GB2369358A - Oxapenems and pharmaceutical compositions thereof - Google Patents

Oxapenems and pharmaceutical compositions thereof Download PDF

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GB2369358A
GB2369358A GB0119165A GB0119165A GB2369358A GB 2369358 A GB2369358 A GB 2369358A GB 0119165 A GB0119165 A GB 0119165A GB 0119165 A GB0119165 A GB 0119165A GB 2369358 A GB2369358 A GB 2369358A
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formula
protonated
oxapenem
compound
caz
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GB0119165D0 (en
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Hans Rudolf Pfaendler
Iain Nelson Simpson
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Amura Ltd
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Amura Ltd
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Priority claimed from EP00309207A external-priority patent/EP1199077A1/en
Priority claimed from GB0105766A external-priority patent/GB0105766D0/en
Application filed by Amura Ltd filed Critical Amura Ltd
Publication of GB0119165D0 publication Critical patent/GB0119165D0/en
Priority to IL15518301A priority Critical patent/IL155183A0/en
Priority to CA002425314A priority patent/CA2425314C/en
Priority to EP01974489A priority patent/EP1326607B1/en
Priority to ES01974489T priority patent/ES2310561T3/en
Priority to US10/399,704 priority patent/US7247622B2/en
Priority to DK01974489T priority patent/DK1326607T3/en
Priority to PCT/GB2001/004527 priority patent/WO2002032423A1/en
Priority to PL361312A priority patent/PL206257B1/en
Priority to MXPA03003280A priority patent/MXPA03003280A/en
Priority to CZ20031214A priority patent/CZ296089B6/en
Priority to KR1020037005390A priority patent/KR100814802B1/en
Priority to CNB018176275A priority patent/CN1219512C/en
Priority to AU9400401A priority patent/AU9400401A/en
Priority to HU0500956A priority patent/HUP0500956A3/en
Priority to BR0114762-5A priority patent/BR0114762A/en
Priority to AU2001294004A priority patent/AU2001294004B2/en
Priority to DE60135002T priority patent/DE60135002D1/en
Priority to AT01974489T priority patent/ATE401884T1/en
Priority to PT01974489T priority patent/PT1326607E/en
Priority to JP2002535661A priority patent/JP4283535B2/en
Publication of GB2369358A publication Critical patent/GB2369358A/en
Priority to IL155183A priority patent/IL155183A/en
Priority to HK03105985A priority patent/HK1053793A1/en
Priority to CY20081101073T priority patent/CY1108381T1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D503/10—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0046—Ear
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Abstract

An oxapenem compound which is, or is capable of forming, a zwitter ion of formula Ia or Ib: <EMI ID=1.1 HE=35 WI=129 LX=498 LY=1280 TI=CF> <PC>wherein R is a C<SB>1</SB>-C<SB>8</SB> branched or straight chain alkyl group which includes a protonated basic substituent. The compounds display superior bioavailability and b -lactamase inhibition.

Description

COMPOSITION The present invention relates to oxapenem compounds, to pharmaceutical compositions containing them and to their medical uses.
-lactam antibiotics (for example penicillins, cephalosporins and carbapenems) are well-known for treatment of bacterial infections, but their prolonged use is associated with increased bacterial resistance.
The principal mechanism of bacterial resistance is by P-lactamases. There are four classes of P-lactamase, known as classes A to D. Clinically, class A and class C - lactamases are the most important. Combination therapy utilising a -lactam antibiotic and a ss-lactamases inhibitor has proven successful at counteracting some forms of resistance. Known combination products are, for example, Tazocim (RTM) which is a combination of piperacillin antibiotic and tazobactam inhibitor, and Augmentin (RTM), a combination of amoxycillin antibiotic and clavulanic acid inhibitor. However, tazobactam and clavulanic acid are only effective against class A p-lactamases, leaving their antibiotic partners unprotected against class B, D and, most
importantly, class C (3-lactamase.
Although -lactamase inhibitors with activity against the class C P-lactamases are known, to date there is no commercially available"broad spectrum"inhibitor active against both class A and C p-lactamases.
EP 0 301394 discloses a wide variety of oxapenem compounds which are antibacterial agents. EP 0 362622 discloses oxapenem compounds which are broad spectrum P- lactamase inhibitors, highly active against class A, class C and class D p-lactamases. EP 0 548790 discloses that the
stereochemistry of a chiral side chain on the 6-carbon of the oxapenem structure has a marked effect on in vitro - lactamase inhibitory activity. Compounds having a (l'S)-l- hydroxylalkyl side chain, with opposite configuration to that of thienamycin, show increased in vitro activity against TEM 1 p-lactamase from E. Coli, a common class A - lactamase. None of the above documents give evidence of particular in vivo activity.
The present applicants have discovered that several novel compounds within the broadest generic disclosure of EP 0 362622 display surprisingly high bioavailability, and superior activity against class A and class C p-lactamases.
According to the present invention in a first aspect there is provided an oxapenem compound which is, or is capable of forming, a zwitter ion of formula Ia or Ib:
wherein R is a Cl-C8 branched or straight chain alkyl group which includes a protonated basic substituent.
Preferably the protonated basic substituent is a protonated nitrogen base. More preferably the protonated basic substituent is a protonated amine or protonated group substituent.
Preferred compounds are those of formula Ia wherein R is- (CH2) 4NH (hereinafter referred to as Compound E); R is - (CH2) 3NH3+ (hereinafter referred to as Compound PFOB) ; R is - (CHNH3+ (hereinafter referred to as Compound A); R is (CH2) 2NHCH : NH2+ (here after referred to as Compound B); or R is-CH2NHCH : NH2+ (hereinafter referred to as Compound D).
It will be appreciated that the protonation of Nitrogen in the R groups of B and D shown above can take place at either Nitrogen. Thus B and D may also be represented by formula Ia wherein R is- (CH2)2NH+CH:NH and -CH2NH+CH:NH.
Also preferred is the compound of formula Ib wherein R is -(CH2NH3+(hereinafter referred to as YOB).
It will be appreciated that there is an equilibrium between the compounds of the invention in their zwitterionic form (i. e. when the basic (e. g. amine) group has been protonated and the carboxylic acid group deprotonated) and their"non ionic"form (when base (e. g. amine) and carboxylic acid groups are neutral). The"non ionic"forms of the compositions, and equilibrium mixtures of zwitterionic and"non ionic"forms, are all within the scope of the invention. Thus, "an oxapenem compound which is capable of forming a zwitter ion"includes oxapenem compounds in the"non ionic"form, that is oxapenem compounds of Formula Ia or Formula Ib wherein the CO,'has been protonated to CO, H, and the"protonated basic group"or "protonated nitogen base"on the R group has been deprotonated. Examples of oxapenem compounds which are capable of forming a zwitter ion are compounds of Formula Ia wherein the CO2+ has been protonated to CO2H and the R groups are -(CH2)4NH2, -(CH2)3NH2, -(CH2)2NH2, -(CH2)2NHCH:NH2, or CH2NHCH : NH ; and compounds of Formula Ib wherein the CO2+ has been protonated to CO2H and the R group is- (CH2) 3NH.
Further, "an oxapenem compound which is capable of forming a zwitter ion"also includes mixtures of the oxapenem compounds in both the zwitterionic and"non ionic"forms.
The applicants have found that the combination of: (a) particular stereochemistry at positions 5 and 6 of the oxapenem double ring structure; and (b) the particular zwitter ionic structure (or the capability of being able to form such a zwitterionic structure); gives compounds with remarkable bioavailability and wide spectrum of activity.
The claimed compounds show remarkably high bioavailability compared to known compounds. The compounds show remarkable activity against class A and C P-lactamases. Compound YOB in particular shows remarkably high activity
and selectivity against class A p-lactamases.
The compounds described in this invention and P-lactam antibiotics are active against a wide range of Gram-positive (staphylococci, streptococci) and Gram-negative (enterobacteriaceae, non-fermentative species) bacteria responsible for infections of the urinary tract, respiratory tract, wounds and intra-abdominal sepsis. The oxapenem compound and antibiotic may be administered concurrently (for example as a mixture), or, for example, as separate medicaments. The oxapenem and antibiotic may be administered at different times.
According to the invention in a further aspect there is provided a pharmaceutical composition comprising a pharmacologically effective amount of an oxapenem compound according to the first aspect of the invention. Preferred pharmaceutical compositions further comprise a pharmacologically effective amount of an antibiotic. The antibiotic may be a ss-lactam antibiotic (e. g. ceftazidime).
According to the invention in a still further aspect there is provided a method of treatment of infection comprising a step of administering to a patient in need thereof a pharmacologically effective amount of a zwitter ion of formula Ia or Ib:
wherein R is a Cl-C8 branched or straight chain alkyl group which includes a protonated basic substituent. Preferably the protonated basic substituent is a protonated nitrogen base. Preferably the protonated basic substituent is a protonated amine or protonated amidino substituent. The method may further comprise a step of administering to the patient a pharmacologically effective amount of an antibiotic. The oxapenem compound and antibiotic may be administered concurrently, or at different times.
Preferably, the method is for treatment of infections of the urinary tract, respiratory tract, wounds and intraabdominal sepsis. The patient may be a human or animal patient.
Brief Description of the Drawings The present invention will now be illustrated with reference to the drawings in which: Fig. 1 shows plasma blood levels of oxapenem analogues following subcutaneous administration at 50 mg per kg in mice ; and
Fig. 2 shows schematic diagram of the synthesis of a compound embodying the invention from a commercially available compound.
Detailed Description of the Invention Over 40 oxapenem analogues have been synthesised and tested in vitro. Structure activity relationship (SAR) studies have identified functions for various parts of the oxapenem molecule with respect to chemical stability, target binding affinity, antibacterial activity and spectrum and extent of p-lactamase inhibition. It has not been possible to predict bioavailability from structure studies.
We have synthesised and tested several oxapenem compounds, known as PFOB, YOB, A, E, B, D, U and XOB. Their structures are shown in Table 1. It can be seen that PFOB, YOB, E, B, D and A are embodiments of the present invention.
The syntheses are discussed below.
Table 1 : Structures of Oxapenem Compounds
Compound Formula R Group PFOB HH- (CH2) 3NH3+ 10 Ia 0 CO, E :.- (CH2) 4NH3 J-"la C02 - (CH2) 2NH3 ". t3-'.
CO, B OH + Cd2 B ?"H (CH2) 2NHCH : NH2 10 Ia co, C02
Compound Formula R Group D OHH-CH2NHCH : NH2 - h... co, YOB OH YOB'H,,- (CH2) 3NH R lb Ib 0 2 Joy' 0 co XOB OH ? 10 Ia co, XOB OH
A. Pharmacokinetic Testing The plasma blood levels in mice (mean of 3 per time point) of compositions XOB, YOB, PFOB and YOB were measured at time points of 5, 10, 20 and 30 minutes following subcutaneous (SC) administration at a dose of 50 mg per kg.
The results are shown in Table 2 and illustrated in Fig. l.
Table 2
Compound Cone. (mg/L) Cone. (mg/L) Cone. (mg/L) Cone. (mg/L) Compound 5 min 10 min 20 min 30 min YOB 40. 12 44. 88 13. 79 10. 40 YOB PFOB 26. 42 25. 39 12. 9 2. 89 XOB 16. 2 10. 43 2. 63 1. 21 U 0. 55 0. 21 0. 03 0
It can be clearly seen from the plasma blood levels at all time points that following sub-cutaneous administration, the compounds of the invention (zwitter ionic compounds PFOB and YOB) have remarkably superior bioavailability when compared with salts XOB and U. Further, it should be noted that the only difference between PFOB and U, and YOB and
XOB, is the amine substituted chain (instead of methyl group) in compounds PFOB and YOB. The amine substituted chain allows the zwitter ionic structure. Thus, the compositions are extremely suitable for use in hospitals in l. p. and s. c administration regimes.
B. In Vitro Activity in Combination with Ceftazidime The assays to determine the Minimum Inhibitory Concentration (MIC) were performed by Agar dilution according to NCCLS guidelines (2000). In the following data the lowest MIC shows the strongest activity.
Class A-lactamases Ceftazidime alone (CAZ), and a 2 : 1 ratio of ceftazidime with each of PFOB, YOB, U and XOB (CAZ+PFOB, CAZ+YOB, CAZ+U and CAZ+XOB) were each tested against a variety of Class Jazz lactamases. The results are shown in Table 3.
Table 3 : Inhibitory Activity vs Class A p-lactamases
Z CAZ CAZ+ CAZ+ CAZ+U CAZ+ CAZ7 Organism PFOB YOB XOB 0 25 E-coli ATCC 25922 0. 25 0. 25 0. 03 0. 125 0. 25 0 125 E. coli ATCC 35218 0. 125 0. 125 0. 125 0. 125 0. 125 0 125 E. coli J53-1 0. 125 0. 125 0. 125 0. 125 0. 25 E. coli TEM-1 0. 25 0. 5 0. 06 0. 25 2 0. 5 . 25 0 E. coli TEM-3 16 2 2 2 2 E. coli TEM-6 > 64 4 2 8 4 E. ccH TEM-9 > 64 8 2 8 4 E-coli TEM-10 > 64 16 2 8
It can be seen that against E. coli TEM-3, TEM-6, TEM-9 and TEM-10 all of the oxapenems, when used in combination with
CAZ, show markedly superior activity compared to CAZ alone. YOB, a composition according to the invention, shows remarkable activity when compared to XOB (a structurally and stereochemically close composition which is not a zwitter ion). This is particularly well demonstrated by the MIC values against E. coli ATCC 25922 and TEM-1 for YOB (0.03 and 0.06) when compared to those for XOB (0.25 and 0.25). It is noted that the MIC values against TEM-9 and TEM-10 also show superiority.
Class C p-lactamases Ceftazidime alone (CAZ), and a 1: 1 ratio of ceftazidime with each of PFOB, YOB, U and XOB (CAZ+PFOB, CAZ+YOB, CAZ+U and CAZ+XOB) were each tested against a variety of Class C lactamases. The results are shown in table 4.1.
Table 4.1 : Inhibitory Activity vs Enterobacteriacaeae derepressed Class C p-lactamases
CAZ CAZ+ CAZ+ CAZ+U CAZ+ Organism PFOB YOB XOB E. clocae P99 32 4 4 2 4 E. clocae > 64 4 16 4 4 Hennessy E. clocae 84-CON > 64 4 8 8 8 C. freundii C2-64 0. 03 4 2 2 con S marcescens S2-1 0. 03 0. 03 0. 25 0. 5 con
It can be seen that against all organisms all of the oxapenems, when used in combination with CAZ, show superior activity compared to CAZ alone.
PFOB, a composition according to the invention, shows remarkable activity when compared to U (a structurally and stereochemically close composition which is not a zwitter ion). This is demonstrated by the MIC values against E. clocae 84-con, C Freundii C2-con and S marcescens S2-con for PFOB (4, 0. 03 and 0. 03, respectively) when compared to those for U (8, 2 and 0. 25). It is also noted that the MIC value for YOB against S marcescens S2-con is markedly superior to that of XOB.
Ceftazidime alone (CAZ), and a 2 : 1 ratio of ceftazidime with each of PFOB, YOB, U and XOB (CAZ+PFOB, CAZ+YOB, CAZ+U and CAZ+XOB) were each tested against a variety of Class C lactamases. The results are shown in table 4. 2.
Table 4. 1 : Inhibitory Activity vs Enterobacteriacaeae derepressed Class C-lactamases (Ratio 2 : 1)
CAZ CAZ+ CAZ+ CAZ+U CAZ+ CAZ+U CAZ+ Organism PFOB YOB XOB E. clocae P99 32 4 8 4 8 E. clocae > 64 4 8 8 8 Hennessy E. clocae 84-CON > 64 4 16 16 16 C. freundii C2-64 2 2 4 4 con S marcescens S2-1 0. 5 1 0. 5 0. 5 con
Once again PFOB, an embodiment of the invention, shows remarkable activity when compared to U (a structurally and
stereochemically close composition which is not a zwitter ion). This is demonstrated by comparison of the MIC values against E. clocae Hennessy, E. clocae 84-con and C Freundii C2-con for PFOB (4,4 and 2, respectively) with those for U (8,16 and 4). It is also noted that the MIC value for YOB against C. freundii C2-con is superior to that of XOB.
Summary It can be seen that the compositions embodying the invention have a remarkable combination of superior bioavailability combined with"broad spectrum"activity against both class A and C P-lactamases.
There is no simple prediction of dependence or relationship between activity of the compound and the stereochemistry of the substituent at C-6: U and PFOB have the (l'R)-l-hydroxyethyl side chain while XOB and YOB have the (l'S)-l-hydroxyethyl side chain. The superior activities of PFOB and YOB could not have been predicted.
C. Synthesis of Compound PFOB, A, E, and YOB C. 1 Synthesis of (5R, 6R, l'R)-3- (4-amino-1, 1-dimethvlbutyl)- 6- (1'-hydroxyethyl)-7-oxo-4-oxa-1-azabicyclo[3. 2. 0] hept-2- ene-2-carboxylic acid [PFOB] The synthesis described below is shown schematically in Figure 2 of the attached drawings.
To a 35 L Pfaudler vessel (GLMS) was charged acetonitrile
(16. 7 kg) and (3R, 4R)-4- (acetoxy)-3- [ (lR)-l- [ [ (l, ldimethylethyl) dimethylsilyl]oxy]ethyl]-2-azetidinone (3. 34 kg, 11. 6 moles). To the header flask was charged 21% sodium
methyl mercaptan (5. 8 L, 17. 4 moles, 1. 5 equivalents). This was added to the batch at 15-20"C (cooling required to control exotherm) over two hours. The batch was then stirred for 1 hour after which time TLC analysis showed completion.
The lower aqueous phase was discharged and the product (acetonitril) phase washed with 6.7L 20% brine prior to being stripped to dryness on a rotary evaporator (20 L). The crude product was then crystallised from hexane (13.3 L) cooling to 0'C from reflux. The crystalline product was filtered and washed with hexane (1 L). Vacuum drying afforded compound III of Fig 2 (2.49kg, 78%) m. p. 93 oc as white needles.
To a 20 vessel (glass) was charged THF (8.25L) followed by
compound (III) (1. 65 kg, 6. 0 moles). The batch was cooled to -40 OC and 2. 5 M butyl lithium (2. 4 L) charged at < -25'C (typically-45 to-35 C), over 1 hour. This was allowed to come to-25 C. To a second vessel was charged THF (4. 1L) and para-nitrobenzyl iodoacetate (1.92 kg, 6.02 moles) which was then cooled to-10 C. The solution of compond (III) was then to transferred to the second solution whilst maintaining temperature < 0 oc (typically < -8 C), over 30 minutes using cannula under vacuum. After stirring to completion (two hours at < -5 C) the batch was cooled to 10 OC and added to a 50 L vessel containing 20% brine (16 L). The lower aqueous phase was back extracted with dichloromethane (13L). The two organic phases were then combined and stripped to dryness to afford crude compound (IV) of Fig 2 (approx 3 kg). THF was charged (approx 2 L) to enable storage of the product as an approx 40% solution.
A THF solution (3.54L) containing approximately 40% compound IV, (1292g, 2.76 moles) is stripped to KF < 0. 1% then redissolved in fresh THF (KF < 0.05%), 7.5 L. To this was added 5-azido-2, 2-dimethylpentanoic acid chloride (1.23 kg, 6. 5 moles, 2.35 equivalents) at < -50'C. A 20 % (1.04 M) solution of lithium bis (trimethylsilyl) amide is added (6000 ml, 6.24 moles, 2.25 equivalents) dropwise at < -65 C. The mixture darkened considerably and was left to stir at-70 OC for 1 hour. The reaction was quenched by charging onto toluene (12.5L) and 10% HC1 (12.5 L). The organic phase was then washed successively with 25% KHCO, (12.5L) water (12.5 L) and saturated brine (6 L). The organic phase was then concentrated and evaporated to afford a dark concentrated solution (approx 30% product).
To 25 kg of flash silica made up with approx 50 L toluene was charged material (from three batches of the above reaction) dissolved in 20% hexane in toluene (20 L). This was eluted under 0.5 bar pressure to load the material onto the column and recycled until fronts began to appear (Fraction 1). A small amount of fronts was separated in this fraction and discarded. The following fractions were then eluted; Fractions 2-4 Toluene (25 L each) Fractions 5-6 6% Ethyl Acetate in Toluene (25 L each) Fractions 7-8 8% Ethyl Acetate in Toluene (25 L each) Fractions 9-10 10% Ethyl Acetate in Toluene (25 L each) The fractions containing product were then stripped to a volume of 25 L of a 13.5% solution of compound V of Fig 2 (3.51kg, 68%) A tetrahydrofuran solution of compound V was stripped on a rotary evaporator until an oil (4.44kg, containing 3.2kg compound V, 5.15mol, including some THF). This oil was redissolved in THF (10.75L) to form a final solution (KF 0.0326%). This was charged to the 100L vessel, followed by acetic acid (2.98L) and tetra-n-butyl-ammonium fluoride (5.36kg, 17.13mol) and more THF (21.5L). This was accompanied
by some foaming during charging. The batch was heated until at reflux (65OC) and then held at close to reflux for 16 hours. Sampling for TLC analysis showed only a trace amount of starting material. Toluene (32L) was added and the vessel contents were cooled to 20oC, prior to quench with 1M potassium bicarbonate solution (27L) over 15 minutes with frothing again.
The organic phase was washed with 1M potassium bicarbonate solution (2 x 27L), 10 % brine (4 x 11L) and 20% brine solution (3L). This washing regime was to ensure the thorough removal of acetic acid.
The toluene solution was stripped to a volume of approximately 5L and stored in a freezer whilst a second batch was prepared giving a further 4.2kg of crude product.
The crude material was purified by dry flash column chromatography using nitrogen pressure (0.5bar).
To a 30cm diameter column was charged a slurry of flash silica (Chrogel Silica I 254,25kg) in toluene (50L), giving a bed depth of 80cm after settling. The toluene was eluted until the silica was partially dry. The crude product from above (8.5kg) was dissolved in toluene (20L) and charged to the silica and loaded onto the column using nitrogen pressure. The product was then eluted with the following solvent mixtures.
100% toluene 50L toluene: ethyl acetate (98: 2) 75L toluene: ethyl acetate (95: 5) 25L toluene: ethyl acetate (80: 20) 100L toluene: ethyl acetate (70 : 30) SOL toluene: ethyl acetate (60 : 40) 50L
toluene : ethyl acetate (60 : 40) + 0. 5'6 isopropanol 50L The following fraction sizes were collected Fraction Number Fraction Size 1-7 25L 18-12 5L 13-20 25L Concentration in vacuo on a 20L rotary evaporator afforded compound VI of Fig 2 as a pale red-orange oil, (single spot by TLC, 4.004kg, 7.88mol, 76.5%).
To a 2L flask was charged dichloromethane (1.02L) and methyl disulphide (398g, 4.23mol). A radical scavenger (3-tertbutyl-4-hydroxy-5-methylphenylsulphide, 1.85g, 0.005mol) was then charged and the batch cooled to-35 oc. Chlorine gas (296g, 8.35mol) was sparged into the solution over 2 hours, resulting in an orange solution of the methyl sulphenyl chloride.
This solution was added to a 20L flask containing dichloromethane (11. 4L) and compound VI (4.97kg of a 38. 2% solution in dichloromethane, 1.9kg active, 3.74mol) at-25 C to-15 C over 25 minutes. The batch was then stirred at-25 C for 20 minutes. When the reaction was complete, as indicated by TLC (absence of starting material), the batch was quenched in a 50L flask containing a solution of sodium hydrogen sulphite (1.196kg) and sodium hydrogen carbonate (0.975kg) in water (23L). The phases were separated and the aqueous phase back-extracted with dichloromethane (1.5kg, 2L). The combined organic phases were washed with saturated brine solution (6L) and dried over magnesium sulphate (lkg) before concentration in vacuo to an oil on a 20L rotary evaporator to yield compound VII of Fig 2 as a crude red oil (1.74kg,
3. 51mol, 93. 7 , crude yield) which was dissolved in tetrahydrofuran (2.71kg) and stored at-30 C for use in the next stage.
Compound VII (1.028kg) was concentrated in vacuo leaving a crude oil, which was dissolved in tetrahydrofuran (9. 5kg, 10. 6L, KF value = 0.02%) and charged to a 20L flask. The flask was then cooled back to < -50 C and triethylamine (848g, 1.168L) added over 5 minutes. The batch was stirred at-50 C
for 1 hour, warmed to 20 C over two hours and then stirred at 20-2SoC for another 2 hours. The reaction was shown to be complete by TLC (disappearance of starting material). Toluene (17.7L) was charged to a 50L flask and the reaction mixture added to this, followed by a rinse with toluene (3. 55L). After settling and splitting, the organic phase was washed with 10 brine solution (3 xl2L), followed by saturated brine solution (3L), dried over sodium sulphate (lkg) before and concentrated in vacuo until a 2L volume of solution of compound VIII of Fig 2 in toluene was obtained which was made up to 4. 5kg with toluene.
A slurry of silica gel 60 (1500g) in diethyl ether: n-pentane (1. 5 : 1) was made up and charged to a jacketed column (80mm i. d. ) and cooled by glycol circulating at-15 C. Crude compound VIII (22. 5-25. 0% w/w, 4SOg solution, 101.3-112. 5g active crude mixture) was charged to the silica and eluted with diethyl ether: n-pentane (1. 5 : 1) pre-cooled to-20 C. The product was eluted with 25L of mixed solvent and 2L of diethyl ether with collection of 1L fractions and concentrated in vacuo at-20 C to give trans compound VIII of Fig 2 (typically 46g) which was stored at-20 C.
To a 10L flask was charged demineralised water (750ml), 10% palladium on charcoal (Johnson Matthey, Type 87L, 60% water, 55g damp solid, 2.2g palladium, 0.0207mol, 0.0211equiv) and
ethyl acetate (1750ml). The flask was purged with nitrogen for 15 minutes then hydrogen and the batch cooled to < 0 C.
Vigorous agitation (450 to 500 rpm) was used throughout.
Trans compound VIII (45g, 0.098mol) was dissolved in ethyl acetate (300ml) at-30 oc, resulting in a final solution temperature of-SOC. This was added to the batch whilst maintaining the reaction and header temperatures at < 0 C.
The batch was hydrogenated for up to 90 minutes, maintaining a steady hydrogen flow throughout. The reaction was deemed complete when HPLC analysis of the organic layer showed an absence of starting material.
The catalyst was removed by filtration through Celite 521 (50g, pre-washed with demineralised water and ethyl acetate) as quickly as possible maintaining a temperature of less than 0 C. The spent catalyst was washed with pre-cooled ethyl
acetate (100ml) and demineralised water (2 x 100ml) at 0 C. After settling, the aqueous phase was isolated, held at 0 C and washed with n-pentane: toluene (3: 1) (225ml) which had been cooled to-200C.
The aqueous phase containing product was successively filtered through 1.6mm glass fibre paper (GF/A grade) and polyethersulphone membrane (pore size 0.2mm, PES grade) with a glass fibre pre-filter cartridge (GFP grade) resulting in a completely clear pale yellow-amber solution. This was was frozen in 200 ml aliquots onto the walls of 500 ml flasks at - 78OC. After freeze-drying for 72 hours (5R, 6R, 1 (4amino-1, 1-dimethylbutyl)-6- (1'-hydroxyethyl)-7-oxo-4-oxa-l- azabicyclo [3. 2. 0] hept-2-ene-2-carboxylic acid (typically-50% corrected yield) was isolated as a voluminous off-white to pale yellow solid.
C. 2 Synthesis of A, E Compounds A and E are made by simple adaptation of the synthesis of PFOB, above.
C. 3 Synthesis of YOB YOB may be made by a combination of the method above and the methods for inversion of stereochemistry disclosed in EP 0 548790. Such a combination will be readily appreciated by the skilled man.
D. Preparations for use as Pharmaceuticals Pharmaceutical preparations may be prepared as follows.
EXAMPLE 1 (Method A) A highly stable pharmaceutical preparation of (5R, 6R, 1'R)-3
(4-amino-l, 1-dimethylbutyl)-6- (1'-hydroxyethyl)-7-oxo-4-oxa1-azabicyclo [3. 2. 0] hept-2-ene-2-carboxylic acid (PFOB) in lactose.
A solution of 3.79 g (8. 25 mmol) p-nitrobenzyl (5R, 6R, l'R) 3- (4 azido-l-dimethylbutyl)-6- (l'-hydroxyethyl)-7-oxo-4-oxa-l- azabicyclo [3. 2. 0] hept-2-ene-2-carboxylate in 30 ml ethyl
acetate was added at 00 via a syringe through a rubber septum to a prehydrogenated mixture of 3. 1 g palladium on charcoal (10) in 120 ml of ethyl acetate and 60 ml of water. After a reaction time of 70 minutes at 0 C, 840 ml of hydrogen have been taken up (theoretical amount 740 ml). The reaction mixture was filtered through a G5 glass filter of 10 cm
diameter, the residue washed with 30 ml of cold water and 30 mol of cold ethyl acetate and the ethyl acetate layer removed from the combined filtrates. The aqueous layer was washed at 0'C with 50 ml of cold ethyl acetate and 50 ml of cold toluene and the resulting aqueous colloidal solution pressed through a membrane filter using a syringe where upon the layers separated. The aqueous layer was evacuated in high vacuum in order to remove residual organic solvents. To the aqueous solution (89.8 ml) a cold solution containing 7.20 g lactose monohydrate in 180 ml water was added and 3 ml portions of the resulting solution filled into glass ampoules. The content was frozen in a dry ice-acetone bath and the water removed in a lyophiliser at-25'C during 4 days at 0.01 mbar. The resulting white powder was dried in a desiccator over phosphorous pentoxide overnight at 0.001 mbar and room temperature leaving 98.3 mg of white powder in each ampoule. UV spectroscopy in water at 262 nm revealed a content of 18.2 mg of title compound and 80.1 mg of lactose in each ampoule. The ampoules were filled with dry nitrogen and sealed or alternatively stored over drying agents.
A pharmaceutical composition may also be prepared as follows: EXAMPLE 2 (5R, 6R, 1'R)-3- (4-amino-1, 1-dimethylbutyl)-6- (1'- hydroxyethyl)-'7-oxo-4-oxa-l-azabicyclo [3. 2. 0] hept-2-ene-2- carboxylic acid. (PFOB)
Following the procedure given in section Cl neat title
compound as a white powder was obtained after simple lyophilization at-25 C (without lactose) and after overnight drying at 0.001 bar and room temperature over phosphorous pentoxide. The compound thus obtained is suitable for administration as a pharmaceutical by known methods, or those discussed below.
EXAMPLE 3 Production of pharmaceutical preparations.
The novel oxapenem compounds may be used in pharmaceutical compositions. The oxapenem compounds may be made into pharmacutical compositions/medicaments by conventional methods, such as those disclosed in EP 0 301394. Other methods of making medicaments include the following: A unit dose form is prepared by mixing 300 mg of the (4: 1) co-lyophilizate of lactose monohydrate and (5R, 6R, 1'R)-3- (4
amino-1, 1-dimethylbutyl)-6- (1'-hydroxyethyl)-7-oxo-4-oxa-lazabicyclo [3. 2. 0] hept-2-ene-2-carboxylic acid (PFOB, Example 1) with 120 mg of cefaclor and 5 mg of magnesium stearate and the 425 mg mixture is added to a gelatine No. 3 capsule.
Similarly, if co-Lyophilisate of a higher content of oxapenem-3-carboxylic acid is used, other dose forms may be prepared likewise and filled into No. 3 gelatin capsules; and should it be necessary to mix more than 425 mg of constituents together, larger capsules, and also compressed tablets and pills, may also be produced. The following examples illustrate the production of pharmaceutical preparations.
TABLE 5 (4 : 1) co-lyophilisate of lactose monohydrate and (5R, 6R, 1'R)-3-(4-amino-1,1-dimethylbuty)-6 (1'-hydroxyethyl)-7-oxo-4-oxa-1-azabicyclo [3. 2. 0] hept-2-ene-2-carboxylic acid 625 mg Cefaclor 250 mg Maize starch V. S. P. 200 mg Dicalcium phosphate 60 mg Magnesium stearate 60 mg The co-lyophilisate and the other active constituent (Ceflacor) are mixed with the dicalcium phosphate and about half of the maize starch. The mixture is then granulated and coarsely sieved. It is dried at 45 C and resieved through sieves of mesh width 1.0 mm (No. 16 screens). The remainder of the maize starch and the magnesium stearate are added and the mixture is compressed to form tablets each weighing 1195 mg and having a diameter of 1.27 cm (0.5 in. ).
Parenteral solution Ampoule (4: 1) co-lyophilisate of lactose monohydrate
and (5R, 6R, 1'R)-3- (4-amino-l, 1-dimethylbutyl)-6 (1'-hydroxyethyl)-7-oxo-4-oxa-l-azabicyclo [3. 2. 0] hept-2 ene-2-carboxylic acid 1250 mg Ceftazidime 500 mg
Sterile water (is added from a separate ampoule using a syringe immediately before use) 5 ml Opthalmic solution (4: 1) co-lyophilisate of lactose monohydrate and (5R, 6R, 1'R)-3- (4-amino-1, 1-dimethylbutyl)-6- (1'-hydroxyethyl)-7-oxo-4-oxa-l-azabicyclo [3. 2. 0] hept- 2-ene-2-carboxylic acid 625 mg Ceftazidime 250 mg Hydroxypropylmethylcellulose 15 mg Sterile water (is added from a separate ampoule using a syringe immediately before use 2 ml Otic solution (4: 1) co-lyophilisate of lactose monohydrate and (5R, 6R, 1'R)-3- (4-amino-1, 1-dimethylbutyl)- 6- (1'-hydroxyethyl)-7-oxo-4-oxa-l-azabicyclo [3. 2. 0] hept-2-ene-2-carboxylic acid 250 mg Ceftazidime 100 mg Benzalkonium chloride 0.1 mg Sterile water (is added from a separate ampoule using a syringe immediately before use) 2 ml Topical cream or ointment (4: 1) co-lyophilisate of lactose monohydrate and (5R, 6R, 1'R)-3- (4-amino-1, 1-dimethylbutyl)- 6- (1'-hydroxyethyl)-7-oxo-4-oxa-l-azabicyclo] 3.2. 0] hept2-ene-2-carboxylic acid 250 mg
Ceftazidime 100 mg Polyethylene glycol 4000 V. S. P. 800 mg Polyethylene glycol 400 V. S. P. 200 mg YOB, A, B, D and E may be used as pharmaceutically active agents in similar examples by simply substition for PFOB in the above formulations.
It should be noted that it is not necessary to co-lyophilise the active oxapenem (PFOB, YOB etc) with carrier (e. g. lactose) before mixing with the other reagents, although colyophilisation should enhance stability.
The active components in the above preparations can be mixed alone or together with other biologically active components, such as lincomycin, a penicillin, streptomycin, novobiocin, gentamycin, neomycin, colistin and klanamycin, or with other therapeutic agents such as probenicid.
It is understood that the specification and examples are illustrative but not limitative of the present invention and that other embodiments within the spirit on a scope of the invention will suggest themselves to those skilled in the art.

Claims (12)

  1. CLAIMS : 1. An oxapenem compound which is, or is capable of forming, a zwitter ion of formula Ia or Ib:
    wherein R is a Cl-C8 branched or straight chain alkyl group which includes a protonated basic substituent.
  2. 2. An oxapenem compound according to claim 1 wherein the protonated basic substituent is a protonated nitrogen base.
  3. 3. An oxapenem compound according to claim 1 or 2 wherein the protonated basic substituent is a protonated amine or protonated amidino group.
  4. 4. An oxapenem compound according to claim 1,2 or 3 having formula Ia wherein R is- (CH2)4NH3+ , -(CH2)3NH3+, - (CH2) 2NH3,- (CH2) 2NHCH: NH2, or R is-CH2NHCH : NH.
  5. 5. An oxapenem compound according to claim 1,2 or 3 having formula Ib wherein R is- (CH2) 3NH3+.
  6. 6. A pharmaceutical composition comprising a pharmacologically effective amount of an oxapenem compound according to any preceding claim.
  7. 7. A pharmaceutical composition according to claim 6 which further comprises a pharmaceutically effective amount of an antibiotic.
  8. 8. A method of treatment of infection comprising a step of administering to a patient in need thereof pharmacologically effective amount of a a zwitter ion of formula Ia or Ib:
    wherein R is a Cl-C8 branched or straight chain alkyl group which includes a protonated basic substituent.
  9. 9. A method of treatment according to claim 8 in which the zwitter ion is of formula Ia wherein R is- (CH2) 4NHg,- (CH2)3NH3+, - (CH2) 2NH3,- (CH2) 2NHCH: NH2+, or-CH2NHCH : NH2 ; or in which the zwitter ion is of formula Ib wherein R is (CH2) 3NH3.
  10. 10. A method according to claim 8 or claim 9 which further comprises a step of administering to the patient a pharmacologically effective amount of an antibiotic.
  11. 11. Use of a zwitter ion of formula Ia or Ib:
    wherein R is a Cl-C8 branched or straight chain alkyl group which includes a protonated basic substituent, in the
    manufacture of a medicament for treatment of infection.
  12. 12. Use according to claim 11 in which the zwitter ion is of formula Ia wherein R is- (CH2)4NH3+, -(CH2)3NH3+, (CH2) 2NH3+, -(CH2)3NHCH:NH3+, or -CH2NHCH: NH,' ; or in which the zwitter ion is of formula Ib wherein R is- (CH2) 3NH3.
GB0119165A 2000-10-19 2001-08-06 Oxapenems and pharmaceutical compositions thereof Withdrawn GB2369358A (en)

Priority Applications (23)

Application Number Priority Date Filing Date Title
AT01974489T ATE401884T1 (en) 2000-10-19 2001-10-11 MEDICINAL COMPOSITIONS CONTAINING OXAPENEM-3-CARBOXYLIC ACIDS
PT01974489T PT1326607E (en) 2000-10-19 2001-10-11 Pharmaceutical compositions containing oxapenem-3-carboxilic acids
JP2002535661A JP4283535B2 (en) 2000-10-19 2001-10-11 Pharmaceutical composition containing oxapenem-3-carboxylic acid
KR1020037005390A KR100814802B1 (en) 2000-10-19 2001-10-11 Pharmaceutical compositions containing oxapenem-3-carboxylic acids
HU0500956A HUP0500956A3 (en) 2000-10-19 2001-10-11 Oxapenem-3-carboxylic acids and pharmaceutical compositions containing them
EP01974489A EP1326607B1 (en) 2000-10-19 2001-10-11 Pharmaceutical compositions containing oxapenem-3-carboxilic acids
ES01974489T ES2310561T3 (en) 2000-10-19 2001-10-11 PHARMACEUTICAL COMPOSITIONS CONTAINING OXAPENEM-3-CARBOXYL ACIDS.
US10/399,704 US7247622B2 (en) 2000-10-19 2001-10-11 Pharmaceutical compositions containing oxapenem-3-carboxylic acids
DK01974489T DK1326607T3 (en) 2000-10-19 2001-10-11 Pharmaceutical composition comprising oxapenem-3-carboxylic acids
PCT/GB2001/004527 WO2002032423A1 (en) 2000-10-19 2001-10-11 Pharmaceutical compositions containing oxapenem-3-carboxylic acids
PL361312A PL206257B1 (en) 2000-10-19 2001-10-11 Pharmaceutical compositions containing oxapenem-3-carboxylic acids
MXPA03003280A MXPA03003280A (en) 2000-10-19 2001-10-11 Pharmaceutical compositions containing oxapenem-3-carboxylic acids.
CZ20031214A CZ296089B6 (en) 2000-10-19 2001-10-11 Oxapenem compounds, pharmaceutical composition and beta-lactamase inhibitor in which these compounds are comprised, and their use
IL15518301A IL155183A0 (en) 2000-10-19 2001-10-11 Pharmaceutical compositions containing oxapenem-3-carboxylic acids
CNB018176275A CN1219512C (en) 2000-10-19 2001-10-11 Pharmaceutical compositions containing oxapenem-3-carboxylic acids
AU9400401A AU9400401A (en) 2000-10-19 2001-10-11 Pharmaceutical compositions containing oxapenem-3-carboxylic acids
CA002425314A CA2425314C (en) 2000-10-19 2001-10-11 Pharmaceutical compositions containing oxapenem-3-carboxylic acids
BR0114762-5A BR0114762A (en) 2000-10-19 2001-10-11 Pharmaceutical compositions containing oxapenem-3-carboxylic acids
AU2001294004A AU2001294004B2 (en) 2000-10-19 2001-10-11 Pharmaceutical compositions containing oxapenem-3-carboxylic acids
DE60135002T DE60135002D1 (en) 2000-10-19 2001-10-11 DRUG COMPOSITIONS CONTAINING OXAPENEM-3-CARBOXYLIC ACIDS
IL155183A IL155183A (en) 2000-10-19 2003-04-01 Oxapenem - 3 - carboxylic acid, pharmaceutical compositions containing it and uses thereof
HK03105985A HK1053793A1 (en) 2000-10-19 2003-08-21 Pharmaceutical compositions containing oxapenem-3-carboxilic acids
CY20081101073T CY1108381T1 (en) 2000-10-19 2008-09-29 PHARMACEUTICAL COMPOSITIONS CONTAINING OXAPENEMO-3-CARBOXYLIC ACIDS

Applications Claiming Priority (2)

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EP00309207A EP1199077A1 (en) 2000-10-19 2000-10-19 Stable compositions of oxapenem-3-carboxylic acids by Co-lyophilisation with pharmaceutical carriers
GB0105766A GB0105766D0 (en) 2001-03-08 2001-03-08 Orally active compounds

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0301394A1 (en) * 1987-07-31 1989-02-01 Pfaendler, Hans Rudolf, Prof. Dr. Stable oxapenem-3-carboxylic acids
EP0362622A1 (en) * 1988-10-04 1990-04-11 Eli Lilly And Company Use of stable oxapenem-3-carboxylic acids for the manufacture of beta-lactamase inhibiting medicaments
EP0548790A1 (en) * 1991-12-20 1993-06-30 Eli Lilly And Company (1'S)-Hydroxyalkyloxapenem-3-carboxylic acids and their use as beta-lactamase inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0301394A1 (en) * 1987-07-31 1989-02-01 Pfaendler, Hans Rudolf, Prof. Dr. Stable oxapenem-3-carboxylic acids
EP0362622A1 (en) * 1988-10-04 1990-04-11 Eli Lilly And Company Use of stable oxapenem-3-carboxylic acids for the manufacture of beta-lactamase inhibiting medicaments
EP0548790A1 (en) * 1991-12-20 1993-06-30 Eli Lilly And Company (1'S)-Hydroxyalkyloxapenem-3-carboxylic acids and their use as beta-lactamase inhibitors

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IL155183A (en) 2009-12-24
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