EP0970065A1 - Antibiotics and process for preparation - Google Patents

Antibiotics and process for preparation

Info

Publication number
EP0970065A1
EP0970065A1 EP97951517A EP97951517A EP0970065A1 EP 0970065 A1 EP0970065 A1 EP 0970065A1 EP 97951517 A EP97951517 A EP 97951517A EP 97951517 A EP97951517 A EP 97951517A EP 0970065 A1 EP0970065 A1 EP 0970065A1
Authority
EP
European Patent Office
Prior art keywords
reaction product
penicillin
antibiotic
cephalosporin
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97951517A
Other languages
German (de)
French (fr)
Other versions
EP0970065A4 (en
Inventor
William L. Truett
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of EP0970065A1 publication Critical patent/EP0970065A1/en
Publication of EP0970065A4 publication Critical patent/EP0970065A4/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Definitions

  • This invention is concerned with the preparation of a wide variety of antibiotics of new and novel structure and antimicrobial activity.
  • the compounds thus prepared are products from the linking of diverse antibiotic moieties via difiinctional organic compounds such as diisocyanates, dianhydrides, diacidchlorides, diepoxides and carbodumides, said antibiotics being drawn from the classes of compounds sulfonamides, penicillins and related, cephalosporins and related, quinolones, chloramphenicol, erythromycins, metronidazole, tetracyclines and aminoglycocides.
  • antimicrobial agents are classified as noted above, and there are many classes in addition to the above-noted ones.
  • This invention is concerned with simple methods of preparing a large number of new and novel structures possessing a wide range of antibiotic activity via linking together two antibiotic moieties.
  • A has the structure drawn from the following classes of antibiotics:
  • aminoglycosides and B drawn from the same classes.
  • L is drawn from a group of difunctional linking reagents.
  • R is a variety of substituents.
  • the sulfonamides listed below are of particular interest:
  • R 3 and R ⁇ are a variety of substituents.
  • the cephalosporins listed below are of particular interest.
  • R 5 is a variety of substituents and the quinoline neucleus contains fluoro atom substitution.
  • the quinolones listed below are of particular interest.
  • the linking reagents are drawn from the type listed below.
  • Y can be aliphatic, alicyciic, aromatic and heterocyclic groups. The particular formulas for each type are listed below.
  • the five linking reagents are: diisocyanates, dianhydrides, diacidchlorides, diepoxides and carbodumides.
  • antibiotics that can be linked are sulfonamides, trimethoprim, penicillins and related structures, cephalosporins and related structures, chloramphenicol, erythromycin, metronidazole, quinolones, tetracyclines and aminoglycosides.
  • Diisocyanates can react with all acid groups, all hydroxyl groups and all primary and secondary amino groups.
  • any antibiotic moiety, A containing a carboxylic acid, hydroxyl or amine function
  • a A can be linked to any other antibiotic moiety B containing a carboxylic acid, hydroxyl or amine function.
  • the diisocyanate can be used to link with an antibiotic moiety containing a single reactive group, as A and B above, or with an antibiotic moiety containing two functional groups as D, carboxylic acid and amine.
  • the diisocyanate can be used to link any two antibiotics containing at least one carboxylic acid, alcohol or amino functional group, and will also effect linkage when each antibiotic moiety contains a plurality of groups.
  • Dianhydrides can be employed to link a wide variety of antibiotic moieties containing hydroxy or primary or secondary amines. The reagent will also link antibiotic molecules where each antibiotic moiety contains a plurality of hydroxy, primary and secondary amine functional groups.
  • Diacidchlorides can be employed to link a wide variety of antibiotic moieties containing hydroxyl and primary or secondary amine functional groups, and also where each moiety contains a plurality of said functions.
  • Diepoxides can be utilized to link a very wide variety of antibiotic moieties where each contains carboxylic acid, alcohol, and primary or secondary amine functional groups, or a plurality of such groups.
  • Carbodumides can be utilized to link a wide variety of antibiotic moieties where each moiety contains at least one of the following functional groups: carboxylic acid, alcohol, and primary or secondary amine. This reagent differs from the four previously discussed since the reagent bonds the two antibiotic moieties via the removal of the elements of water from the functional groups.
  • Moieties containing carboxylic acid groups can be linked with moieties containing carboxylic acid groups to form anhydrides.
  • Moieties containing carboxylic acid groups can be linked to moieties containing alcohols or primary or secondary amines to form esters or amides.
  • Moieties containing hydroxyl groups can be linked to moieties containing hydroxyl or primary or secondary amine groups to form ethers or substituted amines. Where pluralities of the carboxylic acid, hydroxyl or amine functional groups are contained in one or both antibiotic moieties, linkage will occur but the products may be complex and require chromatographic separation.
  • the present invention describes methods for making a number of linked antibiotic molecules.
  • the linked antibiotics are to be utilized in treating various infections in man and animals, without undue adverse side effects such as toxicity, inflammation and allergies.
  • to-be linked compounds There are several groups of these to-be linked compounds which can be enumerated: sulfonamides, penicillins, cephalosporins, quinolones, chloramphenicol, erythryomycin, metronidazole, tetracyclines and aminoglycosides. With each case, the antibiotics to be linked will be taken two at a time from the above groups, thus:
  • Aminoglycosides A streptomycin
  • linking agents that will be used to link the antibiotic moities are drawn from several classes of organic molecules:
  • linking of two antibiotic moieties depends upon the presence of the following groups: carboxyl, amino and hydroxyl and requires a minimum total of two such groups, but with a further plurality may also be utilized.
  • the possible combinations of the three reactive groups are five.
  • the amide product is easily separated from the by-product dicyclo- hexylurea by crystallization or liquid chromatography techniques.
  • the linking rules are as follows:
  • Diisocyanates can react with all acid carboxyl groups, all hydroxyl groups and all primary and secondary amino groups.
  • any antibiotic moiety containing a carboxylic acid group, a hydroxyl group or an amine group can be linked to any other antibiotic moiety also containing a carboxylic acid group, hydroxyl or amine function.
  • a single antibiotic moiety contains a plurality of groups, as a carboxyl group and a hydroxyl group, or a carboxyl group and an amino group
  • this moiety can be linked by reaction with a diisocyanate to a second antibiotic moiety containing a plurality of groups, as a carboxyl group and a hydroxyl group, or a carboxyl group and an amino group.
  • the diisocyanate reagent can be used to link any two antibiotic moieties each containing at least one carboxylic acid, alcohol or amino functional group, and can also be used when each antibiotic contains a plurality of said groups.
  • Dianhydrides can be utilized to link a wide variety of antibiotic moitieties in which each moiety contains at least one hydroxyl or primary or secondary amine group.
  • the dianhydride reagent can also be utilized to link antibiotic moities in which each moiety contains a multiplicity of hydroxyl or amino groups. In cases involving the linking of antibiotic moities containing a multiplicity of groups, a mix of products will be realized but can be separated easily via chromatographic techniques.
  • Diacidchlorides as a linking agent are covered by rules identical to those for dianhydrides.
  • Diacidchlorides can be used to link a wide variety of antibiotic moieties in which each moiety contains at least one hydroxyl or amino group.
  • the aciddichloride reagent can also be used to link antibiotic moieties where each moiety contains a multiplicity of hydroxyl or and amino groups. In cases involving a multiplicity of groups, a mixture of products will be realized which can be separated easily via chromatographic techniques.
  • Diepoxides as linking agents can be used to link antibiotic moities where each moiety contains a carboxyl, hydroxyl, or amino group, or where each moiety contains a plurality of said groups.
  • Diepoxides possessing a plurality of such groups react with the epoxy linking agents a complex mix of products will be formed which can be separated via chromatographic techniques.
  • Carbodumides as linking agents can be utilized to link a very large number of antibiotic types. Antibiotic moieties in which each moiety contains a single carboxyl group yield anhydrides. Antibiotic moities in which one moiety contains a carboxyl group only will react with a moiety containing a single hydroxyl group to form a single ester. Antibiotic moieties containing a plurality of carboxyl and hydroxyl groups will form a complex mixture of esters when reacted with carbodumides. Antibiotic moieties containing a single carboxyl group will react with antibiotic moieties containing a single amino group to form a single product containing an amide group.
  • antibiotic moieties containing a multiplicity of carboxyl, hydroxyl and amino groups are linked via carbodumides, a mixture of esters and amides will be formed.
  • antibiotic moieties containing singular hydroxyl groups or a multiplicity of hydroxyl groups are linked, the products will be singular or multicomponent ethers.
  • the linking of antibiotic moieties containing singular or multiple hydroxyl and amino groups leads to the formation of a single substituted amine, or a multiplicity of amines. All of the mixtures generated by the above said reactions can be separated via chromatographic techniques.
  • Evaluation apply to streaked plate of several cultures ⁇ E. coli, Strep. Group A, P. aruginosa Equipment 250 ml round bottom 3-neck flask equipped with glascol mantle for heating, thermometer, reflux condenser and teflon stirring bar energized by magnetic stirring.
  • reaction time may be as short as 1 hour.
  • IR monitor is via carbodiimide band at 4.50 ⁇ .
  • the dry pyridine solvent 50 ml., is placed in the 250 ml round bottom flask and 1.72 g. (0.01 mole) of p-aminobenzenesulfonamide and 1.68 g. (0.01 mole) of hexyldiisocyanate is added, the temperature raised to 40°C by means of the variac controlling the heating of the glascol mantle. The heating and stirring are continued for 4 hours, and at the end of each hour a small sample is withdrawn from the flask by means of a pippette and examined by means of IR sectroscopy.
  • the IR spectrocopy scan is determined from 2.5 microns to 15.0 microns, and the concentration of diisocyanate is determined from the intensity of the absorption band at 4.45 microns, a band due to the -NCO group.
  • a steady drop in the concentration of the -NCO group indicates progress of the reaction.
  • the concentration of the isocyanate group has dropped by 80 per cent.
  • the reaction is forced to conclusion by raising the temperature to 50°C for two hours, at the end of which time the -NCO group is not detectable by IR spectroscopy.
  • the reaction is terminated by the addition of 50 ml of water and the precipitated reaction product dried in a vacuum oven at 25°C for 2 hours to yield 3.0 g., 8.8 per cent.
  • the product was evaluated for biological activity via applying a 1 per cent solution in pyridine to TLC (thin layer chromatography) plates.
  • the developing solvent used was a 10-90 mixture of acetone and methanol, and the progress was monitored by a UV light.
  • the spots on the chromatogram were evaluated via mechanical removal and the absorbent was separated from the product fraction by dissolving in pyridine, and the pyridine solution was dried onto filter paper. Tabs of the filter paper were applied to ager culture plates streaked with standard bacterial cultures of S. aureus, E. coli and P aureginosa. Standard antibiotics, as p-aminosulfonamide and penicillins were used for comparison. All products showed modest inhibition zones in the vicinity of the filter paper tabs containing the product fractions.

Abstract

A group of reagents, as diisocyanates, dianhydrides, diacidchlorides, diepoxides, carbodiimides and the like are utilized to link a wide variety of antibiotic moieties, reacted two at a time with said reagents, the said antibiotic moieties containing groups reactive with the linking reagents as carboxylic acid, alcohol, primary amine, and secondary amine functional groups, said functional groups being present as singularities or as multiplicities, products being readily purified using chromatographic techniques, and said products of above reactions being valuable for the treatment of microbial infections of man and animals.

Description

ANTIBIOTICS AND PROCESS FOR PREPARATION
FIELD OF THE INVENTION
This invention is concerned with the preparation of a wide variety of antibiotics of new and novel structure and antimicrobial activity. The compounds thus prepared are products from the linking of diverse antibiotic moieties via difiinctional organic compounds such as diisocyanates, dianhydrides, diacidchlorides, diepoxides and carbodumides, said antibiotics being drawn from the classes of compounds sulfonamides, penicillins and related, cephalosporins and related, quinolones, chloramphenicol, erythromycins, metronidazole, tetracyclines and aminoglycocides.
BACKGROUND OF THE INVENTION
The medical literature regarding antimicrobial agents is vast and describes a number of antimicrobials including naturally occurring compounds as well as synthetic or semisynthetic compounds produced in the organic laboratory. These antimicrobial agents are classified as noted above, and there are many classes in addition to the above-noted ones.
It has been realized that the linking of two antibiotic moieties functioning in different fashions, as for example inhibiting cell-wall synthesis or protein synthesis or DNA synthesis, can be of value. Two antibiotic moieties can also be linked in which one is known to attack Gram positive bacteria and another to attack Gram negative bacteria, and this new entity is of value. Usually the synthesis of linked antibiotics requires an extended set of organic laboratory procedures in which prior to the linkage of diverse types, such as quinolones and lactams, certain groups in the molecule must be blocked, the blocked entity then linked to a second antibiotic, which may also require blocking of some functional groups, and also the blocking groups require removal. It has been found surprisingly that a number of difunctional reagents can effect an efficient linkage of very diverse antibiotic structures. Further, the progress of the reaction can easily be followed via IR spectroscopy techniques, and the isolation of meaningful quantities achieved in facile fashion via liquid chromatography techniques.
SUMMARY OF THE IN ENTION
This invention is concerned with simple methods of preparing a large number of new and novel structures possessing a wide range of antibiotic activity via linking together two antibiotic moieties.
A - L - B
wherein A has the structure drawn from the following classes of antibiotics:
1. sulfonamides and related
2. penicillins and related
3. cephalosporins and related
4. quinolones
5. chloramphenicol
6. erythromycin
7. metronidazole
8. tetracyclines
9. aminoglycosides and B, drawn from the same classes.
The classes may be further characterized by the following general formulas and particular examples. L is drawn from a group of difunctional linking reagents. 1. Sulfonamides and Related
where R is a variety of substituents. The sulfonamides listed below are of particular interest:
A. p-aminobenzenesulfonamide
B. sulfamethoxyazole
C. acetylsulfoxazole
D. sulfamethoxypyridazine
E. sulfadiazine
2. Penicillins and Related
n where R is a variety of substituents. The penicillins listed below are of particulai : interest.
A. benzyl penicillin
B. procaine penicillin G
C. phenoxymethyl penicillin
D. ampicillin
E. amoxycillin F. methicillin
G. oxacillin
H. cloxacillin
I. dicloxacillin
J. flucloxacillin
K. nafcillin
L. carbenicillin
M. ticaricillin
N. talampicillin
0. becampicillin
P. pivampicillin
Q. penamcarboxyli ic acid
R. hydroxyethyl penem
S. imipenem
T. amdinocilin
3. CephalosDorins and Related:
where R3 and R^ are a variety of substituents. The cephalosporins listed below are of particular interest.
A. cephalosporin C
B. cephalothin
C. cephaloridine D. cephradine
E. cephazolin
F. cephalexin
G. cefadroxil H. cefaclor
I. cephamandole J. cefuroxine K. cefotaxime L. ceftizoxime M. ceftazidime N. cefoperazone O. cephamycin C P. cefoxitin Q. moxalactam
4. Quinolones
where R5 is a variety of substituents and the quinoline neucleus contains fluoro atom substitution. The quinolones listed below are of particular interest.
A. nalidixic acid
B. norfloxacin C. enoxacin
D. ciprofloxacin
E. ofloxacin
5. Chloramphenicol
6. Ervthromvcin
7. Metronidazole
8. Tetracvclines
where the general formula given above is substituted to yield the particular compounds listed below.
A. tetracycline
B. oxytetracycline
C. chlortetracycline
D. rolitetracycline
E. methacycline
F. doxycycline
G. demeclocycline H. sancycline
I. lymecycline J. clomocycline K. minocycline
9. Aminoglvcosides
Streptomycin (R - CH,NH)
The general formula above is variously substituted to give the particular isomers listed below. A. streptomycin
B. tobramycin C kanamycin
D. amikacin
E. gentamicin Cl
F. nitilimicin
G. neomycin
H. paromomycin I. spectinomycin
The linking reagents are drawn from the type listed below. Diisocyanates NCO - Y - NCO
Diianhydrides
Diacidchlorides O O
I I I I
Cl - C - Y - C - Cl
✓°\ /°\
Diepoxides CH2 - CH - Y - CH - CH2
Carbodumides Y - N = C = N - Y In the above general formulas Y can be aliphatic, alicyciic, aromatic and heterocyclic groups. The particular formulas for each type are listed below. Diisocyanates:
1 ,6-hexamethylenediisocyanate
2,4-tolyldiisocyanate
2,6-tolyldiisocyanate
4,4'-methylene bis phenylisocyanate
4,4-isopropylidene bis phenylisocyanate
1 ,4-phenyldiisothiocyanate
1 ,4-phenyldiisocyanate
Dianhydrides pyromellitic dianhydride bis maleic dianhydride
3,3,4,4'-benzophenonetetracarboxylic dianhydride 1,2,6,7- hexanetetracarboxylic dianhydride 1,2,4,5- naphthalenetetracarboxylic dianhydride
Diacidchlorides terphthaloyl chloride isophthaloyl chloride phthaloyl chloride adipolyl chloride glutaryl chloride Diepoxides 1,3-butane diepoxide 1,5-cyclooctatetraene diepoxide vinylcyclohexene diepoxide 1,4-divinylbenzene diepoxide
Carbodumides dicyclohexylcarbodiimide ditolylcarbodiimide
Rules Based on Linking Agents
Surprisingly only a few rules must be obeyed to take advantage of five different linking reagents applicable to linking two antibiotic molecules. The five linking reagents are: diisocyanates, dianhydrides, diacidchlorides, diepoxides and carbodumides.
The types of antibiotics that can be linked are sulfonamides, trimethoprim, penicillins and related structures, cephalosporins and related structures, chloramphenicol, erythromycin, metronidazole, quinolones, tetracyclines and aminoglycosides.
The linking rules are as follows: 1. Diisocyanates can react with all acid groups, all hydroxyl groups and all primary and secondary amino groups. Thus any antibiotic moiety, A, containing a carboxylic acid, hydroxyl or amine function
COOH OH NH
/ X 7 i A A can be linked to any other antibiotic moiety B containing a carboxylic acid, hydroxyl or amine function.
COOH OH NH
/ / /
B B B
When a single antibiotic moiety contains more than a single functional group, as C,
the diisocyanate can be used to link with an antibiotic moiety containing a single reactive group, as A and B above, or with an antibiotic moiety containing two functional groups as D, carboxylic acid and amine.
COOH D
NH
When a diisocyanate is used to link antibiotic moieties containing a plurality of groups, a mixture of products will be realized, but with chromatographic techniques the mixtures are easily separated.
Summarizing, the diisocyanate can be used to link any two antibiotics containing at least one carboxylic acid, alcohol or amino functional group, and will also effect linkage when each antibiotic moiety contains a plurality of groups. 2. Dianhydrides can be employed to link a wide variety of antibiotic moieties containing hydroxy or primary or secondary amines. The reagent will also link antibiotic molecules where each antibiotic moiety contains a plurality of hydroxy, primary and secondary amine functional groups.
3. Diacidchlorides can be employed to link a wide variety of antibiotic moieties containing hydroxyl and primary or secondary amine functional groups, and also where each moiety contains a plurality of said functions.
4. Diepoxides can be utilized to link a very wide variety of antibiotic moieties where each contains carboxylic acid, alcohol, and primary or secondary amine functional groups, or a plurality of such groups.
5. Carbodumides can be utilized to link a wide variety of antibiotic moieties where each moiety contains at least one of the following functional groups: carboxylic acid, alcohol, and primary or secondary amine. This reagent differs from the four previously discussed since the reagent bonds the two antibiotic moieties via the removal of the elements of water from the functional groups. Moieties containing carboxylic acid groups can be linked with moieties containing carboxylic acid groups to form anhydrides. Moieties containing carboxylic acid groups can be linked to moieties containing alcohols or primary or secondary amines to form esters or amides. Moieties containing hydroxyl groups can be linked to moieties containing hydroxyl or primary or secondary amine groups to form ethers or substituted amines. Where pluralities of the carboxylic acid, hydroxyl or amine functional groups are contained in one or both antibiotic moieties, linkage will occur but the products may be complex and require chromatographic separation.
DESCRIPTION OF THE INVENTION
Section 1
The present invention describes methods for making a number of linked antibiotic molecules. The linked antibiotics are to be utilized in treating various infections in man and animals, without undue adverse side effects such as toxicity, inflammation and allergies.
There are several groups of these to-be linked compounds which can be enumerated: sulfonamides, penicillins, cephalosporins, quinolones, chloramphenicol, erythryomycin, metronidazole, tetracyclines and aminoglycosides. With each case, the antibiotics to be linked will be taken two at a time from the above groups, thus:
sulfonamide + sulfonamide sulfonamide + penicillin sulfonamide + cephalosporin sulfonamide + quinolone sulfonamide + chloramphenicol sulfonamide + erythromycin sulfonamide + metronidazole sulfonamide + tetracycline sulfonamide + aminoglycoside
penicillin + penicillin penicillin + cephalosporin penicillin + quinolones penicillin + chloramphenicol penicillin + erythromycin penicillin + metronidazole penicillin + tetracyclines penicillin + aminoglycosides
cephalosporin + cephalosporin cephalosporin + quinolone cephalosporin + chloramphenicol cephalosporin + erythromycin cephalosporin + metronidazole cephalosporin + tetracyclines cephalosporin + aminoglycoside
quinolone + quinolone quinolone + chloramphenicol quinolone + erythromycin quinolone + metronidazole quinolone + tetracyclines quinolone + aminoglycoside
chloramphenicol + chloramphenicol chloramphenicol + erythromycin chloramphenicol + metronidazole chloramphenicol + tetacyclines chloramphenicol + aminoglycoside erythromycin + erythromycin erythromycin + metronidazole erythromycin + tetracyclines erythromycin + aminoglycoside
metronidazole + metronidazole metronidazole + tetracyclines metronidazole + aminoglycoside
tetracyclines + tetracyclines tetracyclines + aminoglycosides
aminoglycoside + aminoglycoside
Within each of the above groups of antibiotics the members of each to be linked are defined as:
1. Sulfonamides:
A. p-aminobenzenesulfonamide
B. sulfamethoxyazole
C. acetylsulfoxazole
D. sulfamethoxypyridazine
E. sulfadiazine
F. trimethoprim
2. Penicillins:
A. benzyl penicillin
B. procaine penicillin G
C. phenoxymethyl penicillin
D. ampicillin
E. amoxycillin
F. methicillin
G. oxacillin
H. cloxacillin
I. dicloxacillin
J. flucloxacillin
K. nafcillin
L. carbenicillin
M. ticaricillin
N. talampicillin
O. becampiciUin
0 H3C QCHJCHJ
P. pivampicillin
Q. penemcarboxylic acid
Coatf
R. hydroxyethyl penem
S. imipenem
T. amdinocilin
3. Cephalosporins:
A. cephalosporin C
B. cephalothin
C. cephaloridine
D. cephradine
E. cephazolin
F. cephalexin
G. cefadroxil
H. cefaclor
I. cephamandole
J. cefiiroxine
K. cefotaxime
L. ceftizoxime
M. ceftazidime
N. cefoperazone
O. cephamycin C
P. cefoxitin
Q. moxalactam
4. Quinolones:
A. nalidixic acid
B. norfloxacin
C. enoxacin
D. ciprofloxacin
E. ofloxacin
N
5. Chloramphenicol:
6. Erythromycin:
A. erythromycin
7. Metronidazole:
8. Tetracyclines:
B. oxytefracyciine
C. chlortetracycline
D. rolitefracyciine
E. methacycline
F. doxycycline
G. demeclocycline
H. sancycline
I. lymecycline
ccoW. J. clomocycline
K. minocycline
9. Aminoglycosides: A streptomycin
B. tobramycin
C. kanamycin
D. amikacin
E. gentamicin Cl
F. nitilimicin
G. neomycin
H. paromomycin
I. spectinomycin
The linking agents that will be used to link the antibiotic moities are drawn from several classes of organic molecules:
I. Diisocyanates and related structures
II. Dianhydrides
III. Diacidchlorides
IV. Diepoxides V. Dicyclohexylcarbodiimide and related structures The class I linking agents are drawn from the group consisting of the following structures:
I. Diisocyanates and related structures: A. hexamethylene diisocyanate
OCN(CH2)6NCO
B. 2,4-tolyldiisocyanate
C. 2,6-tolyldiisocyanate
D. 4,4 -methylene-bis-phenylisocyanate
E. 4,4'-isopropylidene-bis-phenylisocyanate
F. 1,4-phenyldϋsothiocyanate
G. 1,4-phenyldissocyanate
L fi/J' NC Q
anhydrides:
A. pyromellitic dianhydride
B. bismaleic dianhydride
C. ic anhydride
o D. 1,2,6,7-hexane-tetracarboxylic anhydride
E. 1,2,5,6-naphthalene tetracarboxylic anhydride
III. Diacidchlorides:
A terphthalolyl dichloride
B. isophthaloyl dichloride
C. pthaloyl dichloride
D. adipo
E. glutaryl chloride
IV. Diepoxides and related structures: A. 1,3-butadiene diepoxide
2 _ o / ^o /
B. cyclooctatetraene diepoxide, 1.5
C. vinyl cyclohexene
D. divinylbenzene epoxide
V. Carbodumides and related structures: A. Dicyclohexylcarbodiimide
B. Ditolylcarbodiimide
DESCRIPTION OF THE INVENTION Section 2
Methods of Linking Antibiotic Moieties:
The structure of the two antibiotic moieties being linked will determine the nature of the particular linking agent to be employed. Thus when sulfonamides listed above are to be coupeled the basic sulfonamide structure below shows that the group which will be linking the two sulfonamide
structures is the aromatic amino group. Consideration of the entire group of sulfonamides listed above will show that the only reactive group is the aromatic amino group. Of the five linking reagents listed above, four may be employed: diisocyanates, dianhydrides, diacidchlorides, and diepoxides.
The structures which result from coupling sulfonamides with sulfonamides are shown below.
Y- NCO + li*-® -5 *
When identical sulfonamides are linked only a single product will result, but obviously when two nonidentical sulfonamides species are linked, three products will result as shown below.
K NH* + acN - y~ NCO +- ftW Λltt R '
R H fαW l? '
R H HSO- A)r- H Altt (?
R'H NSi-<g>- NH- £klH - V - NH -f- NH-^ so. NΛ*'
Since, in the experimental section below, equimolar quantities are used in all reactions the mixed products will predominate where the two reacting moieties have diverse structures. The modern methods of liquid chromatography render the separation of such simple mixtures, as above, to be quite simple, thus adequate material can be separated for microbial evaluation tests. Commercial quantities can be separated via preparative scale HPLC (high performance liquid chromatography).
The linking of two antibiotic moieties by utilizing dianhydrides follows a course identical to that described for diisocyanate linking agents, i.e., when a single type moiety is employed, a single product will result, but when two dissimilar moieties are employed, three products will result. As noted with diisocyanates, separation and evaluation of these products is not difficult.
The linking of two antibiotic moieties utilizing diacid chlorides will pursue a course analagous to the reactions of diisocyanates. When a single antibiotic entity reacts with a diacid chloride a single entity results, but when two different entities react, three products are formed.
Symbolically, the three products can be seen as:
H O O H
I ll II I
A-N-C-Y-C-N-A H O O H
I II II I A-N-C-Y-C-N-B
H O O H
I II II I
B-N-C-Y-C-N-B
The reaction of two antibiotic moieties with a diepoxide follows a course similar to the diisocyanate reaction with a single moiety resulting in a single product and two moieties resulting in three products, as shown below.
H ϊ Cfc- CH -V- H -CH* + HaN- -WiNH-a.
K».NWE
It will be noted that in the ring opening reaction the attack occurs on carbon #1 in the epoxy group predominantly.
BNH
A-NH - CH9 - CH - Y - CH - CH - A 1 I i l
OH OH A-NH-CH9 -CH-Y-CH9-CH-B
I I
OH OH
B -NH - CH9 - CH - Y - CH - CH - B
OH OH
The above comments with respect to product mix apply to all antibiotic linking reactions occurring with the linking agents diisocyanates, dianhydrides, diacid chlorides, and diepoxides.
The use of the dicarbodumides with antibiotic moieties follows a different pattern. The situation when linking antibiotic moieties via carbodumides is the result of removing the elements of water from two moieties.
Thus the linking of two antibiotic moieties depends upon the presence of the following groups: carboxyl, amino and hydroxyl and requires a minimum total of two such groups, but with a further plurality may also be utilized. The possible combinations of the three reactive groups are five.
O β // // 1. Y-COOH + Y-COOH-^Y-C-O-C-Y
2. Y-COOH + YOH Y-C-O-Y
P /H 3. Y - COOH + YNH2 ) Y- -N-Y
4. Y-OH-YOH ) Y-O-Y 5. Y-OH + YNH2 > Y-N-Y
1
H
The linking of two antibiotic moieties via the groups above produces the following products:
0 O // //
1. anhydride Y-C-O-C-Y
2. ester Y-C A-O-Y
3. amide Y-C A-NH-Y
4. ether Y-O-Y
5. amine Y-NH-Y
When two antibiotics are linked each containing a single reactive group, as one COOH and one NH2, only a single product will result; see the example below of the reaction of dicyclohexylcarbodiimide with p-aminobenzene- sulfonamide with benzylpenicillin.
>
The amide product is easily separated from the by-product dicyclo- hexylurea by crystallization or liquid chromatography techniques.
When more than two active groups are present on a single moiety as penicillin type, carbenicillin, two products will result when linked with p- aminobenzenesulfonamide via dicyclohexylcarbodiimide, as shown below.
Nrf,
+
Rules are developed in the "Rules" section below to account for all products with all linking reagents linking the many antibiotic moieties.
Linking Rules
The linking rules developed below are based on the interactions of the five linking agents with a large number of eight classes of antibiotics. DESCRIPTION OF THE INVENTION
Section 3
The rules for linking the antibiotic moities are developed by considering all of the above data just concluded for linking all of the individual members of the said eight groups of antibiotics.
The linking rules are as follows:
1. Diisocyanates can react with all acid carboxyl groups, all hydroxyl groups and all primary and secondary amino groups. Thus any antibiotic moiety containing a carboxylic acid group, a hydroxyl group or an amine group, can be linked to any other antibiotic moiety also containing a carboxylic acid group, hydroxyl or amine function.
When a single antibiotic moiety contains a plurality of groups, as a carboxyl group and a hydroxyl group, or a carboxyl group and an amino group, this moiety can be linked by reaction with a diisocyanate to a second antibiotic moiety containing a plurality of groups, as a carboxyl group and a hydroxyl group, or a carboxyl group and an amino group.
When a diisocyanate is utilized to link antibiotic moieties containing a plurality of carboxyl acid, alcohol and amino groups, a mixture of products will be realized, but with chromatographic techniques the mixtures are easily separated.
Summarizing: the diisocyanate reagent can be used to link any two antibiotic moieties each containing at least one carboxylic acid, alcohol or amino functional group, and can also be used when each antibiotic contains a plurality of said groups. 2. Dianhydrides can be utilized to link a wide variety of antibiotic moitieties in which each moiety contains at least one hydroxyl or primary or secondary amine group. The dianhydride reagent can also be utilized to link antibiotic moities in which each moiety contains a multiplicity of hydroxyl or amino groups. In cases involving the linking of antibiotic moities containing a multiplicity of groups, a mix of products will be realized but can be separated easily via chromatographic techniques.
3 Diacidchlorides as a linking agent are covered by rules identical to those for dianhydrides. Diacidchlorides can be used to link a wide variety of antibiotic moieties in which each moiety contains at least one hydroxyl or amino group. The aciddichloride reagent can also be used to link antibiotic moieties where each moiety contains a multiplicity of hydroxyl or and amino groups. In cases involving a multiplicity of groups, a mixture of products will be realized which can be separated easily via chromatographic techniques.
4. Diepoxides as linking agents can be used to link antibiotic moities where each moiety contains a carboxyl, hydroxyl, or amino group, or where each moiety contains a plurality of said groups. When antibiotics possessing a plurality of such groups react with the epoxy linking agents a complex mix of products will be formed which can be separated via chromatographic techniques.
5. Carbodumides as linking agents can be utilized to link a very large number of antibiotic types. Antibiotic moieties in which each moiety contains a single carboxyl group yield anhydrides. Antibiotic moities in which one moiety contains a carboxyl group only will react with a moiety containing a single hydroxyl group to form a single ester. Antibiotic moieties containing a plurality of carboxyl and hydroxyl groups will form a complex mixture of esters when reacted with carbodumides. Antibiotic moieties containing a single carboxyl group will react with antibiotic moieties containing a single amino group to form a single product containing an amide group. When antibiotic moieties containing a multiplicity of carboxyl, hydroxyl and amino groups are linked via carbodumides, a mixture of esters and amides will be formed. When antibiotic moieties containing singular hydroxyl groups or a multiplicity of hydroxyl groups are linked, the products will be singular or multicomponent ethers. The linking of antibiotic moieties containing singular or multiple hydroxyl and amino groups leads to the formation of a single substituted amine, or a multiplicity of amines. All of the mixtures generated by the above said reactions can be separated via chromatographic techniques.
DESCRIPTION OF THE INVENTION
Section 4
Experimental Procedures
General Comments - The procedures outlined and discussed below describe the experimental procedures necessary to carry out the linking procedures with the many antibiotic moieties previously described in this application.
Procedures for each linking reagent.
Coupling reactions using: 1. Diisocyanates:
Solvents pyridine 50 ml anhydrous
DMAC 50 ml anhydrous
DMF 50 ml anhydrous
N-methylpyrrolidone 50 ml anhydrous
Temperature 0 to 50°C
Time 5-10 hours Quantities 0.01 mole each antibiotic moiety, 0.005 mole of linking reagent
Monitor via IR spectroscopy for -NCO group, 4.45 μ Work-up add water to ppt. product achieve separation of products via chromatography; TLC, column or HPLC.
Evaluation apply to streaked plate of several cultures~E. coli, Strep. Group A, P. aruginosa Equipment 250 ml round bottom 3-neck flask equipped with glascol mantle for heating, thermometer, reflux condenser and teflon stirring bar energized by magnetic stirring.
Coupling reactions using:
2. Dianhydrides Solvents Same as "1". Temperature Same as \ Time Same as "1".
Quantities Same as "1". Monitor IR via 5.50 and 5.80 anhydride band Work up See l . Evaluation See l.
Coupling reactions utilizing:
3. Diacid chlorides*
All same as 1, but IR monitor via 5.80 acid chloride band in IR
*Prior to the addition of water to terminate the reaction g. (0.25 ml) of sodium bicarbonate is added in small portions to neutralize all hydrochloric acid.
Coupling reactions utilizing:
4. Diepoxides
All same as in 1, but reaction time may be extended to 24 hours to complete reaction. IR monitor via epoxide band at 9.5 μ. Coupling reactions utilizing: 5. Carbodiimide
All same as 1, but reaction time may be as short as 1 hour. IR monitor is via carbodiimide band at 4.50μ.
Example procedure
1. The reaction p-aminobenzene sulfonamide with sulfapyridine.
The dry pyridine solvent, 50 ml., is placed in the 250 ml round bottom flask and 1.72 g. (0.01 mole) of p-aminobenzenesulfonamide and 1.68 g. (0.01 mole) of hexyldiisocyanate is added, the temperature raised to 40°C by means of the variac controlling the heating of the glascol mantle. The heating and stirring are continued for 4 hours, and at the end of each hour a small sample is withdrawn from the flask by means of a pippette and examined by means of IR sectroscopy. The IR spectrocopy scan is determined from 2.5 microns to 15.0 microns, and the concentration of diisocyanate is determined from the intensity of the absorption band at 4.45 microns, a band due to the -NCO group. A steady drop in the concentration of the -NCO group indicates progress of the reaction. At the end of 4 hours at 40°C the concentration of the isocyanate group has dropped by 80 per cent. The reaction is forced to conclusion by raising the temperature to 50°C for two hours, at the end of which time the -NCO group is not detectable by IR spectroscopy.
The reaction is terminated by the addition of 50 ml of water and the precipitated reaction product dried in a vacuum oven at 25°C for 2 hours to yield 3.0 g., 8.8 per cent. The product was evaluated for biological activity via applying a 1 per cent solution in pyridine to TLC (thin layer chromatography) plates. The developing solvent used was a 10-90 mixture of acetone and methanol, and the progress was monitored by a UV light. The spots on the chromatogram were evaluated via mechanical removal and the absorbent was separated from the product fraction by dissolving in pyridine, and the pyridine solution was dried onto filter paper. Tabs of the filter paper were applied to ager culture plates streaked with standard bacterial cultures of S. aureus, E. coli and P aureginosa. Standard antibiotics, as p-aminosulfonamide and penicillins were used for comparison. All products showed modest inhibition zones in the vicinity of the filter paper tabs containing the product fractions.
Larger quantities of products are obtainable for animal testing most simply via prep scale liquid chromatography.

Claims

What is claimed is:
An acid anhydride of the formula
in which Rj is .
O
II
<^>-0-CH2-C // \N - CH - C -
I o
R2 and R^ are:
O O
II /I
- CH90 - C - CH3, - NH - C - (CH2j 3 -CH - COOH; CH2 OCOCH3, NH -
o
WH
O
-CH3, NH - C - CH -^ - ° H MH .
O
\
CH CH2OCOCH3, NH -
2. A process for preparing the compounds of Claim 1 by reacting a penicillin compound with a cephalosporin compound in the presence of dicyclohexylcarbodiimide in pyridine solution, and isolating the reaction product by means of liquid chromatography and identifying the reaction product by means of IR spectroscopy.
3. A compound of the general formula
where Z is (CH2)n wherein n is 2-20 methylene units and Rj is one of the following groups of antibiotics a) A beta-lactam of the general formula
wherein Y is a side chain containing a pendant amino group;
b) A beta-lactam of the general formula, termed cephalosporin type,
Coo >-J wherein the molecule contains a six-member sulfur-containing ring, R is H, methyl or carboxyl, and R is a complex side chain always carrying a pendant amine group;
c) A quinolone antibacterial of the general formula wherein
R5 is a carbon or a nitrogen atom and the piperazinyl side-chain carries one free secondary amino group;
d) shown containing
a reactive hydroxyl in the 2" position in the diisoamine portion of the erythromycin molecule; all said antibiotics being linked to chloramphenicol;
4. A process for the preparation of the compounds of Claim 3 by reacting 2,2-dichloro-N-[2-hydroxyl-l-hydroxymethyl-2-(4-nitroρhenyl)ethyl] acetamide with a penicillin, a cephalosporin, a quinolone and an erythyromycin in the presence of a diacid chloride of the structure
O O,
Cl - C - (CH2)n - C - Cl wherein n is greater than 2 in pyridine solution and isolating the reaction product by means of liquid chromatography and identifying the reaction product by means of IR spectroscopy.
wherein Z is (CH2)n wherein n is 2-20 and Ri is one of the following groups of antibiotics a) A beta-lactam of the penicillin type where Y is a side chain containing a pendant amino group a) r
I
7 ϋ Co ol'
b) A beta-lactam of the cephalosporin type wherein the molecule contains a 6-membered ring containing sulful, R2 is a methyl, hydrogen or carboxyl group and R3 is a complex side chain carrying one pendant primary amino group,
c) A quinolone antibacterial of the general formula
wherein R5 is a carbon or nitrogen atom and the piperazinyl side- chain carries one free secondary amino group.
6. A process for the preparation of the compounds of Claim 5 by reactioning erythyromvcin with a penicillin, a cephalosporin, and a quinolone in the presence of a diacid chloride, of the structure
wherein n is greater than 2, in pyridine solution and isolating the reaction product by means of liquid chromatography and identifying the reaction product by means of IR spectroscopy.
7. An acid anhydride of the formula
0
in which Rj is equivalent to Rj in Claim 1, and R4 , R5, R^, are respectively
Ethyl, - H, - C = ; Ethyl, H, N = ;
cyclopropyl, H, = C -;
8. A process for the preparation of the compounds of Claim 7 by reacting a penicillin with quinolones in the presence of dicyclohexylcarbodiimide in pyridine solution and isolating the reaction product by means of liquid chromatography and identifying the reaction product by means of IR spectroscopy.
9. A pharmaceutical compound having the following formula
°Z.
where "n" is an integer of 2-12; and where "Z" is selected from the group consi
b)
and
r o /-)
(5
all antibiotic a - e being linked to 2-methyl-5-nitroimidazole-l-ethanol.
10. A process for the preparation of the compounds of Claim 7 by reaction of 2-methyl-5-nitroimidazole-l-ethanol with a penicillin, a cephalosporin, a tetracycline, chloramphenicol, and a quinolone in the presence of a diacid chloride,
O O
Cl - C l - (CH2)n - fc* - Cl wherein n is greater than 2 in pyridine solution and isolating the reaction product by means of liquid chromatography and identifying the reaction product by means of IR spectroscopy.
EP97951517A 1997-11-29 1997-11-29 Antibiotics and process for preparation Withdrawn EP0970065A4 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1997/022012 WO1999028308A1 (en) 1997-11-29 1997-11-29 Antibiotics and process for preparation

Publications (2)

Publication Number Publication Date
EP0970065A1 true EP0970065A1 (en) 2000-01-12
EP0970065A4 EP0970065A4 (en) 2001-03-07

Family

ID=22262179

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97951517A Withdrawn EP0970065A4 (en) 1997-11-29 1997-11-29 Antibiotics and process for preparation

Country Status (2)

Country Link
EP (1) EP0970065A4 (en)
WO (1) WO1999028308A1 (en)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004005309A2 (en) 2002-07-08 2004-01-15 Pliva - Istrazivacki Institut D.O.O. Novel nonsteroidal anti-inflammatory substances, compositions and methods for their use
ATE429441T1 (en) * 2002-07-08 2009-05-15 Glaxosmithkline Zagreb HYBRID MOLECULES OF MACROLIDS WITH STEROIDAL/NON-STEROIDAL ANTI-INFLAMMATORY ACTIVE MOLECULES
AR043050A1 (en) 2002-09-26 2005-07-13 Rib X Pharmaceuticals Inc BIFunctional HETEROCICLICAL COMPOUNDS AND METHODS TO PREPARE AND USE THE SAME
EP1723159B1 (en) 2004-02-27 2019-06-12 Melinta Therapeutics, Inc. Macrocyclic compounds and methods of making and using the same
EP2753326A4 (en) 2011-09-09 2015-04-15 Cubist Pharm Inc Methods for treating intrapulmonary infections
US20140274993A1 (en) 2013-03-15 2014-09-18 Cubist Pharmaceuticals, Inc. Ceftolozane-tazobactam pharmaceutical compositions
CN110279698B (en) 2013-03-15 2022-10-28 默沙东有限责任公司 Ceftolozane antibiotic compositions
US9872906B2 (en) 2013-03-15 2018-01-23 Merck Sharp & Dohme Corp. Ceftolozane antibiotic compositions
US10376496B2 (en) 2013-09-09 2019-08-13 Merck, Sharp & Dohme Corp. Treating infections with ceftolozane/tazobactam in subjects having impaired renal function
US20150094293A1 (en) 2013-09-27 2015-04-02 Calixa Therapeutics, Inc. Solid forms of ceftolozane
WO2016130928A1 (en) 2015-02-12 2016-08-18 Arizona Board Of Regents On Behalf Of Arizona State University Aminoglycoside hydrogel microbeads and macroporous gels with chemical crosslink, method of preparation and use thereof
CN106124683B (en) * 2016-08-26 2017-11-28 中国兽医药品监察所 Method that is a kind of while detecting a variety of antimicrobial components in veterinary drug

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0296573A2 (en) * 1987-06-22 1988-12-28 F. Hoffmann-La Roche Ag Novel nucleosides, their preparation and pharmaceutical compositions
US5180719A (en) * 1988-10-24 1993-01-19 Norwich Eaton Pharmaceuticals, Inc. Antimicrobial quinolonyl lactam esters
US5281703A (en) * 1991-10-01 1994-01-25 Procter & Gamble Pharmaceuticals, Inc. Process for making antimicrobial quinolonyl lactams
US5693791A (en) * 1995-04-11 1997-12-02 Truett; William L. Antibiotics and process for preparation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0296573A2 (en) * 1987-06-22 1988-12-28 F. Hoffmann-La Roche Ag Novel nucleosides, their preparation and pharmaceutical compositions
US5180719A (en) * 1988-10-24 1993-01-19 Norwich Eaton Pharmaceuticals, Inc. Antimicrobial quinolonyl lactam esters
US5281703A (en) * 1991-10-01 1994-01-25 Procter & Gamble Pharmaceuticals, Inc. Process for making antimicrobial quinolonyl lactams
US5693791A (en) * 1995-04-11 1997-12-02 Truett; William L. Antibiotics and process for preparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO9928308A1 *

Also Published As

Publication number Publication date
WO1999028308A1 (en) 1999-06-10
EP0970065A4 (en) 2001-03-07

Similar Documents

Publication Publication Date Title
US5693791A (en) Antibiotics and process for preparation
EP0970065A1 (en) Antibiotics and process for preparation
PL127434B1 (en) Method of obtaining new methanodiole diesters with with penicillines and 1,1-penicillatic acid dioxide
CN1918172B (en) Rifamycin analogs and uses thereof
KR860001279B1 (en) Process for crystalline benzensulfonate salts of sultamicillin
US3935204A (en) Cephalosporin and pharmaceutical preparations containing the same
US4117221A (en) Aminoacyl derivatives of aminoglycoside antibiotics
Zhang et al. Total syntheses of natural metallophores staphylopine and aspergillomarasmine A
Ertan et al. Synthesis and biological evaluation of new N-(2-hydroxy-4 (or 5)-nitro/aminophenyl) benzamides and phenylacetamides as antimicrobial agents
OHI et al. Semisynthetic β-lactam antibiotics I. Synthesis and antibacterial activity of new ureidopenicillin derivatives having catechol moieties
McKee et al. Iron transport mediated drug delivery systems: synthesis and antibacterial activity of spermidine-and lysine-based siderophore-. beta.-lactam conjugates
Berredjem et al. Synthesis and antibacterial activity of novel N-acylsulfonamides
GB2030141A (en) Novel aminoglycosides, their production and use as anti-microbial agents
Dunn et al. Orally active 7-phenylglycyl cephalosporins structure-activity studies related to cefatrizine (SK&F 60771)
US4731362A (en) Alkylcarbamoyloxymethylcephem compounds
IE50057B1 (en) Paromomycin derivatives
CA1340784C (en) 7-(2-methyl-4-aminopyrrolidinyl)naphthyridine and quinoline compounds
US6013647A (en) Benzoxazinedione derivatives, method of producing them and uses thereof
US4358585A (en) 5-Deoxyapramycin
CN106032367B (en) Chinese cymbidium amine/chinese cymbidium 01 derivatives and its preparation method and application
EP0048613B1 (en) 4-0-substituted -2-deoxystreptamine aminoglycoside derivatives, their preparation and formulations containing them
PL110876B1 (en) Process for the preparation of novel 7beta-/d-2-amine-2-/r&#39;-sulfonylaminephenyl/-acetylamine/-3-r-3-cephem-4-carboxylic acids
EP0048614B1 (en) 1-n-acylated and 1-n-alkylated derivatives of 4-0-substituted -2-deoxystreptamine aminoglycosides
GB1350772A (en) Antibiotics and processes for their production
Zhang The Antibacterial Activity of Tricyclic Gyrase (GyrB/ParE) Inhibitor: A New Class of Antibacterial Agents

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19990827

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): DE GB

A4 Supplementary search report drawn up and despatched

Effective date: 20010122

AK Designated contracting states

Kind code of ref document: A4

Designated state(s): DE GB

17Q First examination report despatched

Effective date: 20020923

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20030404