lower alkyl, W represents hydrogen and Z represents a 1,2-dihydroxyethyl or 2-hydroxyethyl group in which at least one hydroxy group is esterified by an aliphatic carboxylic acid having from 14 to 24 carbon atoms and optionally containing one or two unsaturated bonds, or by a natural or synthetic mycolic acid or etherified by an aliphatic alcohol having from 10 to 20 carbon atoms and optionally containing one or two unsaturated bonds, or each of W and Z represents a hydroxymethyl group esterified by an aliphatic carboxylic acid having from 16 to 22 carbon atoms and optionally containing one or two unsaturated bonds, or by a natural or synthetic mycolic acid or etherified by an aliphatic alcohol having from 12 to 18 carbon atoms and optionally containing one of two saturated bonds, and the other of the radicals A 1 and A 2 is hydroxy, lower alkoxy, amino, lower alkylamino or aminocarbonyl-lower alkylamino.

Claim 17

Preparations according to one of claims 1 to 5 wherein X represents carbonyl, R 1 represents lower alkyl or phenyl, R 2 , R 6 and R 7 represent hydrogen, R 3 and R 4 represent hydrogen or methyl, R 5 represents hydrogen, lower alkyl having from 1 to 7 carbon atoms optionally substituted by phenyl, or R 4 and R 5 together represent also trimethylene, wherein A 1 represents hydroxy, lower alkoxy, amino, lower alkylamino or aminocarbonyl-lower alkylamino and A 2 represents a radical of the formula ##STR22## wherein T represents NH or O, Y represents ethylene or a radical of the formulae ##STR23## wherein each of Y 1 and Y 2 independently of the other represents lower alkylene which is unsubstituted or substituted by lower alkyl, W is hydrogen and Z is a 1,2-dihydroxyethyl or 2-hydroxyethyl group in which at least one hydroxy group is esterified by an alkanecarboxylic acid having from 16 to 20 carbon atoms and optionally containing one or two unsaturated bonds, or etherified by an alkanol having from 12 to 18 carbon atoms and optionally containing one or two unsaturated bonds, or each of W and Z represents a hydroxymethyl group esterified by an alkanecarboxylic acid having from 16 to 22 carbon atoms and optionally containing one or two unsaturated bonds, or etherified by an alkanol having from 12 to 18 carbon atoms and optionally containing one or two unsaturated bonds, and those compounds in which the meanings for A 1 and A 2 are interchanged.

Claim 18

Preparations according to one of claims 1 to 5 that contain N-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1',2'-dipalmitoyl-sn-glycero-3'-hydroxyphosphoryloxy)-ethylamide-sodium-salt.

Claim 19

Method according to claim 11, characterised in that the antibiotic is selected from the group consisting of β-lactam antibiotics, aminoglycosides, tetracyclines, macrolides, lincomycins, polyene antibiotics, polypeptide antibiotics, antracyclines, chloramphenicols and thiamphenicols, cycloserines, fusidic acids or rifamycins.

Claim 20

Method according to claim 11, characterised in that the antibiotic is a penicillin, cephalosporin, penem, nocardicin, thienamycin, a clavulanic compound, a streptomycin, neomycin, tobramycin, a kanamycin, gentamycin or sisomycin.

Claim 21

Method according to claim 11, characterised in that the antibiotic is amoxycillin, ampicillin, carbenicillin, cloxacillin, cyclacillin, dicloxacillin, mecillinam, methicillin, penicillin G, penicillin V, pivampicillin, sulbenicillin, azlocillin, ticarcillin, mezlocillin, pivmecillinam, 6-(4-endoazatricyclo[5,2,2,0 2 , 6] undec-8-enyl)-methyleneaminopenicillanic acid, cefaclor, cefazaflur, cefazolin, cefadroxil, cefoxitin, cefuroxime, cephacetril, cephalexin, cephaloglycin, cephaloridine, cephalothin, cefamandole, cephanon, cephapirin, cefatrizine, cephradine, cefroxadin {(7β-[D-2-amino-2-(1,4-cyclohexadienyl)-acetamido]-3-methoxy-3-cephem-4-carboxylic acid}, cefsulodin, cefotaxime, cefotiam, ceftezole, cefazedon, nocardicin A, thienamycin, clavulanic acid, streptomycin, streptomycin A, neomycin B, tobramycin, dibekacin, mixtures of kanamycin A, B and C, anamicacin, mixtures of gentamycin A, C 1 , C 2 or C 1a , sisomycin, netilmycin, lividomycin, ribocamycin, paromomycin, tetracycline, doxycycline, chlorotetracycline, oxytetracycline, methacycline, maridomycin, spiramycin, anerythromycin, oleandomycin, alincomycin, amphothericin B and the methyl ester thereof, nystalin, colistin, gramicidin S, polymyxin B, virginiamycin, tyrothricin, viomycin, vancomycin, rifamycin S, -SV, B or a semisynthetic derivative thereof.

Claim 22

Method according to claim 11, characterised in that the antibiotic is cephacetril, cefadroxil, rifampicin, cefsulodin, cefroxadin, bicozamycin or cefotiam.

Claim 23

Method according to one of claims 11 and 18 to 21, characterised in that in the muramylpeptide X represents carbonyl, R 1 represents optionally substituted alkyl having up to 18 carbon atoms or aryl having up to 30 carbon atoms, R 2 , R 3 , R 4 and R 6 represent hydrogen or lower alkyl, R 5 represents hydrogen; lower alkyl optionally substituted by hydroxy, lower alkoxy, mercapto, lower alkylmercapto, amino, lower alkylamino or by halogen; cycloalkyl or cycloalkyl-lower alkyl, wherein the cycloalkyl radical contains from 4 to 6 carbon atoms; optionally substituted phenyl or phenyl-lower alkyl; heterocycyl or heterocyclyl-lower alkyl, each having 5 or 6 ring members and containing one or two aza atoms, or R 4 and R 5 together represent also alkylene having 3 or 4 carbon atoms, R 7 represents hydrogen, and one of the radicals A 1 and A 2 represents a radical of the formula ##STR24## wherein T represents NH or O, Y represents optionally substituted alkylene that has up to 20 carbon atoms and can also be interrupted by carbonyloxy or carbonylimino, W represents hydrogen, and Z represents a 1,2-dihydroxyethyl or 2-hydroxyethyl group in which at least one hydroxy group is esterfied by an optionally unsaturated long-chain aliphatic carboxylic acid having up to 30 carbon atoms or by a mycolic acid, or is etherified by an optionally unsaturated long-chain aliphatic alcohol having up to 30 carbon atoms, or each of W and Z represents a hydroxymethyl group esterified by an optionally unsaturated long-chain aliphatic carboxylic acid having up to 30 carbon atoms or by a mycolic acid or etherified by an optionally unsaturated long-chain aliphatic alcohol having up to 30 carbon atoms, and the other of the radicals A 1 and A 2 represents free or etherified hydroxy, amino, lower alkylamino or aminocarbonyl-lower alkylamino.

Claim 24

Method according to one of claims 11 and 18 to 21, characterised in that in the muramylpeptide X represents carbonyl, R 1 represents lower alkyl optionally substituted by hydroxy, lower alkoxy or by halogen; or phenyl optionally substituted by hydroxy, lower alkoxy, lower alkyl or by halogen, R 2 , R 4 and R 6 represent hydrogen or methyl, R 3 represents hydrogen, methyl or ethyl, R 5 represents hydrogen; lower alkyl having from 1 to 7 carbon atoms optionally substituted by hydroxy, lower alkoxy, mercapto, lower alkylmercapto or by halogen; 4-aminobutyl; cycloalkyl or cycloalkyl-lower alkyl wherein the cycloalkyl radical contains from 4 to 6 carbon atoms and the lower alkyl radical contains from 1 to 3 carbon atoms; phenyl or phenyl-lower alkyl having from 1 to 3 carbon atoms in the lower alkyl radical and optionally substituted by hydroxy, lower alkoxy or by halogen; 4-imidazolylmethyl or 3-indolylmethyl, or R 4 and R 5 together represent also alkylene having 3 or 4 carbon atoms, R 7 represents hydrogen and one of the radicals A 1 and A 2 represents a radical of the formula ##STR25## wherein T represents NH or O, Y represents lower alkylene or a radical of the formulae --Y.sub.1 --COO--Y.sub.2 (IIIa) or --Y.sub.1 --CONH--Y.sub.2 (IIIe) in which each of Y 1 and Y 2 independently of the other represents lower alkylene that has from 1 to 7 carbon atoms and is optionally substituted by, lower alkyl, W represents hydrogen and Z represents a 1,2-dihydroxyethyl or 2-hydroxyethyl group in which at least one hydroxy group is esterified by an aliphatic carboxylic acid having from 14 to 24 carbon atoms and optionally containing one or two unsaturated bonds, or by a natural or synthetic mycolic acid or etherified by an aliphatic alcohol having from 10 to 20 carbon atoms and optionally containing one or two unsaturated bonds, or each of W and Z represents a hydroxymethyl group esterified by an aliphatic carboxylic acid having from 16 to 22 carbon atoms and optionally containing one or two unsaturated bonds, or by a natural or synthetic mycolic acid or etherified by an aliphatic alcohol having from 12 to 18 carbon atoms and optionally containing one or two unsaturated bonds, and the other of the radicals A 1 and A 2 is hydroxy, lower alkoxy, amino, lower alkylamino or aminocarbonyl-lower alkylamino.

Claim 25

Method according to one of claims 11 and 18 to 21, characterised in that in the muramylpeptide X represents carbonyl, R 1 represents lower alkyl or phenyl, R 2 , R 6 and R 7 represent hydrogen, R 3 and R 4 represent hydrogen or methyl, R 5 represents hydrogen, lower alkyl having from 1 to 7 carbon atoms optionally substituted by phenyl, or R 4 and R 5 together represent also trimethylene, wherein A 1 represents hydroxy, lower alkoxy, amino, lower alkylamino or aminocarbonyl-lower alkylamino and A 2 represents a radical of the formula ##STR26## wherein T represents NH or O, Y represents ethylene or a radical of the formulae ##STR27## wherein each of Y 1 and Y 2 independently of the other represents unsubstituted lower alkylene, W is hydrogen and Z is a 1,2-dihydroxyethyl or 2-hydroxyethyl group in which at least one hydroxy group is esterified by an alkanecarboxylic acid having from 16 to 20 carbon atoms and optionally containing one or two unsaturated bonds, or etherified by an alkanol having from 12 to 18 carbon atoms and optionally containing one or two unsaturated bonds, or each of W and Z represents a hydroxymethyl group esterified by an alkanecarboxylic acid having from 16 to 22 carbon atoms and optionally containing one or two unsaturated bonds, or etherified by an alkanol having from 12 to 18 carbon atoms and optionally containing one or two unsaturated bonds, and those compounds in which the meanings for A 1 and A 2 are interchanged.

Claim 26

Method according to one of claims 11 and 18 to 21, characterised in that in the muramylpeptide X represents carbonyl, R 1 represents lower alkyl optionally substituted by hydroxy, lower alkoxy or by halogen; or phenyl optionally substituted by hydroxy, lower alkoxy, lower alkyl or by halogen, R 2 , R 4 and R 6 represent hydrogen or methyl, R 3 represents hydrogen, methyl or ethyl, R 5 represents hydrogen; lower alkyl having from 1 to 7 carbon atoms optionally substituted by hydroxy, lower alkoxy, mercapto, lower alkylmercapto or by halogen; 4-aminobutyl; cycloalkyl or cycloalkyl-lower alkyl wherein the cycloalkyl radical contains from 4 to 6 carbon atoms and the lower alkyl radical contains from 1 to 3 carbon atoms; phenyl or phenyl-lower alkyl having from 1 to 3 carbon atoms in the lower alkyl radical and optionally substituted by hydroxy, lower alkoxy or by halogen; 4-imidazolylmethyl or 3-indolylmethyl, or R 4 and R 5 together represent also alkylene having 3 or 4 carbon atoms, R 7 represents hydrogen and one of the radicals A 1 and A 2 represents a radical of the formula ##STR28## wherein T represents NH or O, Y represents lower alkylene or a radical of the formulae --Y.sub.1 --COO--Y.sub.2 (IIIa) or --Y.sub.1 --CONH--Y.sub.2 (IIIe) in which each of Y 1 and Y 2 independently of the other represents lower alkylene that has from 1 to 7 carbon atoms and is optionally substituted by lower alkyl, W represents hydrogen and Z represents a 1,2-dihydroxyethyl or 2-hydroxyethyl group in which at least one hydroxy group is esterified by an aliphatic carboxylic acid having from 14 to 24 carbon atoms and optionally containing one or two unsaturated bonds, or by a natural or synthetic mycolic acid or etherified by an aliphatic alcohol having from 10 to 20 carbon atoms and optionally containing one or two unsaturated bonds, or each of W and Z represents a hydroxymethyl group esterified by an aliphatic carboxylic acid having from 16 to 22 carbon atoms and optionally containing one or two unsaturated bonds, or by a natural or synthetic mycolic acid or etherified by an aliphatic alcohol having from 12 to 18 carbon atoms and optionally containing one or two unsaturated bonds, and the other of the radicals A 1 and A 2 is hydroxy, lower alkoxy, amino, lower alkylamino or aminocarbonyl-lower alkylamino.

Claim 27

Method according to one of claims 11 and 18 to 21, characterised in that in the muramylpeptide X represents carbonyl, R 1 represents lower alkyl or phenyl, R 2 , R 6 and R 7 represent hydrogen, R 3 and R 4 represent hydrogen or methyl, R 5 represents hydrogen, lower alkyl having from 1 to 7 carbon atoms optionally substituted by phenyl, or R 4 and R 5 together represent also trimethylene, wherein A 1 represents hydroxy, lower alkoxy, amino, lower alkylamino or aminocarbonyl-lower alkylamino and A 2 represents a radical of the formula ##STR29## wherein T represents NH or O, Y represents ethylene or a radical of the formulae ##STR30## wherein each of Y 1 and Y 2 independently of the other represents lower alkylene which is unsubstituted or substituted by lower alkyl, W is hydrogen and Z is a 1,2-dihydroxyethyl or 2-hydroxyethyl group in which at least one hydroxy group is esterified by an alkanecarboxylic acid having from 16 to 20 carbon atoms and optionally containing one or two unsaturated bonds, or etherified by an alkanol having from 12 to 18 carbon atoms and optionally containing one or two unsaturated bonds, or each of W and Z represents a hydroxymethyl group esterified by an alkanecarboxylic acid having from 16 to 22 carbon atoms and optionally containing one or two unsaturated bonds, or etherified by an alkanol having from 12 to 18 carbon atoms and optionally containing one or two unsaturated bonds, and those compounds in which the meanings for A 1 and A 2 are interchanged.

Claim 28

Method according to one of claims 11 and 18 to 21, characterised in that the muramylpeptide is N-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-al-anine-2-(1',2'-dipalmitoyl-sn-glycero-3'-hydroxyphosphoryloxy)-ethylamide-sodium-salt.

Claim 29

Preparations according to claim 16, that contain per dosage unit between 50 and 1000 mg of antibiotic and, in the case of orally administrable preparations, between 1 mg and 50 mg of muramylpeptide or, in the case of orally administrable coated tablets that are resistant to gastric juice or in the case of injectable preparations, between 0.01 mg and 50 mg of muramylpeptide, together with a pharmaceutically acceptable carrier.

Claim 30

Method according to claim 26, characterised in that between 50 and 1000 mg of antibiotic and 1 mg and 50 mg of muramylpeptide are used.