WO2008116813A2 - Combination medicaments for treating bacterial infections - Google Patents
Combination medicaments for treating bacterial infections Download PDFInfo
- Publication number
- WO2008116813A2 WO2008116813A2 PCT/EP2008/053336 EP2008053336W WO2008116813A2 WO 2008116813 A2 WO2008116813 A2 WO 2008116813A2 EP 2008053336 W EP2008053336 W EP 2008053336W WO 2008116813 A2 WO2008116813 A2 WO 2008116813A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutically acceptable
- acceptable salt
- formula
- substituted
- unsubstituted
- Prior art date
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- 239000003814 drug Substances 0.000 title claims abstract description 16
- 208000035143 Bacterial infection Diseases 0.000 title claims abstract description 15
- 208000022362 bacterial infectious disease Diseases 0.000 title claims abstract description 15
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- 230000003115 biocidal effect Effects 0.000 claims abstract description 62
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 claims abstract description 56
- -1 oxyimino group Chemical group 0.000 claims abstract description 56
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- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 26
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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Definitions
- the present invention relates to the use of monobactam antibiotic of formula (I) as described herein below and novel pharmaceutical products comprising a combination comprising said compound and a carbapenem antibiotic.
- ⁇ -Lactam antibiotics have been widely used for the treatment of bacterial infections both in hospitals and in the general public.
- ⁇ -lactam antibiotics include the penicillins, cephalosporins, cephamycins, carbacephems, oxace- phems, carbapenems and monobactams .
- Monobactam antibiotics e.g. aztreonam
- aztreonam Monobactam antibiotics
- WO 98/47895 is directed to 2-oxo-l-azetidine sulfonic acid derivatives of the general formula
- ⁇ anti' is an older term used to designate the trans-isomer of an oxime compound (the prefix ⁇ syn' was accordingly used to designate the cis- of an oxime); cf. IUPAC Gold Book; IUPAC Compendium of Chemical Terminology, Electronic version, http://goldbook.iupac.org/E0204.html and PAC, 1996, 68, 2193 Basic terminology of stereochemistry (IUPAC Recommendations 1996) on page 2207.
- the disclosed 2-oxo-l-azetidine sulfonic acid derivatives are to be used in combination with carbap- enem antibiotics including Imipenem, Meropenem or Biapenem for the treatment of bacterial infections.
- Rl Re f is preferably a 2-thienyl group and is used in all exemplified inventive compounds of said reference.
- R2 Re f. can among other groups e.g. be a group of formula:
- Example 1 of the reference e.g. refers to (3S) -trans-3- [ (E) -2- (2-thienyl) -2- ⁇ (1, 5-dihydroxy-4-pyridon-2-ylmethoxy) imino ⁇ - acetamido] -4-methyl-2-oxazetidine-l-sulfonic acid and is shown to have, together with ceftazidime, antibacterial activity against numerous strains of pathogenic bacteria.
- This invention is based on the recent finding of novel monobactam antibiotics and, more particularly, on the novel finding that a specific embodiment of these monobactams, the monobactam antibiotic of formula (I) as described herein below, when used in combination with other antibiotics, in par- ticular carbapenem antibiotics, shows improved efficacy against a broad range of bacteria, including Gram-positive and especially Gram-negative bacteria, including Enterobacte- riaceae and Pseudomonas aeruginosa.
- the efficacy of the novel combinations of the monobactam antibiotic of formula (I) with carbapenem antibiotics is for many strains of important pathogenic bacteria significantly improved with regard to combinations of Aztreonam with the respective carbapenem antibiotics, e.g. the combinations of Aztreonam with Meropenem or Imipenem.
- the combinations of the present invention frequently exhibit a significantly improved efficacy against bacteria when compared to the best efficacy of the combination partners alone, and frequently exhibits a synergistic effect i.e. an effect which is more potent than what one would expect from a purely additive effect.
- the invention in another aspect relates to pharmaceutical products comprising a monobactam antibiotic of formula (I) as described above or a pharmaceutically acceptable salt thereof and one or more than one carbapenem antibiotic, or pharmaceutically acceptable salt thereof.
- These pharmaceutical products represent improved medicaments for the treatment of infections caused by pathogenic bacteria, including Gram-positive and particularly Gram-negative bacteria .
- Particularly preferred according to the invention is the use of the monobactam antibiotic of formula (I) or a salt thereof for the manufacture of a medicament for the treatment of a bacterial infection in combination with a single carbapenem antibiotic, or a pharmaceutically acceptable salt thereof.
- the monobactam antibiotic of formula (I) can e.g. be prepared according to the following general Scheme 1:
- R A represents an amine protecting group such as formyl, trifluoroacetyl, O-nitrophenoxyacetyl, chloroacetyl, tri- chloroacetyl, ⁇ -chlorobutyryl, benzyloxycarbonyl, p- chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p- bromobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, diphenyl- methoxycarbonyl, ter-butyloxycarbonyl, isopropyloxycarbonyl, diphenylmethyl, triphenylmethyl, benzyl, p-methoxybenzyl, 3, 4-dimethoxybenzyl; and
- R B and R c represent independently of one another an alcohol protecting group such as benzyloxycarbonyl, p- chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p- bromobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, diphenyl- methoxycarbonyl, ter-butyloxycarbonyl, isopropyloxycarbonyl, diphenylmethyl, triphenylmethyl, benzyl, p-methoxybenzyl, 3, 4-dimethoxybenzyl, trialkylsilane such as trimethylsilane, triethylsilane or ter-butyldimethylsilane .
- an alcohol protecting group such as benzyloxycarbonyl, p- chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p- bromobenzyloxycarbonyl, p-methoxybenzyloxycarbony
- Said amine and alcohol protecting groups can be easily removed, e.g. by acid hydrolysis or other well known techniques, [for more detail see e.g. T. W. Greene et al . Protec- tive Groups in Organic Chemistry, Wiley intersience, 1999].
- the protecting groups in compounds of general formula Ia can easily be introduced by well known synthetic methods, [for more detail see e.g. T. W. Greene et al . Protective Groups in Organic Chemistry, Wiley intersience, 1999].
- the deprotection of functional groups may be carried out either by hydrogenation or hydrolysis with appropriate acids, such as hydrochloric acid, formic acid, acetic acid, trifluoroacetic acid, phosphoric acid, NaH 2 PO 4 , Na 2 HPO 4 , p- toluenesulfonic acid or methanesulfonic acid, in solvents such as methanol, ethanol, propanol, ethyl acetate, acetoni- trile, methylene chloride or ethylene chloride.
- the hydrogenation is usually carried out in the presence of a metal catalyst, such as Pd, Pt or Rh under normal to high pressure.
- the deprotection of the different functional groups can be carried out either simultaneously or sequentially.
- the solvents of choice for the reaction are selected based upon the reactants used and from solvents such as benzene, toluene, acetonitrile, tetrahydrofurane, ethanol, methanol, chloroform, ethyl acetate, methylene chloride, dimethyl for- mamide, dimethyl sulfoxide, hexamethyl phosphoric triamide or the like. Solvents mixtures may also be used.
- Reaction temperatures would generally range from between -70 0 C to 150 0 C.
- the preferred molar ratio of the reactants is 1:1 to 1:5.
- the reaction time range from 0.5 to 72 hours, depending on the reactants.
- Examples of pharmaceutically acceptable salts of the compound of formula (I) include e.g. salts of inorganic base like am- monium salts, alkali metal salts, in particular sodium or potassium salts, alkaline earth metal salts, in particular magnesium or calcium salts; salts of organic bases, in particular salts derived from cyclohexylamine, benzylamine, oc- tylamine, ethanolamine, diethylolamine, diethylamine, triethylamine, ethylendiamine, procaine, morpholine, pyr- roline, piperidine, N-ethylpiperidine, N-methylmorpholine, piperazine as the organic base; or salts with basic amino acids, e.g. lysine, arginine, ornithine, histidine and the like.
- salts of inorganic base like am- monium salts, alkali metal salts, in particular sodium or potassium salts, alka
- Such salts can be manufactured in a way known per se, e.g. by reacting the compound of formula (I) with an appropriate base, preferably at room temperature or below, e.g. from about 2°C to about 25°C and isolating the salt formed, e.g. by lyophilization .
- the compounds of formula (I) are optionally used in substantially crystalline form.
- a substantially crystalline compound of formula (I) has not yet been described before. It can be obtained by crystallisation methods, e.g. as described in the Examples of the present application.
- substantially crystalline means that an X-Ray Powder Diffraction (XRPD) diagram of a corresponding substance shows one or more distinct peaks which have a maximum height corresponding to at least the fivefold of their width at half-maximum.
- XRPD X-Ray Powder Diffraction
- the degree of crys- tallinity of a substance increases with an increasing average value for the ratio of the height of a certain peak to its width at half-maximum.
- base line a substantially constant base line
- a further subject of the present invention is therefore the compound of formula (I) being in substantially crystalline form.
- Said substantially crystalline compound of formula (I) shows peaks in the X-Ray Powder Diffractogram (XRPD) having a relative Intensity of more than 50%, recorded with Cu K-alpha Radiation and given in [° 2-Theta] , at about 6.8 ⁇ 0.1, 15.1 ⁇ 0.1, 15.6 ⁇ 0.1 and 25.4 ⁇ 0.1, and exhibits a X-Ray Powder Diffrac- tion pattern, recorded with Cu K-alpha radiation, essentially as follows:
- vst stands for a relative intensity of 100% to 90%
- st stands for a relative intensity of less than 90% to 65%
- m stands for a relative intensity of less than 65% to 50%
- w stands for a relative intensity of less than 50% to 30%, more specifically the following X-Ray Powder Diffraction pattern recorded with Cu K-alpha radiation and indicating the diffraction peaks with a relative Intensity of 20% and more:
- Figure 1 shows the XRPD diagram of typical crystalline material of the compound of formula (I) recorded with Cu K-alpha radiation.
- the compound of formula (I) and its pharmaceutically compatible salts are used according to the invention in combination with other antibiotics like in particular carbapenem antibi- otics or pharmaceutically acceptable salts thereof as antibi- otically effective medicaments in the control or prevention of infectious diseases in mammals, human and non-human, in particular bacterial infections, more particularly infections in which Gram-positive bacteria and mostly preferred in which Gram-negative bacteria are involved, such as e.g. nosocomial pneumonia, community-acquired pneumonia, urinary tract infection, complicated intra-abdominal infection, complicated skin/skin structure infection, infectious exacerbations of cystic fibrosis, sepsis, melioidosis.
- other antibiotics like in particular carbapenem antibi- otics or pharmaceutically acceptable salts thereof as antibi- otically effective medicaments in the control or prevention of infectious diseases in mammals, human and non-human, in particular bacterial infections, more particularly infections in which Gram-positive bacteria and mostly preferred in which Gram-negative bacteria are involved, such
- the compound of formula (I) and its pharmaceutically acceptable salts are used according to the invention in combination with a carbapenem antibiotic or pharmaceutically acceptable salt thereof for such treatment.
- a carbapenem antibiotic or pharmaceutically acceptable salt thereof for such treatment.
- carboxyribon antibiotic refers to antibiotically effective compounds comprising the structural element:
- carbapenem antibiotics are known in the art, and can, in general, be used for the purposes of the present in- vention. Suitable examples are described e.g. in A. BRYSKIER "Carbapenems", ANTIMICROBIAl AGENTS: ANTIBACTERIALS AND ANTIFUNGALS, page 270 - 321, Publisher: American Society for Microbiology, Washington D. C, 2005, and references cited therein.
- the term "carbapenem antibiotic” includes inner salts like e.g. ME 1036 or Biapenem.
- salts of carbapenem antibiotics may also be used for the purposes of the present invention, e.g. acid ad- dition salts derived from pharmaceutically acceptable organic and/or inorganic acids.
- the carbapenem antibiotics used according to the present invention are compounds of formula (II), or pharma- ceutically acceptable salt thereof: wherein
- R 1 represents hydrogen or Ci-C ⁇ alkyl
- R 2 represents hydrogen or Ci-C ⁇ alkyl
- R 3 represents hydrogen, Ci-C ⁇ alkyl, Ci-C ⁇ alkoxy; - (Ci n H 2n ) -R 5 or -0- (C 1n H 2n ) -R 5 ;
- R 5 represents halogen, cyano, Ci-C ⁇ alkoxy, amino, (Ci-C ⁇ alkyl) amino, di (Ci-C ⁇ alkyl) amino, or a group of formula -CO-R 6 , -NH-CO-R 6 -CO-NH 2 , -NH-CO-NH 2 , -NH-SO 2 -NH 2 or
- R 9 represents Ci-C ⁇ alkyl, unsubstituted or substituted with one or more of a substituent S 3 ; phenyl, unsubstituted or substituted with one or more of a substituent S 3 ; or a 3-6 membered heterocyclyl group containing one or more than one heteroatom selected from nitrogen, sulfur and oxygen, which heterocyclyl group may furthermore optionally be fused to a phenyl ring or a 5-6 membered heterocyclic ring and which whole group is unsubstituted or substituted with one or more of a substituent S 3 , wherein each
- Ci-C 4 alkyl groups are Ci-C 4 alkyl groups.
- Ci-C ⁇ alkoxy means an alkoxy group based on a Ci-C ⁇ alkyl according to the above definition.
- C3-C 7 polymethylene group refers to a group of for- mula - (CH 2 ) 3 _ 7 - which may comprise one or two double bonds and which may be unsubstituted or substituted as specified.
- heterocyclyl group and “heterocyclic ring” refer to corresponding groups which are saturated or unsaturated.
- a 3-6 membered heterocyclyl group containing one or more than one heteroatom selected from nitrogen, sulfur and oxygen, which heterocyclyl group may furthermore optionally be fused to a phenyl ring or a 5-6 membered heterocyclic ring refers e.g.
- heterocyclic groups for the purposes of the inven- tion are known to the skilled persons and/or can be readily found in the literature.
- Preferred are 5-6 membered heterocyclic groups containing one or more than one heteroatom selected from nitrogen, sulfur and oxygen, in particular nitrogen and sulphur, which heterocyclyl group may furthermore op- tionally be fused to a phenyl ring or a 5-6 membered heterocyclic ring containing one or more than one heteroatom selected from nitrogen, sulfur and oxygen, in particular nitrogen and sulphur.
- Substituted by one or more than one means preferably “substituted by one or two", e.g. "substituted by one".
- halogen refers to fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
- R 4 represents a group of formula -(S) m -R 7 , m is 0 or 1 and R 7 represents a 3-6 membered heterocyclic group containing one or more than one heteroatom selected from nitrogen, sulfur and oxygen, which heterocyclyl group may furthermore optionally be fused to a phenyl ring or a 5-6 membered heterocyclic ring and which whole group is un- substituted or substituted as defined in detail above.
- Even more preferred are such compounds of formula (II), when m is 1.
- R 1 represents hydrogen or Ci-C ⁇ alkyl
- R 2 represents hydrogen or Ci-C ⁇ alkyl
- R 3 represents Ci-C ⁇ alkyl; in particular, when one of R 1 and R 2 represents hydrogen and the other -CH 3 and R 3 is -CH 3 .
- Y represents nitrogen or >CH-
- carbapenem antibiotics or their pharmaceutically acceptable salts are specifically preferred examples useful in the present invention:
- Panipenem In medicinal practice Panipenem is generally used together with Betamipron, a renal inhibitor which inhibits renal up- take of Panipenem as known in the art.
- carbapenem antibiotics for use in the present invention are selected from the following compounds:
- a further preferred subject of the present invention is the use of the monobactam antibiotic of formula (I) as described above or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a bacterial infection in combination with Imipenem or a pharmaceutically acceptable salt thereof.
- Imipenem is generally used together with Cilastin, an inhibitor of the renal dipeptidase in the proximal tubulus of the kidney, which is used in order to stabilize Imipenem against inacti- vation, similar as the Betamipron in combination with Panipenem as mentioned above.
- Another preferred subject of the present invention is use of the monobactam antibiotic of formula (I) as described above or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a bacterial infection in combination with Meropenem or a pharmaceutically acceptable salt thereof.
- Meropenem is sometimes also used together with Cilastin similar to Imipenem (Antimicrob. Agents Chemother. 2000, 44, 885-890) .
- Another preferred subject of the present invention is use of the monobactam antibiotic of formula (I) as described above or a pharmaceutically acceptable salt thereof for the manu- facture of a medicament for the treatment of a bacterial infection in combination with Ertapenem or a pharmaceutically acceptable salt thereof.
- Yet another preferred subject of the present invention is use of the monobactam antibiotic of formula (I) as described above or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a bacterial infection in combination with Doripenem or a pharmaceutically acceptable salt thereof.
- the compound of formula (I) or the pharmaceutically accept- able salts thereof can be administered according to the invention before, simultaneously with or after the administration of the carbapenem antibiotic or the pharmaceutically acceptable salt thereof. Substantially simultaneous or an exactly simultaneous administration of the combination partners is generally preferred.
- the compounds of formula (I) or pharmaceutically acceptable salts thereof and the carbapenem antibiotics or pharmaceutically acceptable salts thereof can be administered by any route of administration, preferably in the form of a pharmaceutical composition adapted to such route. Dosage and route of administration should be determined by susceptibility of the causative organisms, severity and site of infection, and the specific condition of the patient and be selected accord- ingly. Preferred types of pharmaceutical compositions are, for example, administered orally, by inhalation or more preferably parenterally e.g. intravenously or intramuscularly.
- Formulations for parenteral administration include but are not limited to the form of aqueous isotonic sterile injections, solutions, concentrates or solutions for further dilutions (e.g. for infusions), or suspensions, including nano- suspensions and nanocrystals .
- These solutions or suspensions can be prepared from sterile powders, granules or lyophili- zates.
- the compounds can be dissolved in sterile water or in various sterile buffers that may contain, but are not limited to contain, sodium chloride, polyethylene glycol, propylene glycol, ethanol, sucrose, glucose, arginine, lysine, citric acid, lactic acid phosphoric acid and corresponding salts.
- the formulation can contain from 0.1% to 99% by weight, preferably 10% - 90% by weight, of each of the active ingredi- ents. If the compositions contain dosage units, each unit preferably contains from 50mg to 4g of each active substance.
- a further subject of the present invention is accordingly a pharmaceutical product comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and a carbap- enem antibiotic or a pharmaceutically acceptable salt thereof .
- a pharmaceutical product according to the invention can e.g. comprise one or more than one dosage unit of a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more than one other dosage unit containing a carbap- enem antibiotic or a pharmaceutically acceptable salt thereof and being free of the compound of formula (I) .
- a pharmaceutical product of the invention may comprise two separate packages, each of them comprising a pharmaceutical formulation comprising just one of the combination partners in an appropriate dosage form.
- Another embodiment of the pharmaceutical product according to the invention comprises one or more than one dosage unit, and each dosage unit comprises both, the compound of formula (I) or a pharmaceutically acceptable salt thereof and a carbap- enem antibiotic or a pharmaceutically acceptable salt thereof.
- a fixed dose combination generally comprises the compound of formula (I) or the pharmaceutically acceptable salt thereof and the carbapenem antibiotic or the phar- maceutically acceptable salt thereof as well as a pharmaceutically acceptable carrier and optionally appropriate further excipients as typical for the respective dosage form.
- the pharmaceutical products according to the present invention comprise the compound of formula (I) or the pharmaceutically acceptable salt thereof and the carbapenem antibiotic or the pharmaceutically acceptable salt thereof in an appropriate weight ratio, e.g. in a weight ratio of 10:1 to 1:10, preferably from 5:1 to 1:5, more preferably from 3:1 to 1:3 like e.g. from 2:1 to 1:2 or about 1:1.
- the pharmaceutical products according to the present invention are active against a variety of bacterial organisms, in particular against Gram-positive bacteria including for example Staphylococcus aureus, Staphylococccus epidermidis, En- terococcus faecalis, Streptococcus pneumonia and Gram- negative bacteria, including Enterobacteriaceae, for example Escherichia coli, Enterobacter cloacae, Enterobacter aero- genes, Citrobacter freundii , Klebsiella pneumoniae, Klebsiella oxytoca, Proteus vulgaris, Providencia rettgeri; Pseu- domonas for example P. aeruginosa; Acinetobacter for example A. baumannii; Burkholderia, for example B. cepacea; B. mallei; B. pseudomallei; Stenotrophomonas for example 5. mal- tophilia; Haemophilus influenzae .
- Gram-positive bacteria including
- the products can thus be used for treatment of infectious diseases including e.g. nosocomial pneumonia, community- acquired pneumonia, urinary tract infection, complicated in- tra-abdominal infection, complicated skin/skin structure infection, cystic fibrosis, sepsis.
- the dosage of the compound of formula I and of the pharmaceutically compatible salts thereof and the carbapenem antibiotics or salts thereof for said treatment can vary within wide limits and will be fitted in each particular case to the in- dividual requirements of the patient to be treated and to the pathogens to be controlled. In general, a dosage of about 0.1 to about 4 g, e.g. about 0.5 to about 2 g, of total antibiotic administered one to four times over a 24 hours period should be appropriate.
- the monobactam antibiotic I is prepared according to the synthesis outlined in Scheme 4 and according to the procedures described below.
- the compound of formula (I) is generally obtained in an amorphous form. Although it may be used in said form it may optionally be converted into crystalline material, e.g. as described herein below.
- the crystalline material is characterized by an infrared spectrum as listed in the following table (FTIR recorded with powder at a resolution of 2 cm "1 , collecting 16 scans from 4000 to 500 cm ' ⁇ Bruker Vector 22 spectrometer with ATR Golden gate) .
- the crystalline material exhibits an X-Ray Power Diffraction ("XRPD”) pattern obtained using CuKCC radiation as shown in the following Table and in Figure 1.
- XRPD X-Ray Power Diffraction
- the 2 ⁇ angles have an error of about ⁇ 0.1°. It is known that the values for the relative Intensity of the peaks are more strongly dependent from certain properties of the measured sample than the line position, e.g. from the size of the crystals and their orientation in the sample. Variations of ⁇ 20% of the shown peak intensities are therefore likely to occur .
- the crystalline material is furthermore characterized by Thermal Gravimetric Analysis ("TGA") data as indicated in the Table below and obtained using a scan rate of 10 deg/min (Perkin-Elmer TGS2) .
- TGA Thermal Gravimetric Analysis
- the weight loss of the material is about 7% when the temperature of the material is raised from room temperature to 100 0 C. A further weight loss is observed at 192-193°C corresponding to the melting/decomposition temperature of the sample.
- Antimicrobial activity of the compounds and of their combinations is determined against a selection of organisms according to standard procedures described by the National Commit- tee for Clinical Laboratory Standards (NCCLS document M7-A6) .
- the compounds are dissolved in 100% DMSO or sterile broth according to their aqueous solubility and are diluted to the final reaction concentration (0.06 - 32 ⁇ g/mL) in microbial growth media (IsoSensiTest Broth + 16 ⁇ g/mL 2, 2 ' -bipyridyl) . In all cases the final concentration of DMSO incubated with the bacteria is less than or equal to 1%.
- MIC minimal inhibitory concentrations
- the strains used are: Pseudomonas aeruginosa 6067 (Accession number at the DSMZ- Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Inhoffenstr. 7 B, D-38124 Braunschweig: DSM 18987), Pseudomo- nas aeruginosa (67/2B)2R.A. (DSM 18988), Achromobacter (formerly Alcaligenes) xylosoxidans QK3/96 (DSM 18991), Entero- bacter aerogenes Zayakosky 5 (DSM 18992) .
- Table 1 shows that combining of equal weights of the monobac- tam antibiotic of formula (I) according to the present invention and carbapenems of formula II lowers the MIC of the car- bapenem against carbapenem-resistant strains by an amount that is more than expected from the combination of two active compounds.
- the MIC of the combinations according to the invention is also less than the MIC of a similar equigravimet- ric combination of aztreonam and the corresponding carbap- enems .
- the combinations of the present invention exhibit lower MIC values than combinations according to WO 98/47895, e.g. WO 98/47895, Example 1, which corresponds to Compound A referred to in Table 1.
- Fractional inhibitory concentrations are determined according to the formula:
- Table 2 shows the interaction between compound of formula I, or the reference compounds Aztreonam, compound A and compound B, and carbapenems using the checkerboard titration method. Additive or synergistic interactions are only observed between the compound of formula I and carbapenem antibiotics. Under the same conditions, combinations with Aztreonam, compound A or compound B show indifference or even antagonism.
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Abstract
Use of a monobactam antibiotic of formula (I) wherein the oxyimino group i.e. >C=N-O- has Z-orientation, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a bacterial infection in combination with a carbapenem antibiotic or a pharmaceutically acceptable salt thereof.
Description
Combination medicaments for treating bacterial infections
The present invention relates to the use of monobactam antibiotic of formula (I) as described herein below and novel pharmaceutical products comprising a combination comprising said compound and a carbapenem antibiotic.
β-Lactam antibiotics have been widely used for the treatment of bacterial infections both in hospitals and in the general public. There are several classes of β-lactam antibiotics that have found clinical application, these include the penicillins, cephalosporins, cephamycins, carbacephems, oxace- phems, carbapenems and monobactams .
The efficiency of all of these classes to cure bacterial in- fections has been impaired by the appearance of bacteria that are resistant towards the antibiotics. The prevalent cause of this resistance in Gram-negative bacteria is the expression by the bacteria of enzymes known as β-lactamases that are able to hydrolyse the β-lactam antibiotics rendering them in- active. Bacteria are able to produce a variety of β- lactamases, including penicillinases, cephalosporinases, cephamycinases, carbapenemases, monobactamases, broad-spectrum β-lactamases and extended-spectrum β-lactamases.
Monobactam antibiotics (e.g. aztreonam) have been regarded as stable towards many β-lactamases. Nevertheless there are many strains of Gram-negative bacteria that now exhibit β-lactamase-mediated resistance towards aztreonam.
Combinations between Aztreonam, i.e. (Z) -2- [ [ [ (2-amino-4- thiazolyl) [ [ (2S, 3S) -2-methyl-4-oxo-l-sulfo-3-azetidinyl] - carbamoyl ] methylene] amino] oxy] -2-methylpropionic acid, and carbapenems (Imipenem or Meropenem) have been investigated as a possible way to overcome bacterial resistance. Although some synergy between aztreonam and a carbapenem was observed against bacteria belonging to the Enterobacteriaceae [Sader HS, Huynh HK, Jones RN; Contemporary in vitro synergy rates for aztreonam combined with newer fluoroquinolones and β-lactams tested against Gram-negative bacilli; Diagn. Microbiol. Infect. Dis. 47 (2003) 547-550], the activity of the combinations against Pseudomonas aeruginosa was devoid of synergy or even showed antagonism [Sader HS, Huynh HK, Jones RN; Contemporary in vitro synergy rates for aztreonam combined with newer fluoroquinolones and β-lactams tested against Gram-negative bacilli; Diagn. Microbiol. Infect. Dis. 47 (2003) 547-550; Yamaki K, Tanaka T, Takagi K, Ohta M; Effects of aztreonam in combination with antipseudomonal antibiotics against Pseudomonas aeruginosa isolated from patients with chronic or recurrent lower respiratory tract infection. J. Infect. Chemother. 4(1998) 50-55].
WO 98/47895 is directed to 2-oxo-l-azetidine sulfonic acid derivatives of the general formula
orientation as shown in the above formula. λanti' is an older term used to designate the trans-isomer of an oxime compound (the prefix λsyn' was accordingly used to designate the cis- of an oxime); cf. IUPAC Gold Book; IUPAC Compendium of Chemical Terminology, Electronic version, http://goldbook.iupac.org/E0204.html and PAC, 1996, 68, 2193 Basic terminology of stereochemistry (IUPAC Recommendations 1996) on page 2207. The disclosed 2-oxo-l-azetidine sulfonic acid derivatives are to be used in combination with carbap- enem antibiotics including Imipenem, Meropenem or Biapenem for the treatment of bacterial infections. RlRef is preferably a 2-thienyl group and is used in all exemplified inventive compounds of said reference. R2Ref. can among other groups e.g. be a group of formula:
The λanti' (trans) orientation of the oxyimino fragment is described to provide excellent synergy with ceftazidime. Example 1 of the reference e.g. refers to (3S) -trans-3- [ (E) -2- (2-thienyl) -2- { (1, 5-dihydroxy-4-pyridon-2-ylmethoxy) imino } - acetamido] -4-methyl-2-oxazetidine-l-sulfonic acid and is shown to have, together with ceftazidime, antibacterial activity against numerous strains of pathogenic bacteria.
There is however an increasing formation of resistance towards conventional monobactam antibiotics, like e.g. Aztreo- nam. Particularly in view of this growing resistance, there
- A -
is an ongoing need for novel alternatives to known monobactam antibiotics as well as for finding novel antibiotic combinations .
This invention is based on the recent finding of novel monobactam antibiotics and, more particularly, on the novel finding that a specific embodiment of these monobactams, the monobactam antibiotic of formula (I) as described herein below, when used in combination with other antibiotics, in par- ticular carbapenem antibiotics, shows improved efficacy against a broad range of bacteria, including Gram-positive and especially Gram-negative bacteria, including Enterobacte- riaceae and Pseudomonas aeruginosa. In particular, the efficacy of the novel combinations of the monobactam antibiotic of formula (I) with carbapenem antibiotics is for many strains of important pathogenic bacteria significantly improved with regard to combinations of Aztreonam with the respective carbapenem antibiotics, e.g. the combinations of Aztreonam with Meropenem or Imipenem.
Furthermore, the combinations of the present invention frequently exhibit a significantly improved efficacy against bacteria when compared to the best efficacy of the combination partners alone, and frequently exhibits a synergistic effect i.e. an effect which is more potent than what one would expect from a purely additive effect.
Thus the present invention relates to the use of the monobactam antibiotic of formula (I)
In another aspect the invention relates to pharmaceutical products comprising a monobactam antibiotic of formula (I) as described above or a pharmaceutically acceptable salt thereof and one or more than one carbapenem antibiotic, or pharmaceutically acceptable salt thereof.
These pharmaceutical products represent improved medicaments for the treatment of infections caused by pathogenic bacteria, including Gram-positive and particularly Gram-negative bacteria .
Particularly preferred according to the invention is the use of the monobactam antibiotic of formula (I) or a salt thereof for the manufacture of a medicament for the treatment of a
bacterial infection in combination with a single carbapenem antibiotic, or a pharmaceutically acceptable salt thereof.
The monobactam antibiotic of formula (I) can e.g. be prepared according to the following general Scheme 1:
Scheme 1
wherein "HOBT" stands for "hydroxybenzotriazole", "DCC" for "dicyclohexylcarbodiimide" and "TFA" for "trifluoroacetic acid". The reaction of compound of general formula Ia and compound 2 according to said scheme is described in Org. Process Res.& Dev. 2002, 863. Alternatively, the coupling reaction of compound of general formula Ia with compound 2 can e.g. be performed with the corresponding acyl chloride (Chem. Pharm. Bull. 1983, 2200) or with an activated ester of compound 1, such as the N-hydroxysuccinimidyl ester (see Org. Process Res.& Dev. 2002, 863), or the benzothiazolyl thio- ester (see J. Antibiotics 2000, 1071). Alternatively, other coupling reagents, such as hydroxyazabenzotriazole (HOAT) , 2- (lH-7-azabenzotriazol-l-yl) -1,1,3, 3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) , O-Benzotriazole- N, N, N' , N' -tetramethyl-uronium-hexafluoro-phosphate (HBTU), used for amino acid coupling reactions, can replace hydroxy-
benzotriazole (HOBT) or benzotriazolyloxytris (dimethyl- amino) phosphonium hexafluorophosphate (PyBOP) (For more detail on suitable coupling reagents, see N. Sewald, H. -D. Ja- kubke, Peptides: Chemistry and Biology, Wiley-VCH, 2002).
The preparation of compound of general formula Ia can be carried out in a customary way by reacting the appropriate keto acid 1-A3 with the appropriately etherified hydroxylamine 1-A4 as shown in Scheme 2 below:
R N
1-AO 1-A2
1-A3
1-A3
Scheme 2
In the above scheme 2, the preparation of compound 1-A4 from kojic acid and its reaction with compound 1-A3 are described in detail e.g. in EP-A-O 251 299. Compound 1-A3 can be obtained starting from compound 1-AO as shown in the upper part of above scheme 2. The compounds 1-AO can be prepared according to known methods and are partially commercially avail- able, e.g. ethyl 2- (2-amino-l, 3-thiazol-4-yl) acetate (R in formula 1-AO = ethyl) from CHEMOS GmbH, 93128 Regenstauf, Germany) . The oxidation of 1-AO to 1-A2 with e.g. selenium
dioxide may be performed in analogy to the oxidation described in the second step of example 1 of GB-A-I 575 804.
Compound 2 of Scheme 1 can e.g. be manufactured according to the route in Scheme 3:
Scheme 3
wherein "DMF SO3" stands for the dimethylformamide-sulphur trioxide complex and "TFA" for trifluoroacetic acid. In the above scheme 3, starting material 2-A3 can be prepared as described on page 2790 of Tetrahedron Lett. 1986, p. 2789-2792 (a direct synthesis for the optically active (S)-N-Boc-3- hydroxyvaline, required in turn there as the starting material, can be found in the last example of J. Org. Chem. 2003, 68, p. 177-179) . The conversions from 2-A3 to 2-A4, to 2-A5 and to 2 are described in more detail e.g. in the examples of J. Antibiotics, 1985, p. 1536-1549 (see Scheme 1 of said ref- erence) .
In scheme 1 above
RA represents an amine protecting group such as formyl, trifluoroacetyl, O-nitrophenoxyacetyl, chloroacetyl, tri- chloroacetyl, γ-chlorobutyryl, benzyloxycarbonyl, p- chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p- bromobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, diphenyl- methoxycarbonyl, ter-butyloxycarbonyl, isopropyloxycarbonyl,
diphenylmethyl, triphenylmethyl, benzyl, p-methoxybenzyl, 3, 4-dimethoxybenzyl; and
RB and Rc represent independently of one another an alcohol protecting group such as benzyloxycarbonyl, p- chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p- bromobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, diphenyl- methoxycarbonyl, ter-butyloxycarbonyl, isopropyloxycarbonyl, diphenylmethyl, triphenylmethyl, benzyl, p-methoxybenzyl, 3, 4-dimethoxybenzyl, trialkylsilane such as trimethylsilane, triethylsilane or ter-butyldimethylsilane .
Said amine and alcohol protecting groups can be easily removed, e.g. by acid hydrolysis or other well known techniques, [for more detail see e.g. T. W. Greene et al . Protec- tive Groups in Organic Chemistry, Wiley intersience, 1999]. The protecting groups in compounds of general formula Ia can easily be introduced by well known synthetic methods, [for more detail see e.g. T. W. Greene et al . Protective Groups in Organic Chemistry, Wiley intersience, 1999].
The deprotection of functional groups may be carried out either by hydrogenation or hydrolysis with appropriate acids, such as hydrochloric acid, formic acid, acetic acid, trifluoroacetic acid, phosphoric acid, NaH2PO4, Na2HPO4, p- toluenesulfonic acid or methanesulfonic acid, in solvents such as methanol, ethanol, propanol, ethyl acetate, acetoni- trile, methylene chloride or ethylene chloride. The hydrogenation is usually carried out in the presence of a metal catalyst, such as Pd, Pt or Rh under normal to high pressure. The deprotection of the different functional groups can be carried out either simultaneously or sequentially.
The solvents of choice for the reaction are selected based upon the reactants used and from solvents such as benzene, toluene, acetonitrile, tetrahydrofurane, ethanol, methanol, chloroform, ethyl acetate, methylene chloride, dimethyl for- mamide, dimethyl sulfoxide, hexamethyl phosphoric triamide or the like. Solvents mixtures may also be used.
Reaction temperatures would generally range from between -700C to 1500C. The preferred molar ratio of the reactants is 1:1 to 1:5. The reaction time range from 0.5 to 72 hours, depending on the reactants.
Examples of pharmaceutically acceptable salts of the compound of formula (I) include e.g. salts of inorganic base like am- monium salts, alkali metal salts, in particular sodium or potassium salts, alkaline earth metal salts, in particular magnesium or calcium salts; salts of organic bases, in particular salts derived from cyclohexylamine, benzylamine, oc- tylamine, ethanolamine, diethylolamine, diethylamine, triethylamine, ethylendiamine, procaine, morpholine, pyr- roline, piperidine, N-ethylpiperidine, N-methylmorpholine, piperazine as the organic base; or salts with basic amino acids, e.g. lysine, arginine, ornithine, histidine and the like.
Such salts can be manufactured in a way known per se, e.g. by reacting the compound of formula (I) with an appropriate base, preferably at room temperature or below, e.g. from about 2°C to about 25°C and isolating the salt formed, e.g. by lyophilization .
The compounds of formula (I) are optionally used in substantially crystalline form. A substantially crystalline compound of formula (I) has not yet been described before. It can be obtained by crystallisation methods, e.g. as described in the Examples of the present application. For the purposes of this application the term "substantially crystalline" means that an X-Ray Powder Diffraction (XRPD) diagram of a corresponding substance shows one or more distinct peaks which have a maximum height corresponding to at least the fivefold of their width at half-maximum. Generally, the degree of crys- tallinity of a substance increases with an increasing average value for the ratio of the height of a certain peak to its width at half-maximum. Furthermore, the XRPD diagram shall show a substantially constant base line (baseline = a line connecting the minima of the XRPD diagram curve) over the entire scanned 2-theta range, indicating the substantial absence of amorphous material, in the recorded sample. "Substantially constant base line" means for the purposes of this application that the baseline does preferably not rise for more than the height of the lowest peak of said diagram.
A further subject of the present invention is therefore the compound of formula (I) being in substantially crystalline form.
Said substantially crystalline compound of formula (I) shows peaks in the X-Ray Powder Diffractogram (XRPD) having a relative Intensity of more than 50%, recorded with Cu K-alpha Radiation and given in [° 2-Theta] , at about 6.8±0.1, 15.1±0.1, 15.6±0.1 and 25.4±0.1, and exhibits a X-Ray Powder Diffrac-
tion pattern, recorded with Cu K-alpha radiation, essentially as follows:
2Θ [°±0.1°] ReI Int ** 2Θ [°±0.1°] ReI Int**
6.86 64 + 13 24.49 22 + 4
13.32 27 ± 6 25.37 52 ± 10
13.72 28 ± 6 26.32 36 + 7
15.11 69 + 14 27.08 34 + 7
15.57 100 ± 20 28.38 33 + 7
17.41 29 ± 6 28.74 32 + 6
17.88 20 ± 4 31.00 23 + 5
22.84 31 ± 6
** with typical variation of the indicated values for the relative intensity
It is known that the values for the relative Intensity of the peaks are more strongly dependent from certain properties of the measured sample than the line position, e.g. from the size of the crystals and/or their orientation in the sample. Variations of about ± 20% of the shown peak intensities are therefore likely to occur.
Figure 1 shows the XRPD diagram of typical crystalline material of the compound of formula (I) recorded with Cu K-alpha radiation.
The compound of formula (I) and its pharmaceutically compatible salts are used according to the invention in combination with other antibiotics like in particular carbapenem antibi- otics or pharmaceutically acceptable salts thereof as antibi- otically effective medicaments in the control or prevention of infectious diseases in mammals, human and non-human, in particular bacterial infections, more particularly infections in which Gram-positive bacteria and mostly preferred in which Gram-negative bacteria are involved, such as e.g. nosocomial pneumonia, community-acquired pneumonia, urinary tract infection, complicated intra-abdominal infection, complicated skin/skin structure infection, infectious exacerbations of cystic fibrosis, sepsis, melioidosis.
In this sense, the compound of formula (I) and its pharmaceutically acceptable salts are used according to the invention in combination with a carbapenem antibiotic or pharmaceutically acceptable salt thereof for such treatment. Although not preferred, there may be certain situations, wherein the use of compound (I) or a salt thereof with two or even more
different carbapenem antibiotics may be of advantage and indicated.
For the purposes of this application, the term "carbapenem antibiotic" refers to antibiotically effective compounds comprising the structural element:
Numerous carbapenem antibiotics are known in the art, and can, in general, be used for the purposes of the present in- vention. Suitable examples are described e.g. in A. BRYSKIER "Carbapenems", ANTIMICROBIAl AGENTS: ANTIBACTERIALS AND ANTIFUNGALS, page 270 - 321, Publisher: American Society for Microbiology, Washington D. C, 2005, and references cited therein. The term "carbapenem antibiotic" includes inner salts like e.g. ME 1036 or Biapenem.
In addition to the mentioned inner salts other pharmaceutically acceptable salts of carbapenem antibiotics may also be used for the purposes of the present invention, e.g. acid ad- dition salts derived from pharmaceutically acceptable organic and/or inorganic acids.
Preferably, the carbapenem antibiotics used according to the present invention, are compounds of formula (II), or pharma- ceutically acceptable salt thereof:
wherein
R1 represents hydrogen or Ci-Cεalkyl; R2 represents hydrogen or Ci-Cεalkyl; R3 represents hydrogen, Ci-Cεalkyl, Ci-Cεalkoxy; - (CinH2n) -R5 or -0- (C1nH2n) -R5; wherein
R5 represents halogen, cyano, Ci-Cεalkoxy, amino, (Ci-Cεalkyl) amino, di (Ci-Cβalkyl) amino, or a group of formula -CO-R6, -NH-CO-R6 -CO-NH2, -NH-CO-NH2, -NH-SO2-NH2 or
-NH- (C=NH) -NH2, in which groups one or more of the hydrogen atoms may also be replaced with R or the -NH2 residue of the group can be replaced with a 5-6 membered heterocyclic ring bound to the group via a nitrogen atom present in the ring which heterocyclic ring may be unsubstituted or substituted with one or more of a substituent S2 , wherein each S2 has independently of other substituents S2 one of the meanings defined below; and R6 represents Ci-Cεalkyl, phenyl or a 5-6 membered heterocyc- lie ring and may be unsubstituted or substituted with one or more of a substituent S1, wherein each S1 has independently of other substituents S1 one of the meanings defined below; and n is an integer from 1 to 6; R4 represents a group of formula -(S)m-R7, wherein m is 0 or 1 and
R7 represents hydrogen; Ci-Cεalkyl, unsubstituted or substituted with one or more of a substituent S1; phenyl, unsubstituted or substituted with one or more of a substituent S1; or a 3-6 membered heterocyclyl group containing one or more than one heteroatom selected from nitrogen, sulfur and oxygen, which heterocyclyl group may furthermore optionally be fused to a phenyl ring or a 5-6 membered heterocyclic ring and which whole group is unsubstituted or substituted with one or more of a substituent S1; wherein each S1 is independently of other substituents S1 selected Ci-
Cεalkyl, unsubstituted or substituted with one or more of a substituent S2; phenyl, unsubstituted or substituted with one or more of a substituent S2; or a 3-6 membered heterocyclyl group containing one or more than one heteroatom selected from nitrogen, sulfur and oxygen, which heterocyclyl group may furthermore optionally be fused to a phenyl ring or a 5-6 membered heterocyclic ring and which whole group is unsubstituted or substituted with one or more of a substituent S2; Ci-Cεalkoxy, hydroxyl, carboxy, amino, Ci-Cεalkyl amino, di (Ci-Cβ) alkyl amino, cyano, halogen, or a group of formula - CO-R8, -NH-CO-NH2, -CO-NH2, -NH-CH=NH, - (C=NH) -Ci-C6alkyl, -NH-CO-NH2, -NH-SO2-NH2 Or -NH-(C=NH)-NH2, in which groups one or more of the hydrogen atoms may also be replaced with R8 or the -NH2 residue of the group can be replaced with a 5-6 mem- bered heterocyclic ring bound to the group via a nitrogen atom present in the ring which heterocyclic ring may be unsubstituted or substituted with one or more of a substituent S2, wherein each S2 has independently of other substituents S2 one of the meanings defined below; and R8 represents Ci-Cβalkyl, unsubstituted or substituted with one or more of a substituent S2; phenyl, unsubstituted or substituted with one or more of a substituent S2; or a 3-6
membered heterocyclyl group containing one or more than one heteroatom selected from nitrogen, sulfur and oxygen, which heterocyclyl group may furthermore optionally be fused to a phenyl ring or a 5-6 membered heterocyclic ring and which whole group is unsubstituted or substituted with one or more of a substituent S2, wherein each
S2 is independently from other substituents S2 selected from Ci-Cεalkyl, unsubstituted or substituted with one or more of a substituent S3; phenyl, unsubstituted or substituted with one or more of a substituent S3; or a 3-6 membered heterocyclyl group containing one or more than one heteroatom selected from nitrogen, sulfur and oxygen, which heterocyclyl group may furthermore optionally be fused to a phenyl ring or a 5-6 membered heterocyclic ring and which whole group is un- substituted or substituted with one or more of a substituent S3; Ci-Cδalkoxy, hydroxyl, carboxy, amino, Ci-Cεalkyl amino, di (Ci-Cε) alkyl amino, cyano, halogen, or a group of formula - CO-R9, -NH-CO-R9; -CO-NH2, -NH-CH=NH, -NH-CO-NH2, -NH-SO2-NH2 or -NH- (C=NH) -NH2, in which groups one or more of the hydro- gen atoms may also be replaced with R9 or the -NH2 residue of the group can be replaced with a 5-6 membered heterocyclic ring bound to the group via a nitrogen atom present in the ring which heterocyclic ring may be unsubstituted or substituted with one or more of a substituent S3, wherein each S3 has independently of other substituents S3 one of the meanings defined below; and
R9 represents Ci-Cεalkyl, unsubstituted or substituted with one or more of a substituent S3; phenyl, unsubstituted or substituted with one or more of a substituent S3; or a 3-6 membered heterocyclyl group containing one or more than one heteroatom selected from nitrogen, sulfur and oxygen, which heterocyclyl group may furthermore optionally be fused to a
phenyl ring or a 5-6 membered heterocyclic ring and which whole group is unsubstituted or substituted with one or more of a substituent S3, wherein each
S3 independently of other substituents S3 represents unsub- stituted Ci-Cεalkyl, unsubstituted phenyl or an unsubstituted 5-6 membered heterocyclic ring; Ci-Cεalkoxy, hydroxyl, car- boxy, amino, Ci-Cεalkyl amino, di (Ci-Cε) alkyl amino, cyano, halogen, or a group of formula -NH-CO-NH2, -CO-NH2, -NH- CH=NH, -NH-CO-NH2, -NH-SO2-NH2 Or -NH-(C=NH)-NH2; or R3 and R4 together form a C3-C7polymethylene group, which is unsubstituted or substituted with one or more of a substituent S3, wherein each S3 has independently of other substituents S3 one of the meanings defined above.
The term "Ci-C6alkyl" and "-(CinH2n)-", as used in the present application, refers to branched or, preferably, straight- chain Ci-Cβalkyl or -(CinH2n)-, wherein n is an integer from 1 to 6, preferably from 1 to 4, such as in particular methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, tert-butyl or neopentyl . Preferred are Ci-C4alkyl groups. The term "Ci-Cεalkoxy" means an alkoxy group based on a Ci-Cεalkyl according to the above definition.
The term "C3-C7polymethylene group" refers to a group of for- mula - (CH2) 3_7- which may comprise one or two double bonds and which may be unsubstituted or substituted as specified.
The terms "heterocyclyl group" and "heterocyclic ring" refer to corresponding groups which are saturated or unsaturated.
The term "a 3-6 membered heterocyclyl group containing one or more than one heteroatom selected from nitrogen, sulfur and
oxygen, which heterocyclyl group may furthermore optionally be fused to a phenyl ring or a 5-6 membered heterocyclic ring" refers e.g. to azetidin, thiophen, benzothiophen, fu- ran, pyran, benzofuran, isobenzofuran, pyrrol, imidazole, pyrazole, pyridin, pyrazin, pyrimidin, pyridazin, indazolin, indol, isoindol, indazol, purin, oxazol, isooxazol, furazan, pyrrolidin, pyrrolin, imidazolidin, piperidin, piperazin, thiazol, isothiazol, thiazepine or hydrothiazepin . Many other suitable heterocyclic groups for the purposes of the inven- tion are known to the skilled persons and/or can be readily found in the literature. Preferred are 5-6 membered heterocyclic groups containing one or more than one heteroatom selected from nitrogen, sulfur and oxygen, in particular nitrogen and sulphur, which heterocyclyl group may furthermore op- tionally be fused to a phenyl ring or a 5-6 membered heterocyclic ring containing one or more than one heteroatom selected from nitrogen, sulfur and oxygen, in particular nitrogen and sulphur.
"Substituted by one or more than one" means preferably "substituted by one or two", e.g. "substituted by one".
More preferably R5 represents halogen, cyano, Ci-Cεalkoxy, amino, (Ci-Cβalkyl) amino, di (Ci-Cβalkyl) amino, or a group of formula -CO-R6, -NH-CO-R6 -CO-NH2, -NH-CO-NH2, -NH-SO2-NH2 or -NH-(C=NH)-NH2, wherein R represents Ci-Cβalkyl, phenyl or a 5-6 membered heterocyclic ring and may be unsubstituted or substituted with one or more of a substituent selected from one of the substituents S3 as defined above.
The term halogen refers to fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
Another group of particularly preferred compounds of formula (II) are the compounds, wherein R4 represents a group of formula -(S)m-R7, m is 0 or 1 and R7 represents a 3-6 membered heterocyclic group containing one or more than one heteroatom selected from nitrogen, sulfur and oxygen, which heterocyclyl group may furthermore optionally be fused to a phenyl ring or a 5-6 membered heterocyclic ring and which whole group is un- substituted or substituted as defined in detail above. Even more preferred are such compounds of formula (II), when m is 1.
Also preferred are the compounds of formula (II), wherein R1 represents hydrogen or Ci-Cεalkyl; R2 represents hydrogen or Ci-Cεalkyl; and R3 represents Ci-Cεalkyl; in particular, when one of R1 and R2 represents hydrogen and the other -CH3 and R3 is -CH3.
The compounds of formula (III),
Y represents nitrogen or >CH-;
S4 represents hydrogen or has the meaning of S1 as defined above; and
R represents hydrogen; Ci-C4alkyl, in particular methyl, or - (N=H) -Ci-C4alkyl, in particular -(N=H)-CH3, or S4 and R together the nitrogen atom or group Y to which they are bound form a 5-6 membered heterocyclic ring; R being most preferably hydrogen or methyl, or pharmaceutically acceptable salts thereof, form another group of embodiments of a carbapenem which is particularly preferred for the purposes of the present invention .
The following carbapenem antibiotics or their pharmaceutically acceptable salts are specifically preferred examples useful in the present invention:
Biapenem
In medicinal practice Panipenem is generally used together with Betamipron, a renal inhibitor which inhibits renal up- take of Panipenem as known in the art.
Particularly preferred carbapenem antibiotics for use in the present invention are selected from the following compounds:
or a pharmaceutically acceptable salt thereof.
A further preferred subject of the present invention is the use of the monobactam antibiotic of formula (I) as described above or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a bacterial infection in combination with Imipenem or a pharmaceutically acceptable salt thereof. In medicinal practice Imipenem is generally used together with Cilastin, an inhibitor of the renal dipeptidase in the proximal tubulus of the kidney, which is used in order to stabilize Imipenem against inacti- vation, similar as the Betamipron in combination with Panipenem as mentioned above.
Another preferred subject of the present invention is use of the monobactam antibiotic of formula (I) as described above or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a bacterial infection in combination with Meropenem or a pharmaceutically acceptable salt thereof. Meropenem is sometimes also used together with Cilastin similar to Imipenem (Antimicrob. Agents Chemother. 2000, 44, 885-890) .
Another preferred subject of the present invention is use of the monobactam antibiotic of formula (I) as described above or a pharmaceutically acceptable salt thereof for the manu- facture of a medicament for the treatment of a bacterial infection in combination with Ertapenem or a pharmaceutically acceptable salt thereof.
Yet another preferred subject of the present invention is use of the monobactam antibiotic of formula (I) as described above or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a bacterial
infection in combination with Doripenem or a pharmaceutically acceptable salt thereof.
The compound of formula (I) or the pharmaceutically accept- able salts thereof can be administered according to the invention before, simultaneously with or after the administration of the carbapenem antibiotic or the pharmaceutically acceptable salt thereof. Substantially simultaneous or an exactly simultaneous administration of the combination partners is generally preferred.
The compounds of formula (I) or pharmaceutically acceptable salts thereof and the carbapenem antibiotics or pharmaceutically acceptable salts thereof can be administered by any route of administration, preferably in the form of a pharmaceutical composition adapted to such route. Dosage and route of administration should be determined by susceptibility of the causative organisms, severity and site of infection, and the specific condition of the patient and be selected accord- ingly. Preferred types of pharmaceutical compositions are, for example, administered orally, by inhalation or more preferably parenterally e.g. intravenously or intramuscularly.
Formulations for parenteral administration include but are not limited to the form of aqueous isotonic sterile injections, solutions, concentrates or solutions for further dilutions (e.g. for infusions), or suspensions, including nano- suspensions and nanocrystals . These solutions or suspensions can be prepared from sterile powders, granules or lyophili- zates. The compounds can be dissolved in sterile water or in various sterile buffers that may contain, but are not limited to contain, sodium chloride, polyethylene glycol, propylene
glycol, ethanol, sucrose, glucose, arginine, lysine, citric acid, lactic acid phosphoric acid and corresponding salts. The formulation can contain from 0.1% to 99% by weight, preferably 10% - 90% by weight, of each of the active ingredi- ents. If the compositions contain dosage units, each unit preferably contains from 50mg to 4g of each active substance.
A further subject of the present invention is accordingly a pharmaceutical product comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and a carbap- enem antibiotic or a pharmaceutically acceptable salt thereof .
A pharmaceutical product according to the invention can e.g. comprise one or more than one dosage unit of a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more than one other dosage unit containing a carbap- enem antibiotic or a pharmaceutically acceptable salt thereof and being free of the compound of formula (I) . By the way of example, a pharmaceutical product of the invention may comprise two separate packages, each of them comprising a pharmaceutical formulation comprising just one of the combination partners in an appropriate dosage form.
Another embodiment of the pharmaceutical product according to the invention comprises one or more than one dosage unit, and each dosage unit comprises both, the compound of formula (I) or a pharmaceutically acceptable salt thereof and a carbap- enem antibiotic or a pharmaceutically acceptable salt thereof. Such a fixed dose combination generally comprises the compound of formula (I) or the pharmaceutically acceptable salt thereof and the carbapenem antibiotic or the phar-
maceutically acceptable salt thereof as well as a pharmaceutically acceptable carrier and optionally appropriate further excipients as typical for the respective dosage form.
The pharmaceutical products according to the present invention comprise the compound of formula (I) or the pharmaceutically acceptable salt thereof and the carbapenem antibiotic or the pharmaceutically acceptable salt thereof in an appropriate weight ratio, e.g. in a weight ratio of 10:1 to 1:10, preferably from 5:1 to 1:5, more preferably from 3:1 to 1:3 like e.g. from 2:1 to 1:2 or about 1:1.
The pharmaceutical products according to the present invention are active against a variety of bacterial organisms, in particular against Gram-positive bacteria including for example Staphylococcus aureus, Staphylococccus epidermidis, En- terococcus faecalis, Streptococcus pneumonia and Gram- negative bacteria, including Enterobacteriaceae, for example Escherichia coli, Enterobacter cloacae, Enterobacter aero- genes, Citrobacter freundii , Klebsiella pneumoniae, Klebsiella oxytoca, Proteus vulgaris, Providencia rettgeri; Pseu- domonas for example P. aeruginosa; Acinetobacter for example A. baumannii; Burkholderia, for example B. cepacea; B. mallei; B. pseudomallei; Stenotrophomonas for example 5. mal- tophilia; Haemophilus influenzae .
The products can thus be used for treatment of infectious diseases including e.g. nosocomial pneumonia, community- acquired pneumonia, urinary tract infection, complicated in- tra-abdominal infection, complicated skin/skin structure infection, cystic fibrosis, sepsis.
The dosage of the compound of formula I and of the pharmaceutically compatible salts thereof and the carbapenem antibiotics or salts thereof for said treatment can vary within wide limits and will be fitted in each particular case to the in- dividual requirements of the patient to be treated and to the pathogens to be controlled. In general, a dosage of about 0.1 to about 4 g, e.g. about 0.5 to about 2 g, of total antibiotic administered one to four times over a 24 hours period should be appropriate.
The present invention is further illustrated by the following non-limiting examples.
Example 1
Preparation of (3S) -3- { (2Z) -2- (2-amino (1, 3-thiazol-4-yl) ) -3- [ (1, 5-dihydroxy-4-oxo (2-hydropyridyl) ) methoxy] -3-azaprop-2- enoylammo } -4 , 4-dimethyl-2-oxoazetidinyl hydroxysulfonate (compound of formula (I))
The monobactam antibiotic I is prepared according to the synthesis outlined in Scheme 4 and according to the procedures described below.
Scheme 4
Preparation of (3S) -3- { (2Z) -3- {[ 1, 5-bis (diphenylmethoxy) -4- OXO (2-hydropyridyl) ] methoxy} -2- { 2- [ (triphenylmethyl) amino] ( 1 , 3-thiazol-4-yl) } -3-azaprop-2-enoylamino } -4 , 4-dimethyl-2- oxoazetidinyl hydroxysulfonate (3)
Using HOBt as coupling reagent
(2Z)-3-{[l,5-Bis (diphenylmethoxy) -4-oxo (2-hydropyridyl) ] - methoxy} -2- { 2- [ (triphenylmethyl) amino] (1, 3-thiazol-4-yl) } -3- azaprop-2-enoic acid 1 (0.89 g, 0.95 mmol, J. Antibiotics 1990, 1450 and WO-A-02/22613) , hydroxybenzotriazol (HOBT) (0.14 g, 1.03 mmol) and dicyclohexylcarbodiimide (0.26 g, 1.41 mmol) are dissolved in DMF (25 mL) at room temperature. First, (3S) -3-Amino-4, 4-dimethyl-2-oxoazetidinyl hydroxysul- fonate 2 (0.2Og, 0.95 mmol, J. Org. Chem. 2003, 177 and Tet- rahedron Lett. 1986, 2786) and then 30 min later NaHCO3 (0.09 g, 1.05 mmol) are added to the previous solution. The resulting mixture is stirred for 18h. The precipitate formed is filtrated and ethyl acetate is added to the filtrate. The organic phase is washed twice with an aqueous solution satu- rated with NaCl, dried over Na2SO4 and the solvents are evaporated in vacuo. The residue is triturated in ethyl acetate (30 mL) to afford 0.5g of the desired compound 3 as white solid after filtration.
HPLC purity: 98%.
Using HATU as coupling reagent
A solution of DMSO (10 mL) containing HATU (1.38 g, 3.64 mmol) is added at room temperature to a suspension of (2Z) -3- {[1,5-Bis (diphenylmethoxy) -4-oxo (2-hydropyridyl) ] methoxy} -2- { 2- [ (triphenylmethyl) amino] (1, 3-thiazol-4-yl) } -3-azaprop-2- enoic acid 1 (3.0 g, 3.16 mmol, J. Antibiotics 1990, 1450 and
WO-A-02/22613) and (35) -3-mino-4, 4-dimethyl-2-oxoazetidinyl hydroxysulfonate 2 (l.lδg, 5.06 mmol, J. Org. Chem. 2003, 177 and Tetrahedron Lett. 1986, 2786) in DMSO (20 mL) . Then NaHCθ3 (0.81 g, 9.65 mmol) is added as solid. The resulting mixture, which becomes a solution after 1 h, is stirred for 24h at room temperature. Ethyl acetate (50 mL) is then added and the resulting solution is washed 6 times with brine (6 X 30 mL) . The organic phase dried over Na2SO4 and the mixture is concentrated by evaporation of the solvent in vacuo until about 25 mL of solution remain in the flask. At room temperature, cyclohexane (40 mL) is added dropwise to the yellow solution. The resulting precipitate is collected by filtration and the cake is then washed with cyclohexane (2 X 5 mL) to give 3.3g of the desired compound 3.
HPLC purity: 95%.
Both methods give a product with the same NMR and MS spectra. IH-NMR (DMSO-d&) δ: 1.05 (s, 3H), 1.34 (s, 3H), 4.49 (d, IH, J = 7.8 Hz), 4.62 (m, 2H), 6.12 (s, IH), 6.33 (s, IH), 6.39 (s, IH), 6.72 (s, IH), 7.20 - 7.43 (m, 35H), 7.72 (s, IH), 8.83 (1, IH), 9.52 (d, IH, J = 7.8 Hz).
Preparation of (3S) -3- { (2Z) -2- (2-amino (1, 3-thiazol-4-yl) ) -3- [ (1, 5-dihydroxy-4-oxo (2-hydropyridyl) ) methoxy] -3-azaprop-2- enoylamino } -4, 4-dimethyl-2-oxoazetidinyl hydroxysulfonate (I)
(a) Using trifluoroacetic acid
(35) -3-{ (2Z) -3-{ [1, 5-Bis (diphenylmethoxy) -4-oxo (2- hydropyridyl) ] methoxy} -2- { 2- [ (triphenylmethyl) amino] (1,3- thiazol-4-yl) } -3-azaprop-2-enoylamino } -4, 4-dimethyl-2- oxoazetidinyl hydroxysulfonate 3 (0.25 g, 0.23 mmol) and
triethylsilane (0.08 g, 0.69 mmol) are dissolved in dichloro- methane (15 mL) and cooled at -100C. Then trifluoroacetic acid (1.04 g, 9.2 mmol) is slowly added to the cooled mixture. The temperature is slowly raised to 25°C and the reac- tion is stirred for an additional 4 h. The solvent is removed in vacuo and the residue was triturated with a solvent mixture containing hexane and ethyl acetate (1:4) to give 0,11 g of the desired compound I as a solid.
HPLC purity: 94%.
(b) Using formic acid
In formic acid (3 mL) at 5°C, (35) -3- { (2Z) -3- { [ 1, 5-
Bis (diphenylmethoxy) -4-oxo (2-hydropyridyl) ] methoxy} -2- { 2- [ (triphenylmethyl) amino] (1, 3-thiazol-4-yl) } -3-azaprop-2- enoylamino } -4, 4-dimethyl-2-oxoazetidinyl hydroxysulfonate 3 (0.40 g, 0.31 mmol) is added and the clear solution is stirred for 5h at 5-100C. Then ethyl acetate (40 mL) is added and the resulting precipitate is filtrated off. The white precipitate is washed with additional ethyl acetate (2 x 5 mL) and give after drying under vacuum 0.09 g of the desired compound I
HPLC purity: 92%.
Both methods give a product with the same NMR and MS spectra. IH-NMR (DMSO-d&) δ: 1.22 (s, 3H), 1.42 (s, 3H), 4.63 (d, IH, J = 7.7 Hz), 5.28 (s, 2H), 6.81 (s, IH), 7.13 (s, IH), 7.27 (br s, 2H), 8.19 (s, IH), 9.59 (d, IH, J = 1.1 Hz).
-ESI-MS spectrum: m/z: 517 [M-H]+.
According to the methods described above, the compound of formula (I) is generally obtained in an amorphous form. Although it may be used in said form it may optionally be converted into crystalline material, e.g. as described herein below.
Crystallisation procedure for compound of formula I The crude material of compound of formula I previously prepared (1.31 g) is suspended in acetonitrile (15 mL) at room temperature. Then water (3.30 mL) is added to the previous suspension. The clear solution (if solution is not clear, the suspension could be gently warmed) is stirred at room temperature for a few minutes until the crystallisation started. The suspension is stirred for Ih at room temperature and an additional hour at 00C. After filtration, 1.05g of compound of formula I is obtained as white crystalline material, which has the same NMR and MS spectra as reported previously for amorphous material.
The crystalline material is characterized by an infrared spectrum as listed in the following table (FTIR recorded with powder at a resolution of 2 cm"1, collecting 16 scans from 4000 to 500 cm'^Bruker Vector 22 spectrometer with ATR Golden gate) .
FTIR spectrum of crystalline material of the compound of formula (I) :
The crystalline material exhibits an X-Ray Power Diffraction ("XRPD") pattern obtained using CuKCC radiation as shown in the following Table and in Figure 1.
XRPD Diagram
The crystalline material is furthermore characterized by Thermal Gravimetric Analysis ("TGA") data as indicated in the Table below and obtained using a scan rate of 10 deg/min (Perkin-Elmer TGS2) . The weight loss of the material is about 7% when the temperature of the material is raised from room temperature to 1000C. A further weight loss is observed at 192-193°C corresponding to the melting/decomposition temperature of the sample.
Temperature [°C] Weight loss [%]
25 1.12
50 4.46
75 5.70
100 8.05
125 8.09
150 8.14
175 8.29
200 55.60
225 56.10
250 56.31
275 56.52
300 56.75
325 57.06
350 57.55
375 58.35
400 29.54
425 60.99
450 62.51
475 63.95
500 65.30
Example 2
(a) Preparation of the sodium salt of compound of formula I
Sodium hydrogen carbonate (0.0077g, 0.095 mmol) is added por- tionwise to a water solution (20 mL) cooled at 5°C containing compound of formula I (0.05g, 0.1 mmol) (pH 2-3) . The clear solution is stirred for 15 minutes at 5°C (pH 5-6) . The solution is frozen and lyophilized over the night to give 0.052 g of a white solid.
IH-NMR (DMSO-d&) δ: 1.24 (s, 3H), 1.45 (s, 3H), 4.65 (d, IH, J = 1.1 Hz), 5.20 (s, 2H), 6.82 (s, IH), 6.90 (s, IH), 7.26 (br s, 2H), 7.95 (s, IH), 9.60 (d, IH, J = 1.1 Hz).
(b) Preparation of the L-arginine salt of compound of for- mula I
Compound of formula I (0.20 g, 0.39 mmol) and L-arginine (0.0672g, 0.39 mmol) are vigorously mixed as solid together at room temperature. The resulting powder is dissolved in water (40 mL) and stirred for 2-3 min at room temperature. The solution is frozen and lyophilized over the night to give 0.260 g of a white solid.
IH-NMR (DMSO-d&) δ: 1.24 (s, 3H), 1.44 (s, 3H), 1.50 - 1.80 (m, 4H), 3.11 (br m, 2H), 3.53 (br m, IH), 4.65 (d, IH, J = 1.1 Hz), 5.10 (s, 2H), 6.72 (s, IH), 6.80 (s, IH), 7.22 (br s, 2H), 7.72 (s, IH), 8.13 (br s, IH), 9.60 (d, IH, J = 1.1 Hz) .
(c) Preparation of the L-lysine salt of compound of formula I
Compound of formula I (0.2O g, 0.39 mmol) and L-lysine (0.0564g, 0.39 mmol) are vigorously mixed as solid together at room temperature. The resulting powder is dissolved in water (45 mL) and stirred for 2 - 3 min at room temperature. The solution is frozen and lyophilized over the night to give 0.250 g of a white solid.
IH-NMR (DMSO-d&) δ: 1.24 (s, 3H), 1.30 - 1.80 (m, 9H), 2.77 (br m, 2H), 3.50 (br m, IH), 4.66 (d, IH, J = 1.1 Hz), 5.11 (s, 2H), 6.73 (s, IH), 6.79 (s, IH), 7.22 (br s, 2H), 7.73 (s, IH), 9.61 (d, IH, J = 1.1 Hz).
Example 3
Antimicrobial activity of the compounds and of their combinations is determined against a selection of organisms according to standard procedures described by the National Commit- tee for Clinical Laboratory Standards (NCCLS document M7-A6) . The compounds are dissolved in 100% DMSO or sterile broth according to their aqueous solubility and are diluted to the final reaction concentration (0.06 - 32 μg/mL) in microbial growth media (IsoSensiTest Broth + 16 μg/mL 2, 2 ' -bipyridyl) . In all cases the final concentration of DMSO incubated with the bacteria is less than or equal to 1%. For estimation of the minimal inhibitory concentrations (MIC) , 2-fold dilutions of compounds are added to wells of a microtitre plate containing 106 bacteria/mL . Plates are incubated overnight at an appropriate temperature (30 0C or 37°C) and optical densities assessed by eye. The MIC value is defined as the lowest compound concentration completely inhibiting visible growth of the test organism. Synergism tests are performed under the
same conditions as described above but with two antimicrobial agents dispensed in checkerboard format [Isenberg HD (1992) Synergism testing: Broth microdilution checkerboard and broth macrodilution methods. In: Clinical Microbiology Procedures Manual vol. 1. Washington, DC: American Society for Microbiology. Sections 5.18.1 to 5.18.28.]. The strains used are: Pseudomonas aeruginosa 6067 (Accession number at the DSMZ- Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Inhoffenstr. 7 B, D-38124 Braunschweig: DSM 18987), Pseudomo- nas aeruginosa (67/2B)2R.A. (DSM 18988), Achromobacter (formerly Alcaligenes) xylosoxidans QK3/96 (DSM 18991), Entero- bacter aerogenes Zayakosky 5 (DSM 18992) .
Aztreonam as well as compound A and compound B, the latter both disclosed in WO 98/47895, which are structurally similar to the compound of formula I are used as comparators.
Table 1 shows that combining of equal weights of the monobac- tam antibiotic of formula (I) according to the present invention and carbapenems of formula II lowers the MIC of the car- bapenem against carbapenem-resistant strains by an amount that is more than expected from the combination of two active
compounds. The MIC of the combinations according to the invention is also less than the MIC of a similar equigravimet- ric combination of aztreonam and the corresponding carbap- enems . Finally, it is shown that the combinations of the present invention exhibit lower MIC values than combinations according to WO 98/47895, e.g. WO 98/47895, Example 1, which corresponds to Compound A referred to in Table 1.
Table 1: Minimum Inhibitory Concentrations (mg/L) of repre- sentative Combinations between Monobactam Antibiotics and Carbapenems
^,^ MIC of άrua A in corahinaiiύn MIC of drua B in cύnώhι.aiu>n ' AfTC o/ drug Λ alone .MIC o/ drug B alone
[Isenberg HD (1992) ; Eliopoulos, G. M. & Moellering, R. C. (1996) . In Antibiotics in Laboratory Medicine, 4th edn, (Lo- rian, V., Ed.)/ PP- 330-96. Williams and Wilkins, Baltimore, MD . ] .
Table 2 shows the interaction between compound of formula I, or the reference compounds Aztreonam, compound A and compound B, and carbapenems using the checkerboard titration method. Additive or synergistic interactions are only observed between the compound of formula I and carbapenem antibiotics. Under the same conditions, combinations with Aztreonam, compound A or compound B show indifference or even antagonism.
The interpretation of the FIC values is according to the definitions given by Sader HS, Huynh HK, Jones RN; Contemporary in vitro synergy rates for aztreonam combined with newer fluoroquinolones and β-lactams tested against Gram-negative bacilli; Diagn. Microbiol. Infect. Dis. 47 (2003) 547-550, namely as follows:
S = FIC ≤ 0.5: synergism s = 0.5< FIC<1: partial synergism
D = FIC = 1: additive effect I = 1<FIC<4: indifferent
N = 4 ≤ FIC: antagonism
Table 2: Fractional Inhibitory Concentrations (FIC) Observed for Representative Combinations between Monobactam Antibiotics and Carbapenems
Claims
1. Use of monobactam antibiotic of formula (I]
2. Use according to claim 1, wherein the medicament is for the treatment of an infection with Gram-positive and/or Gram- negative bacteria, especially with Gram-negative bacteria.
3. Use according to claim 1 or 2 for treatment of a bacterial infection in combination with one carbapenem antibiotic, or a pharmaceutically acceptable salt thereof.
4. Use according to any one of claims 1 to 3, wherein the carbapenem antibiotic is a compound of formula (II) 
wherein
R1 represents hydrogen or Ci-Cεalkyl; R2 represents hydrogen or Ci-Cεalkyl; R3 represents hydrogen, Ci-Cεalkyl, Ci-Cεalkoxy; - (CinH2n) -R5 or -0- (C1nH2n) -R5; wherein
R5 represents halogen, cyano, Ci-Cεalkoxy, amino; (Ci- Cεalkyl) amino, di (Ci-Cβalkyl) amino, or a group of formula -CO- R6, -NH-CO-R6 -CO-NH2, -NH-CO-NH2, -NH-SO2-NH2 Or -NH-(C=NH)- NH2, in which groups one or more of the hydrogen atoms may also be replaced with R or the -NH2 residue of the group can be replaced with a 5-6 membered heterocyclic ring bound to the group via a nitrogen atom present in the ring which het- erocyclic ring may be unsubstituted or substituted with one or more of a substituent S2 , wherein each S2 has independently of other substituents S2 one of the meanings defined below; and R6 represents Ci-Cεalkyl, phenyl or a 5-6 membered heterocyc- lie ring and may be unsubstituted or substituted with one or more of a substituent S1, wherein each S1 has independently of other substituents S1 one of the meanings defined below; and n is an integer from 1 to 6; R4 represents a group of formula -(S)m-R7, wherein m is 0 or 1 and R7 represents hydrogen; Ci-Cεalkyl, unsubstituted or substituted with one or more of a substituent S1; phenyl, unsubstituted or substituted with one or more of a substituent S1; or a 3-6 membered heterocyclyl group containing one or more than one heteroatom selected from nitrogen, sulfur and oxygen, which heterocyclyl group may furthermore optionally be fused to a phenyl ring or a 5-6 membered heterocyclic ring and which whole group is unsubstituted or substituted with one or more of a substituent S1; wherein each S1 is independently of other substituents S1 selected Ci-
Cεalkyl, unsubstituted or substituted with one or more of a substituent S2; phenyl, unsubstituted or substituted with one or more of a substituent S2; or a 3-6 membered heterocyclyl group containing one or more than one heteroatom selected from nitrogen, sulfur and oxygen, which heterocyclyl group may furthermore optionally be fused to a phenyl ring or a 5-6 membered heterocyclic ring and which whole group is unsubstituted or substituted with one or more of a substituent S2; Ci-Cεalkoxy, hydroxyl, carboxy, amino, (Ci-Cεalkyl) amino, di (Ci-Cβ) alkyl amino, cyano, halogen, or a group of formula -CO-R8, -NH-CO-NH2, -CO-NH2, - (C=NH) -Ci-C6alkyl, -NH-CH=NH, -NH-CO-NH2, -NH-SO2-NH2 Or -NH-(C=NH)-NH2, in which groups one or more of the hydrogen atoms may also be replaced with R8 or the -NH2 residue of the group can be replaced with a 5-6 mem- bered heterocyclic ring bound to the group via a nitrogen atom present in the ring which heterocyclic ring may be unsubstituted or substituted with one or more of a substituent S2, wherein each S2 has independently of other substituents S2 one of the meanings defined below; and R8 represents Ci-Cβalkyl, unsubstituted or substituted with one or more of a substituent S2; phenyl, unsubstituted or substituted with one or more of a substituent S2; or a 3-6 membered heterocyclyl group containing one or more than one heteroatom selected from nitrogen, sulfur and oxygen, which heterocyclyl group may furthermore optionally be fused to a phenyl ring or a 5-6 membered heterocyclic ring and which whole group is unsubstituted or substituted with one or more of a substituent S2, wherein each
S2 is independently from other substituents S2 selected from Ci-Cεalkyl, unsubstituted or substituted with one or more of a substituent S3; phenyl, unsubstituted or substituted with one or more of a substituent S3; or a 3-6 membered heterocyclyl group containing one or more than one heteroatom selected from nitrogen, sulfur and oxygen, which heterocyclyl group may furthermore optionally be fused to a phenyl ring or a 5-6 membered heterocyclic ring and which whole group is un- substituted or substituted with one or more of a substituent S3; Ci-Cδalkoxy, hydroxyl, carboxy, amino, (Ci-Cεalkyl) amino, di (Ci-Cε) alkyl amino, cyano, halogen, or a group of formula - CO-R9, -NH-CO-R9; -CO-NH2, -NH-CH=NH, -NH-CO-NH2, -NH-SO2-NH2 or -NH- (C=NH) -NH2, in which groups one or more of the hydro- gen atoms may also be replaced with R9 or the -NH2 residue of the group can be replaced with a 5-6 membered heterocyclic ring bound to the group via a nitrogen atom present in the ring which heterocyclic ring may be unsubstituted or substituted with one or more of a substituent S3, wherein each S3 has independently of other substituents S3 one of the meanings defined below; and
R9 represents Ci-Cεalkyl, unsubstituted or substituted with one or more of a substituent S3; phenyl, unsubstituted or substituted with one or more of a substituent S3; or a 3-6 membered heterocyclyl group containing one or more than one heteroatom selected from nitrogen, sulfur and oxygen, which heterocyclyl group may furthermore optionally be fused to a phenyl ring or a 5-6 membered heterocyclic ring and which whole group is unsubstituted or substituted with one or more of a substituent S3, wherein each
S3 independently of other substituents S3 represents unsub- stituted Ci-Cεalkyl, unsubstituted phenyl or an unsubstituted 5-6 membered heterocyclic ring; Ci-Cεalkoxy, hydroxyl, car- boxy, amino, (Ci-Cεalkyl) amino, di (Ci-Cε) alkyl amino, cyano, halogen, or a group of formula -NH-CO-NH2, -CO-NH2, -NH- CH=NH, -NH-CO-NH2, -NH-SO2-NH2 Or -NH-(C=NH)-NH2; or R3 and R4 together form a C3-C7 polymethylene group, which is unsubstituted or substituted with one or more of a substituent S3, wherein each S3 has independently of other substituents S3 one of the meanings defined above, or a pharmaceutically acceptable salt thereof.
5. Use according to any one of claims 1 to 4, wherein R4 represents a group of formula -(S)m-R7, wherein m is 0 or 1 and
R7 represents a 3-6 membered heterocyclyl group containing one or more than one heteroatom selected from nitrogen, sulfur and oxygen, which heterocyclyl group may furthermore optionally be fused to a phenyl ring or a 5-6 membered heterocyclic ring and which whole group is unsubstituted or substituted as defined in claim 4, or a pharmaceutically acceptable salt thereof.
6. Use according to claim 5, wherein m is 1 , or a pharmaceutically acceptable salt thereof.
7. Use according to any one of claims 1 to 6, wherein R1 represents hydrogen or Ci-Cεalkyl; R2 represents hydrogen or Ci-Cεal kyl ; and
R3 represents Ci-Cεal kyl , or a pharmaceutically acceptable salt thereof.
8. Use according to any one of claims 1 to 7, wherein one of R1 and R2 represents hydrogen and the other -CH3; and
R3 represents -CH3, or a pharmaceutically acceptable salt thereof.
9. Use according to any one of claim 1 to 8, wherein the car- bapenem antibiotic is selected from the compounds of formula (III) :
Y represents nitrogen or >CH-;
S4 represents hydrogen or has the meaning of S1 as defined in claim 4; and
R represents hydrogen; d-C4alkyl, in particular methyl, or - (N=H) -Ci-C4alkyl, in particular -(N=H)-CH3, or
S4 and R together the nitrogen atom or group Y to which they are bound form a 5-6 membered heterocyclic ring;
R being most preferably hydrogen or methyl, or a pharmaceutically acceptable salt thereof.
10. Use according to any one of claims 1 to 9, wherein the carbapenem antibiotic is selected from the following compounds :
or a pharmaceutically acceptable salt thereof, with the pre- viso that Panipenem is used in further combination with Be- tamipron .
11. Use according to any one of claims 1 to 9, wherein the carbapenem antibiotic is:
or a pharmaceutically acceptable salt thereof which is used in further combination with Cilastin.
12. Use according to any one of claims 1 to 9, wherein the carbapenem antibiotic is:
Meropenem
or a pharmaceutically acceptable salt thereof, optionally in further combination with Cilastin.
13. Use according to any one of claims 1 to 9, wherein the carbapenem antibiotic is:
Ertapenem or a pharmaceutically acceptable salt thereof.
14. Use according to any one of claims 1 to 9, wherein the carbapenem antibiotic is: 
Doripenem or a pharmaceutical ly acceptable salt thereof .
15. A pharmaceutical product comprising a monobactam antibiotic of formula (I)
16. A pharmaceutical product according to claim 15, comprising one or more than one dosage unit comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more than one dosage unit comprising a carbapenem antibiotic or pharmaceutically acceptable salt thereof.
17. A pharmaceutical product according to claim 15, comprising one or more than one dosage unit, each of said dosage units comprising both, a monobactam antibiotic of formula (I]
18. A pharmaceutical product according to claim 16 or 17, wherein the carbapenem antibiotic is selected from the following compounds:
19. A pharmaceutical product according to claim 16 or 17, wherein the carbapenem antibiotic is Imipenem or a pharmaceutically acceptable salt thereof, in combination with Cilastin .
20. A pharmaceutical product according to claim 16 or 17, wherein the carbapenem antibiotic is Meropenem or a pharmaceutically acceptable salt thereof, optionally in combination with Cilastin.
21. A pharmaceutical product according to claim 16 or 17, wherein the carbapenem antibiotic is Ertapenem or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical product according to claim 16 or 17, wherein the carbapenem antibiotic is Doripenem or a pharmaceutically acceptable salt thereof.
23. A pharmaceutical product according to any one of claims 15 to 22, comprising the monobactam antibiotic of formula (I) or the pharmaceutically acceptable salt thereof and the carbapenem antibiotic or the pharmaceutically acceptable salt thereof in a weight ratio of 10:1 to 1:10, preferably 5:1 to 1:5.
24. A pharmaceutical product according to claim 23, wherein the weight ratio of the monobactam antibiotic of formula (I) or the pharmaceutically acceptable salt thereof and the carbapenem antibiotic or the pharmaceutically acceptable salt thereof is from 3:1 to 1:3, preferably from 2:1 to 1:2, e.g. about 1:1.
25. A pharmaceutical product according to any one of claims 15 to 24, which is a composition comprising the monobactam antibiotic of formula (I) or the pharmaceutically acceptable salt thereof and a carbapenem antibiotic or a pharmaceuti- cally acceptable salt thereof and a pharmaceutically acceptable carrier.
26. A pharmaceutical product according to any one of claims 15 to 25, which exhibits synergistic efficacy against bacte- ria, in particular Gram-negative bacteria as compared to the efficacy of the compound of formula (I) and the carbapenem antibiotic or a pharmaceutically acceptable salt thereof comprised in the product when used alone.
26. A pharmaceutical product according to any one of claims 15 to 25 for the treatment of nosocomial pneumonia, community-acquired pneumonia, urinary tract infection, complicated intra-abdominal infection, complicated skin/skin structure infection, infectious exacerbations of cystic fibrosis, sep- sis, melioidosis.
27. A method for treating a bacterial infection in a mammal, in particular a human, in need of such treatment comprising administering to said mammal or particularly to said human, a monobactam antibiotic of formula (I)
28. A method according to claim 27, wherein the carbapenem antibiotic is a compound as claimed in any one of claims 4 to 14, in particular in any one of claims 10 to 14.
29. A method according to claim 27 to 28, wherein a synergistic combination of the monobactam antibiotic of formula (I) or salt thereof and a carbapenem antibiotic or salt thereof is administered to said mammal or, preferably, said human.
30. A method according to any one of claims 27 to 28 for the treatment of nosocomial pneumonia, community-acquired pneumonia, urinary tract infection, complicated intra-abdominal infection, complicated skin/skin structure infection, infectious exacerbations of cystic fibrosis, sepsis, melioidosis.
31. The compound of formula (I) as shown in claim 1 being in substantially crystalline form.
Priority Applications (13)
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| RU2009139004/15A RU2488394C2 (en) | 2007-03-23 | 2008-03-19 | Combined therapeutic agents for treating bacterial infections |
| NZ579375A NZ579375A (en) | 2007-03-23 | 2008-03-19 | Combination medicaments for treating bacterial infections |
| AU2008231854A AU2008231854B2 (en) | 2007-03-23 | 2008-03-19 | Combination medicaments for treating bacterial infections |
| MX2009009918A MX2009009918A (en) | 2007-03-23 | 2008-03-19 | Combination medicaments for treating bacterial infections. |
| JP2009554024A JP2010521517A (en) | 2007-03-23 | 2008-03-19 | Combination drugs for the treatment of bacterial infections |
| US12/532,243 US8486929B2 (en) | 2007-03-23 | 2008-03-19 | Combination medicaments for treating bacterial infections |
| CN2008800093460A CN101641095B (en) | 2007-03-23 | 2008-03-19 | Combination medicaments for treating bacterial infections |
| CA2680018A CA2680018C (en) | 2007-03-23 | 2008-03-19 | Combination medicaments for treating bacterial infections |
| KR1020097019585A KR101320718B1 (en) | 2007-03-23 | 2008-03-19 | Combination medicaments for treating bacterial infections |
| BRPI0809147-1A BRPI0809147A2 (en) | 2007-03-23 | 2008-03-19 | COMBINED DRUGS FOR TREATMENT OF BACTERIAL INFECTIONS |
| EP08718057.6A EP2124942B1 (en) | 2007-03-23 | 2008-03-19 | Combination medicaments for treating bacterial infections |
| HK10103422.0A HK1138184A1 (en) | 2007-03-23 | 2010-04-07 | Combination medicaments for treating bacterial infections |
| US13/915,833 US8809315B2 (en) | 2007-03-23 | 2013-06-12 | Combination medicaments for treating bacterial infections |
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| EP07006053.8 | 2007-03-23 | ||
| EP07006053 | 2007-03-23 |
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| US12/532,243 A-371-Of-International US8486929B2 (en) | 2007-03-23 | 2008-03-19 | Combination medicaments for treating bacterial infections |
| US13/915,833 Division US8809315B2 (en) | 2007-03-23 | 2013-06-12 | Combination medicaments for treating bacterial infections |
Publications (3)
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| WO2008116813A2 true WO2008116813A2 (en) | 2008-10-02 |
| WO2008116813A9 WO2008116813A9 (en) | 2008-11-27 |
| WO2008116813A3 WO2008116813A3 (en) | 2009-01-22 |
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| PCT/EP2008/053336 WO2008116813A2 (en) | 2007-03-23 | 2008-03-19 | Combination medicaments for treating bacterial infections |
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| US (2) | US8486929B2 (en) |
| EP (1) | EP2124942B1 (en) |
| JP (2) | JP2010521517A (en) |
| KR (1) | KR101320718B1 (en) |
| CN (1) | CN101641095B (en) |
| AU (1) | AU2008231854B2 (en) |
| BR (1) | BRPI0809147A2 (en) |
| CA (1) | CA2680018C (en) |
| HK (1) | HK1138184A1 (en) |
| MX (1) | MX2009009918A (en) |
| NZ (1) | NZ579375A (en) |
| RU (1) | RU2488394C2 (en) |
| WO (1) | WO2008116813A2 (en) |
| ZA (1) | ZA200906349B (en) |
Cited By (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010064261A1 (en) * | 2008-12-01 | 2010-06-10 | Glade Organics Private Limited | Synergistic combinations of aztreonam with the carbapenems meropenem and ertapenem |
| US8252782B2 (en) | 2008-12-19 | 2012-08-28 | Pfizer Inc. | Monocarbams |
| WO2013110643A1 (en) | 2012-01-24 | 2013-08-01 | Aicuris Gmbh & Co. Kg | Amidine substituted beta - lactam compounds, their preparation and use as antibacterial agents |
| US9012491B2 (en) | 2011-08-31 | 2015-04-21 | Rempex Pharmaceuticals, Inc. | Heterocyclic boronic acid ester derivatives and therapeutic uses thereof |
| US9101638B2 (en) | 2013-01-04 | 2015-08-11 | Rempex Pharmaceuticals, Inc. | Boronic acid derivatives and therapeutic uses thereof |
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| US9241947B2 (en) | 2013-01-04 | 2016-01-26 | Rempex Pharmaceuticals, Inc. | Boronic acid derivatives and therapeutic uses thereof |
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| US9687497B1 (en) | 2014-05-05 | 2017-06-27 | Rempex Pharmaceuticals, Inc. | Salts and polymorphs of cyclic boronic acid ester derivatives and therapeutic uses thereof |
| WO2018014823A1 (en) | 2016-07-21 | 2018-01-25 | 中国科学院上海药物研究所 | Monocyclic β-lactam-iron carrier conjugate, and manufacturing method and application thereof |
| WO2018065636A1 (en) | 2016-12-21 | 2018-04-12 | Aicuris Anti-Infective Cures Gmbh | COMBINATION THERAPY WITH AMIDINE SUBSTITUTED ß-LACTAM COMPOUNDS AND ß-LACTAMASE INHIBITORS FOR INFECTIONS WITH ANTIBIOTIC RESISTANT BACTERIAL STRAINS |
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| US10294249B2 (en) | 2016-06-30 | 2019-05-21 | Qpex Biopharma, Inc. | Boronic acid derivatives and therapeutic uses thereof |
| WO2019144969A1 (en) | 2018-01-29 | 2019-08-01 | 南京明德新药研发股份有限公司 | Monocyclic β-lactam compound for treating bacterial infection |
| US10385074B2 (en) | 2014-05-05 | 2019-08-20 | Rempex Pharmaceuticals, Inc. | Synthesis of boronate salts and uses thereof |
| US10561675B2 (en) | 2012-06-06 | 2020-02-18 | Rempex Pharmaceuticals, Inc. | Cyclic boronic acid ester derivatives and therapeutic uses thereof |
| US10618918B2 (en) | 2015-03-17 | 2020-04-14 | Qpex Biopharma, Inc. | Substituted boronic acids as antimicrobials |
| US10662205B2 (en) | 2014-11-18 | 2020-05-26 | Qpex Biopharma, Inc. | Cyclic boronic acid ester derivatives and therapeutic uses thereof |
| WO2020125670A1 (en) | 2018-12-18 | 2020-06-25 | 南京明德新药研发有限公司 | APPLICATION OF MONOCYCLIC β-LACTAM COMPOUND IN PHARMACY |
| WO2020168265A1 (en) | 2019-02-14 | 2020-08-20 | Singapore Eye Research Institute | Antibacterial compositions |
| WO2021121387A1 (en) | 2019-12-19 | 2021-06-24 | 南京明德新药研发有限公司 | Application of compound in drug preparation |
| US11286270B2 (en) | 2017-10-11 | 2022-03-29 | Qpex Biopharma, Inc. | Boronic acid derivatives and synthesis thereof |
| US12016868B2 (en) | 2018-04-20 | 2024-06-25 | Qpex Biopharma, Inc. | Boronic acid derivatives and therapeutic uses thereof |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ579375A (en) * | 2007-03-23 | 2012-02-24 | Basilea Pharmaceutica Ag | Combination medicaments for treating bacterial infections |
| KR101315483B1 (en) * | 2011-06-23 | 2013-10-07 | 주식회사 아리바이오 | A composition comprising antibiotics and lysophosphatidylcholine for enhancing immune or treating bacterial infection |
| RU2618433C2 (en) * | 2015-08-10 | 2017-05-03 | Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Санкт-Петербургский государственный университет" (СПбГУ) | ANTIMICROBIAL COMBINATION IN TERMS OF CARBAPENEM RESISTANTGRAM-NEGATIVE PSEUDOMONAS AERUGINOSA BACTERIA, PRODUCING METAL-β-LACTAMASE |
| RU2666619C2 (en) * | 2016-12-01 | 2018-09-11 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Санкт-Петербургский государственный университет" (СПбГУ) | ANTIMICROBIAL COMBINATION FOR CARBAPENEM-RESISTANT GRAM-NEGATIVE BACTERIA OF THE SPECIES ACINETOBACTER BAUMANNII PRODUCING METAL-β-LACTAMASE |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998047895A1 (en) | 1997-04-24 | 1998-10-29 | Naeja Pharmaceutical Inc. | 2-OXO-1-AZETIDINE SULFONIC ACID DERIVATIVES AS POTENT β-LACTAMASE INHIBITORS |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1575803A (en) | 1976-03-09 | 1980-10-01 | Fujisawa Pharmaceutical Co | 3,7 disubstituted 3 cephem 4 carboxylic acid compounds andprocesses for the preparation thereof |
| US4822786A (en) | 1986-07-01 | 1989-04-18 | Kaken Pharmaceutical Co., Ltd. | Cephalosporin compounds, and antibacterial agents |
| US5994340A (en) | 1997-08-29 | 1999-11-30 | Synphar Laboratories, Inc. | Azetidinone derivatives as β-lactamase inhibitors |
| CN1189469C (en) | 2000-09-14 | 2005-02-16 | 潘斯瑞克有限公司 | 3-(heteroaryl acetamido)-2-oxo-azetidine-1-sulfonic acid derivatives as anti-bacterial agents |
| US20050065141A1 (en) * | 2003-07-31 | 2005-03-24 | Odink Debra A. | Carbapenems useful in treating and preventing pulmonary infections, pharmaceutical compositions thereof and modes of administration thereof |
| PL1965798T3 (en) | 2005-12-07 | 2012-02-29 | Basilea Pharmaceutica Ag | Useful monobactam antibiotics |
| NZ579375A (en) * | 2007-03-23 | 2012-02-24 | Basilea Pharmaceutica Ag | Combination medicaments for treating bacterial infections |
-
2008
- 2008-03-19 NZ NZ579375A patent/NZ579375A/en not_active IP Right Cessation
- 2008-03-19 EP EP08718057.6A patent/EP2124942B1/en active Active
- 2008-03-19 KR KR1020097019585A patent/KR101320718B1/en not_active IP Right Cessation
- 2008-03-19 US US12/532,243 patent/US8486929B2/en not_active Expired - Fee Related
- 2008-03-19 BR BRPI0809147-1A patent/BRPI0809147A2/en not_active IP Right Cessation
- 2008-03-19 CA CA2680018A patent/CA2680018C/en not_active Expired - Fee Related
- 2008-03-19 MX MX2009009918A patent/MX2009009918A/en active IP Right Grant
- 2008-03-19 CN CN2008800093460A patent/CN101641095B/en not_active Expired - Fee Related
- 2008-03-19 AU AU2008231854A patent/AU2008231854B2/en not_active Ceased
- 2008-03-19 WO PCT/EP2008/053336 patent/WO2008116813A2/en active Application Filing
- 2008-03-19 JP JP2009554024A patent/JP2010521517A/en active Pending
- 2008-03-19 RU RU2009139004/15A patent/RU2488394C2/en not_active IP Right Cessation
-
2009
- 2009-09-11 ZA ZA200906349A patent/ZA200906349B/en unknown
-
2010
- 2010-04-07 HK HK10103422.0A patent/HK1138184A1/en not_active IP Right Cessation
-
2013
- 2013-06-12 US US13/915,833 patent/US8809315B2/en not_active Expired - Fee Related
- 2013-08-19 JP JP2013169657A patent/JP5779209B2/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998047895A1 (en) | 1997-04-24 | 1998-10-29 | Naeja Pharmaceutical Inc. | 2-OXO-1-AZETIDINE SULFONIC ACID DERIVATIVES AS POTENT β-LACTAMASE INHIBITORS |
Non-Patent Citations (1)
| Title |
|---|
| ANTIMICROB. AGENTS CHEMOTHER., vol. 44, 2000, pages 885 - 890 |
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| AU2008231854B2 (en) | 2013-03-21 |
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| NZ579375A (en) | 2012-02-24 |
| WO2008116813A9 (en) | 2008-11-27 |
| MX2009009918A (en) | 2009-10-19 |
| RU2009139004A (en) | 2011-04-27 |
| ZA200906349B (en) | 2010-06-30 |
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