WO2019020810A1 - Forme cristalline de l'acide (2s)-2-[[(z)-[-1-(2-amino-4-thiazolyl)-2-[[(3s)-2,2-diméthyl-4-oxo-1-(sulfooxy)-3-azétidinyl]amino]-2-oxoéthylidène]amino]oxy]-3-[4-[imino[(3r)-3- pipéridinylamino]méthyl]phénoxy]-propanoïque - Google Patents

Forme cristalline de l'acide (2s)-2-[[(z)-[-1-(2-amino-4-thiazolyl)-2-[[(3s)-2,2-diméthyl-4-oxo-1-(sulfooxy)-3-azétidinyl]amino]-2-oxoéthylidène]amino]oxy]-3-[4-[imino[(3r)-3- pipéridinylamino]méthyl]phénoxy]-propanoïque Download PDF

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WO2019020810A1
WO2019020810A1 PCT/EP2018/070475 EP2018070475W WO2019020810A1 WO 2019020810 A1 WO2019020810 A1 WO 2019020810A1 EP 2018070475 W EP2018070475 W EP 2018070475W WO 2019020810 A1 WO2019020810 A1 WO 2019020810A1
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formula
compound
crystalline
water
pharmaceutical composition
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PCT/EP2018/070475
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English (en)
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Burkhard Klenke
Wilfried Schwab
Susanne BONSMANN
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Aicuris Anti-Infective Cures Gmbh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to the first crystalline form of (2S)-2-[[(Z)-[l-(2-amino-4-thiazolyl)-2- [[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-3- [4-[imino[(3R)-3-piperidinylamino]methyl]phenoxy]-propanoic acid, i.e. compound of formula (I).
  • Patent WO 2013110643 describes amidine substituted mono-cyclic ⁇ -lactam compounds, their preparation, pharmaceutical composition and use. These compounds are active as novel ⁇ -lactam antibiotics, particularly useful for the treatment of Gram-negative infections.
  • the compounds is also (2S)-2-[[(Z)-[l-(2-amino-4-thiazolyl)-2-[[(3S)-2,2-dimethyl-4-oxo-l- (sulfooxy)-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-3-[4-[imino[(3R)-3- piperidinylamino]methyl]phenoxy] -propanoic acid with a broad profile against Gram- negative pathogens.
  • the reaction generally takes place in protic solvents or in solvent mixtures containing at least one protic solvent at a temperature ranging from 0°C to 100°C for 1-24 hours.
  • Suitable protic solvents are for example methanol, ethanol, iso-propanol, tert-butanol, water or acetic acid.
  • Solvents suitable to form mixtures are for example dichloro- methane, trichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile and N,N- dimethylformamide.
  • the reaction is carried out in a mixture of anhydrous ethanol and chloroform or anhydrous ethanol and dichloromethane at 20-30°C overnight.
  • the reaction generally takes place in inert solvents in the presence of a coupling reagent and where applicable with addition of a base at a temperature ranging from -20°C to 80°C for 1-24 hours, preferably at a temperature of 20-30°C overnight.
  • Inert solvents are for example dichloromethane (DCM), trichloromethane, benzene, toluene, tetrahydrofuran (THF), 1,4-dioxane, ⁇ , ⁇ -dimethylformamide (DMF), N,N- dimethylacetamide (DMA), N-methylpyrrolidin-2-one (NMP) and acetonitrile as well as mixtures of the aforementioned solvents.
  • a preferred solvent is N,N- dimethy lformamide .
  • Suitable coupling reagents are for example carbodiimides such as ⁇ , ⁇ '-diethyl-, ⁇ , ⁇ ,'-dipropyl-, ⁇ , ⁇ '-diisopropyl , ⁇ , ⁇ '-dicyclohexylcarbodiimide, N-(3-di- methylaminoisopropyl)-N'-ethylcarbodiimid-hydrochloride (EDC), N- cyclohexylcarbo-diimid-N'-propyloxymethyl-polystyrene (PS-Carbodiimide) or carbonyl compounds such as carbonyl-di-imidazole (CDI), or 1 ,2-oxazolium compounds such as 2-ethyl-5 -phenyl- 1 ,2-oxazolium-3 -sulfate or 2-tert.-butyl-5- methyl-isoxazolium-perchlorate, or acyla
  • Suitable bases are for example carbonates and bicarbonates, triethylamine, diisopropylethylamine, N- methylmorpholine, N-methylpiperidine or 4-dimethylaminopyridine.
  • reactions are carried out with a mixture of a carbodiimide and 1-hydroxybenzotriazole with or without the addition of sodium bicarbonate as base.
  • Acidic conditions may involve treating intermediate IM2 with formic acid, acetic acid, trifluoroacetic acid or hydrochloric acid with optional addition of an inert organic solvent and a scavenger at temperatures ranging from 0°C to 100°C for a time ranging from 10 min to 16 hours, preferably with 90% formic acid or trifluoroacetic acid / dichloromethane (1 :1) at a temperature of 30-60°C for 30-60 min.
  • Suitable inert additive organic solvents are for example dichloromethane, chloroform and 1,4- dioxane.
  • Suitable additive scavenger systems are for example anisole and triethylsilane.
  • the crystal state of a compound may be, however, important when the compound is used for pharmaceutical purposes, e.g. in terms of API stability, DP manufacturing process and DP stability.
  • the solid physical properties of a crystalline compound may change from one solid form to another one, which may affect its suitability for pharmaceutical use.
  • different solid forms of a crystalline form can incorporate different types and/or different amounts of impurities.
  • Different solid forms of compound can also have different chemical stability upon exposure to heat and/or water over a period of time.
  • solid crystalline forms may exist as hydrates, solvates or hydrates of solvates impacting on the mentioned properties.
  • amorphous zwitterionic materials may be converted into their corresponding salts or co-crystals to obtain crystalline forms.
  • subject matter of the invention is a crystalline compound of formula (I), whereas said crystalline form has a KF -value of 18-25%, preferably 21%.
  • the KF value water content
  • the KF value is determined following pharmacopeial methods, e.g. ⁇ USP 921> Method Ic or Ph. Eur. 2.5.12 Method A.
  • Total amounts of water significantly below 21% may indicate partial conversion to amorphous material.
  • a potential 1-3% error margin of the detection method should be taken into account with KF measurements in the range of 21%.
  • Amorphous material may contain 7-10 wt% residual water without any crystalline material being detectable.
  • subject matter of the invention is a crystalline compound of formula (I), wherein said crystalline form is a deca-hydrate.
  • a deca-hydrate form (compound of formula (I) ⁇ 10 H 2 0) corresponds to a theoretical water content of 21%..
  • subject matter of the invention is a crystalline compound of formula (I), whereas said crystalline form has an X-ray powder diffraction pattern (XRPD) that exhibits characteristic peaks at 2 ⁇ angles ⁇ 0.3° of the following values: 6.2, 7.5, 8.4, 9.7,
  • XRPD X-ray powder diffraction pattern
  • subject matter of the invention is a crystalline compound of formula (I), whereas said crystalline form has an X-ray powder diffraction pattern according to Figure 13 - XRPD of crystalline material (Form A).
  • Figure 13 - XRPD X-ray powder diffraction pattern according to Figure 13 - XRPD of crystalline material
  • Figure 1 For comparison the X-ray powder diffraction pattern of amorphous compound of formula (I), which is exhibiting no significant peaks at 2 ⁇ angles in the rage of 4-40° is shown in Figure 1.
  • subject matter of the invention is a crystalline compound of formula (I), whereas said crystalline form has the single crystal structure according to Figure 15 - Single crystal x-ray structure of crystalline material (Form A).
  • the obtained single crystal structure confirms both the identity and the absolute configuration of compound of formula (I).
  • subject matter of the invention is a crystalline compound of formula (I), whereas said crystalline form has a differential scanning calorimetry thermogram (DSC) and a thermogravimetric analysis according to Figure 16 - DSC and TGA of crystalline material (Form A) showing a significant endotherm around 98 °C corresponding to the evaporation of water and a weight loss of ⁇ 8% corresponding to the loss of water.
  • DSC differential scanning calorimetry thermogram
  • TGA thermogravimetric analysis
  • Compound of formula (I) can be further characterised by infra-red spectroscopy (IR), Raman spectroscopy (Raman), lH-nmr spectroscopy (lH-nmr) and determination of optical rotation (OR). There are only very minor, non-significant differences between data obtained from amorphous and crystalline compound of formula (I). Full characterisations are provided in Example 3 and Example 17.
  • Crystalline material (Form A) of compound of formula (I) shows an advantage in terms of storage stability compared to amorphous compound of formula (I). While crystalline material shows hardly any degradation on storage at -20°C (12 months), 5 °C (12 months) and 25 °C (6 months), degradation is observed for amorphous material; especially, increasing with storage time and temperature. Details are exemplified in Example 4 and Example 18.
  • Crystalline material shows the same biological activity as the amorphous material.
  • the crystalline form is obtainable and may be obtained by transformation of the amorphous material.
  • One embodiment of the invention relates to a crystalline compound of formula (I) that is
  • One embodiment of the invention relates to a crystalline compound of formula (I) according to embodiment i), wherein said crystalline form has a KF -value of 18-25%, preferably 21 %.
  • One embodiment of the invention relates to a crystalline compound of formula (I) according to embodiments i) or ii), wherein said crystalline form is a deca-hydrate.
  • One embodiment of the invention relates to a crystalline compound of formula (I) according to any of embodiments i) to iii), wherein said crystalline form has an X-ray powder diffraction pattern (XRPD) that exhibits characteristic peaks at 20 angles ⁇ 0.3° of the following values: 6.2, 7.5, 8.4, 9.7, 10.6, 11.1, 12.5, 12.7, 13.3, 14.5, 14.8, 16.1, 16.3, 16.5, 16.8, 17.9, 18.3, 18.4, 18.8, 19.4, 19.7, 20.2, 21.0, 21.3, 22.1, 22.5, 22.8, 23.2, 23.4, 23.6, 23.9, 24.0, 25.0, 25.2, 25.7, 26.2, 26.5 and 26.8°.
  • XRPD X-ray powder diffraction pattern
  • One embodiment of the invention relates to a crystalline compound of formula (I) according to any of embodiments i) to iv), wherein said crystalline form has an X-ray powder diffraction pattern according to Figure 13 - XRPD of crystalline material (Form A).
  • One embodiment of the invention relates to a crystalline compound of formula (I) according to any of embodiments i) to vi), wherein said crystalline form has a differential scanning calorimetry spectrum (DSC) according to Figure 16 - DSC and TGA of crystalline material (Form A).
  • DSC differential scanning calorimetry spectrum
  • viii) One embodiment of the invention relates to a use of a crystalline compound of formula (I) according to any of embodiments i) to vii) for making a pharmaceutical composition / formulation.
  • One embodiment of the invention relates to a pharmaceutical composition obtainable by a method comprising the following steps:
  • One embodiment of the invention relates to a pharmaceutical composition obtainable according to embodiment viii) or according to embodiment ix), wherein said pharmaceutical composition is suitable for intravenous, parenteral administration
  • a pharmaceutical composition according to embodiments ix) or x) wherein said pharmaceutical composition comprises at least one further anti-infective compound.
  • xii) One embodiment of the invention relates to a pharmaceutical composition according to any of embodiments ix), x), or xi), wherein said pharmaceutical composition further comprises a beta-lactamase inhibitor.
  • xiii) One embodiment of the invention relates to a compound according to any of embodiments i) to vii) or the pharmaceutical composition according to any of embodiments ix) to xii) for use in treatment or prophylaxis of bacterial infections.
  • xiv) One embodiment of the invention relates to a compound according to any of embodiments i) to vii) or the pharmaceutical composition according to any of embodiments ix) to xii) for use in treatment or prophylaxis of bacterial infections, wherein said bacterial infection is a gram-negative bacterial infection.
  • One embodiment of the invention relates to a compound according to any of embodiments i) to vii) or the pharmaceutical composition according to any of embodiments ix) to xii) for use in treatment or prophylaxis of bacterial infections, wherein said compound or composition is administered parenterally.
  • One embodiment of the invention relates to a method of treating or preventing a bacterial infection in a subject, in particular a gram-negative bacterial infection, comprising administering to a patient in need thereof a therapeutically effective amount of the compound according to any of embodiments i) to vii) or the pharmaceutical composition according to any of embodiments ix) to xii).
  • xvii) One embodiment of the invention relates to a method of treating or preventing a bacterial infection in a subject according to embodiment xvi) wherein said compound or composition is administered parenterally.
  • xviii) One embodiment of the invention relates to a use of a crystalline compound of formula (I) according to any of embodiments i) to vii) or the pharmaceutical composition according to any of embodiments ix) to xii) for the manufacture of a medicament for the treatment and/or prophylaxis of diseases.
  • One embodiment of the invention relates to a use of a crystalline compound of formula (I) according to any of embodiments i) to vii) or the pharmaceutical composition according to any of embodiments ix) to xii) for the manufacture of a medicament for the treatment and/or prophylaxis of diseases, wherein said disease is a bacterial infection in a subject, in particular a gram-negative bacterial infection.
  • One embodiment of the invention relates to a use of a crystalline compound of formula (I) according to any of embodiments i) to vii) or the pharmaceutical composition according to any of embodiments ix) to xii) for the manufacture of a medicament for the treatment and/or prophylaxis of diseases in particular a gram- negative bacterial infection, wherein said compound or composition is administered parenterally.
  • a method of making a crystalline compound of formula (I) according to any of embodiments i) to vii) comprising the steps of
  • amorphous compound in an aqueous solvent system that is water or a mixture of water and one or more organic solvents at a temperature that is within a range of 0-50 °C;
  • One embodiment of the invention relates to a method of making a crystalline compound of formula (I) according to embodiment xxi), wherein said aqueous solvent system is selected from the group comprising THF/water or acetonitrile/water or acetone/water or methylethyl-keton/water mixed in the range of 80:20 to 20:80 at a temperature that is within the range of 0-35°C.
  • One embodiment of the invention relates to a method of making a crystalline compound of formula (I) according to embodiment xxi) or xxii), wherein said aqueous solvent system is THF/water mixed in the range of 40:60 to 20:80 at a temperature that is within the range of 0-30°C.
  • One embodiment of the invention relates to a method of making a crystalline compound of formula (I) according any of embodiments xxi) to xxiii), wherein said aqueous solvent system is THF/water mixed in the range of 50:50 at a temperature that is within the range of 20-30 °C and that is further diluted with water to obtain a THF/water system that is between 40:60 und 20:80 before cooling said aqueous solvent system comprising said compound.
  • xxv) One embodiment of the invention relates to a method of making a crystalline compound of formula (I) according any of embodiments xxi) to xxiv), wherein said crystallisation step is finalized at a temperature that is within 2-8 °C.
  • One embodiment of the invention relates to a method of making a crystalline compound of formula (I) according any of embodiments xxi) to xxv), wherein said aqueous solvent system is acetonitrile/water.
  • One embodiment of the invention relates to a method of making a crystalline compound of formula (I) according any of embodiments xxi) to xxv), wherein said aqueous solvent system is acetone/water.
  • Subject matter of the present invention is also a method of making a crystalline compound of formula (I) according to the present invention comprising the steps of
  • Subject matter of the present invention is also a method of making a crystalline compound of formula (I) according to the present invention wherein said aqueous solvent system is selected from the group comprising THF/water or acetonitrile/water or acetone/water or methylethyl- keton/water mixed in the range of 80:20 to 20:80 at a temperature that is within the range of 0-35°C.
  • said aqueous solvent system is selected from the group comprising THF/water or acetonitrile/water or acetone/water or methylethyl- keton/water mixed in the range of 80:20 to 20:80 at a temperature that is within the range of 0-35°C.
  • Subject matter of the present invention is also a method of making a crystalline compound of formula (I) according to the present invention wherein said aqueous solvent system is THF/water mixed in the range of 40:60 to 20:80 at a temperature that is within the range of 0- 30°C.
  • Subject matter of the present invention is also a method of making a crystalline compound of formula (I) according to the present invention wherein said aqueous solvent system is THF/water mixed in the range of 50:50 at a temperature that is within the range of 20-30 °C and that is further diluted with water to obtain a THF/water system that is between 40:60 und 20:80 before cooling said aqueous solvent system comprising said compound.
  • said aqueous solvent system is THF/water mixed in the range of 50:50 at a temperature that is within the range of 20-30 °C and that is further diluted with water to obtain a THF/water system that is between 40:60 und 20:80 before cooling said aqueous solvent system comprising said compound.
  • Subject matter of the present invention is also a method of making a crystalline compound of formula (I) according to the present invention wherein said crystallisation (4) step is finalized at a temperature that is within 2-8 °C.
  • Conversion into amorphous material was observed in dynamic vapour sorption (DVS) experiments after exposure to a relative humidity environment ⁇ 20% RH. Similarly, low relative humidity may also be established by applying low pressure conditions. Conversion of crystalline material into amorphous material was observed on exposure to ⁇ 200 mbar for 48 hours at 25 °C.
  • DVS dynamic vapour sorption
  • the solid forms disclosed herein may be further processed into any type of solid pharmaceutical preparations or dosage forms, which are known to the person of skill in the art.
  • the solid forms may be suitable for reconstitution with a pharmaceutically acceptable vehicle for administration.
  • a pharmaceutical composition as described herein may be in an injectable form.
  • the composition may contain stabilizing agents.
  • the composition may be in suitable sterile solid form for reconstitution to form an injectable solution. Particularly preferred are injectable dosage forms.
  • subject matter of the invention is therefore the use of a crystalline compound of formula (I) as described above for making a pharmaceutical composition / formulation.
  • a pharmaceutical composition according to the present invention comprising of crystalline compound of formula (I) may be a lyophilisate for reconstitution and dilution prior to direct injection or infusion.
  • Such a pharmaceutical composition is obtainable by a method comprising the following steps:
  • a pharmaceutical composition according to the present invention comprising of crystalline compound of formula (I) may be a sterile solution for direct injection or infusion.
  • Such a pharmaceutical composition is obtainable by a method comprising the following steps:
  • a pharmaceutical composition according to the present invention comprising of crystalline compound of formula (I) may be a sterile solution for dilution prior to direct injection or infusion.
  • Such a pharmaceutical composition is obtainable by a method comprising the following steps:
  • the pharmaceutical composition according to the present invention comprising of API, represented by crystalline compound of formula (I), may be a pure sterile API powder for reconstitution and dilution prior to direct injection or infusion.
  • Such a pharmaceutical composition is obtainable by a method comprising the following steps:
  • the pharmaceutical composition according to the present invention comprising of API, represented by crystalline compound of formula (I), may be a pure sterile API powder for reconstitution and dilution prior to direct injection or infusion.
  • Such a pharmaceutical composition is obtainable by a method comprising the following steps:
  • a pharmaceutical composition according to the present invention comprising of API, represented by crystalline compound of formula (I), may be a sterile powder blend of API and one or more suitable excipients for reconstitution and dilution prior to direct injection or infusion.
  • Such a pharmaceutical composition is obtainable by a method comprising the following steps:
  • step 2 Dispensing the powder blend resulting from step 1 by powder filling into a suitable container closure system
  • a pharmaceutical composition according to the present invention comprising of API, represented by crystalline compound of formula (I), is a sterile powder blend of API and one or more suitable excipients for reconstitution and dilution prior to direct injection or infusion.
  • Such a pharmaceutical composition is obtainable by a method comprising the following steps:
  • a pharmaceutical composition according to the present invention comprising of API, represented by crystalline compound of formula (I), is a sterile powder blend of API and one or more suitable excipients for reconstitution and dilution prior to direct injection or infusion.
  • Such a pharmaceutical composition is obtainable by a method comprising the following steps:
  • a vehicle is a carrier or inert medium used as a solvent or diluent in which the medicinally active agent is formulated and administered.
  • suitable vehicles and excipients as well as methods for making such pharmaceutical preparations can for example be found in R.C. Rowe, P.J. Sheskey, W.G. Cook, M.E. Fenton, Handbook of Pharmaceutical Excipients, 7th edition (2012), Pharmaceutical Press (Publ); ISBN 978 0 85711 027 5.
  • the physical form of API, represented by the compound of formula (I), in the final pharmaceutical composition according to the present invention is crystalline or amorphous.
  • the pharmaceutical composition according to the present invention is suitable for intravenous, parenteral administration.
  • the pharmaceutical composition according to the present invention may further comprise at least one further therapeutic agent.
  • the further therapeutic agent is an additional drug selected from the group of but not limited to anti-infective agents such as antifungal agents, antiviral agents, antiparasitic agents, antimycotic agents, antimycobacterial agents, intestinal antiinfective agents, biologicals (monoclonal antibodies, vaccines and the like), bactericidal/permeability- increasing protein product (BPI), antivirulence drugs, efflux pump inhibitors, probiotics, lysins, antimicrobial peptides, anti-biofilm agents, anti-resistance nucleic acids, anti-bacterial nucleic acids, antibiotic-degrading enzymes, alphamers, medical devices, antimalaria agents, anti-inflammatory agents, antiallergic agents, and/or centrally and peripherally acting analgesic drugs, anaesthetic drugs, immunomodulators, immune suppressive agents, monoclonal antibodies, anti-neoplastic drugs, anti-cancer drugs, anti-e
  • the therapeutic agent is an additional antibacterial agent.
  • antibacterial agents for use in pharmaceutical combinations of the invention may be selected from but are not limited to other clinically useful antibiotic agents such as penicillins, cephalosporins, penems, carbapenems, carbacephems, oxacephems, cephamycins, monobactams, trinems aminoglycosides, bacteriocins, quinolones, fluoroquinolones, macrolides, ketolides, tetracyclines, glycylcyclines, oxazolidinones, lipopeptides, polypeptides, polymyxins, rifamycins, pleuromutilins, nitrofurans, amphenicols, nitroimidazoles, glycopeptides, lipoglycopeptides, streptogramins, ansamycins, lincosamides, steroid antibacterials, folate pathway inhibitors,
  • the pharmaceutical composition according to the present invention may further comprise a beta-lactamase inhibitor.
  • ⁇ -lactamase inhibitors for use in pharmaceutical combinations of the invention may be selected from the group comprising: clavulanic acid, tazobactam, sulbactam and other ⁇ -lactamase inhibitors belonging to the groups but are not limited to oxapenams, penam sulfones, bridged monobactams, monobactams, tribactams, cephem sulfones, carbapenems, penems, diazabicyclooctane inhibitors, transition state analog BLIs, metallo- ⁇ -lactamase inhibitors and derivatives and combinations thereof.
  • combination is meant either a fixed combination in one dosage unit form, or a kit or instruction for the combined administration where a compound of the present invention and a combination partner may be administered simultaneously, separately and/or sequentially with or without any medical device.
  • the compound or the pharmaceutical composition according to the present invention may be used in treatment or prophylaxis of bacterial infections.
  • the compound or the pharmaceutical composition according to the present invention may be used in treatment or prophylaxis of bacterial infections wherein said bacterial infection is a gram-negative bacterial infection.
  • the compound or the pharmaceutical composition according to the present invention may be used in treatment or prophylaxis of bacterial infections wherein said compound or composition is administered parenteral.
  • Subject matter of the present invention is also a method of treating or preventing a bacterial infection in a subject, in particular a gram-negative bacterial infection, comprising administering to a patient in need thereof a therapeutically effective amount of the compound according to the present invention or the pharmaceutical composition according to the present invention.
  • Subject matter of the present invention is also a method of treating or preventing a bacterial infection in a subject according to the present invention wherein said compound or composition is administered parenteral.
  • Subject matter of the present invention is also the use of a crystalline compound of formula (I) according to the present invention or the pharmaceutical composition according to the present invention for the manufacture of a medicament for the treatment and/or prophylaxis of diseases.
  • Subject matter of the present invention is also the use of a crystalline compound of formula (I) according to the present invention or the pharmaceutical composition according to the present invention for the manufacture of a medicament for the treatment and/or prophylaxis of diseases, wherein said disease is a bacterial infection in a subject, in particular a gram- negative bacterial infection.
  • Subject matter of the present invention is also the use of a crystalline compound of formula (I) according to the present invention or the pharmaceutical composition according to the present invention for the manufacture of a medicament for the treatment and/or prophylaxis of diseases, wherein said compound or composition is administered parenteral.
  • X-Ray Powder Diffraction analysis Approximately 20 mg of sample were prepared in standard sample holders using two foils of polyacetate. The samples were analysed as received without further manipulation. Powder diffraction patterns were acquired at room temperature on a Bruker D8 Advance Series 2Theta/Theta powder diffraction system using CuKai -radiation (1.54060 A) in transmission geometry. The system is equipped with a VANTEC-1 single photon counting PSD, a Germanium monochromator, a ninety positions autochanger sample stage, fixed divergence slits and a radial soller. The generator intensity for the generation of the X-ray beam is set to 40 mA and 40 kV.
  • VT-XRPD Variable Temperature X-Ray Powder Diffraction analysis
  • Programs used Data collection with APEX II (Data collection with APEX II version v2009.1-02. Bruker (2007).
  • DSC Differential scanning calorimetry analysis
  • Thermogravimetric analysis (TGA): Thermogravimetric analyses were recorded in a Mettler Toledo TGA/SDTA851 with a balance MT1 type. Approximately 3-4 mg of sample were weighed (using a MX5 Mettler Toledo microbalance) into 40 aluminium crucibles with a pinhole lid and heated under nitrogen (10 mL/min) at 10 °C/min from 30 to 300 °C. Programs used: Data collection and evaluation with software STARe.
  • Proton nuclear magnetic resonance spectroscopy 1 H-NMR: Proton nuclear magnetic resonance analyses were recorded in deuterated DMSO (DMSO- ⁇ ) in a Bruker Avance 400 Ultrashield NMR spectrometer. Spectra were acquired solving 8-10 mg of sample in 0,7 mL of deuterated solvent.
  • FT-Infrared spectroscopy The FT-IR spectra were recorded using a Bruker Alpha spectrometer, equipped with a Bruker Diamond single reflection ATR system, a mid-infrared source as the excitation source and a DTGS detector. The spectra were acquired in 32 scans at a resolution of 4 cm -1 in the range 4000-400 cm -1 . No sample preparation was required to perform the analysis.
  • FT-Raman spectroscopy (FTR): FT-Raman spectra were recorded using a NXR FT-Raman module added to the Thermo Nicolet FT-IR 5700 Nexus spectrometer equipped with InGaAs and Ge detectors, CaF 2 beamsplitter and Nd:YV0 4 laser (1064 nm) providing approximately 40 mW of laser power at the sample. The spectra were acquired in 256 scans at a resolution of 4 cm -1 in the range 4000-400 cm -1 . No sample preparation was required to perform the analysis.
  • PSD Particle size distribution analysis
  • DVS Dynamic Vapour Sorption analysis
  • Missing atoms were subsequently located from difference Fourier synthesis and added to the atom list. Least-squares refinement on Fo 2 using all measured intensities was carried out using the program SHELXL 2015 (SHELXL; Sheldrick, G.M. Acta Cryst. 2015 C71, 3-8.). All non-hydrogen atoms were refined including anisotropic displacement parameters.
  • Optical rotation Specific optical rotation measurements were carried out on a Jasco P-1030 model polarimeter equipped with a PMT detector using the Sodium line at 589 nm. The solutions were prepared in DMSO with a concentration of 0.01 g/mL and measured in a 1dm cell at room temperature.
  • Ultra-violet spectroscopy Measurements were performed in a double beam UV-Vis Shimadzu spectrophotometer model UV-2401PC with a Peltier thermostated (7-60 °C) sample holder. Optical range measured was from 200 to 900 nm. The measurement was carried out at different concentrations in DMSO at room temperature.
  • MIC Determination Compounds of this invention were tested for antimicrobial activity by determining minimum inhibitory concentrations (MICs, in ⁇ g/mL) using the broth microdilution method according to the guidelines of the Clinical Laboratories and Standards Institute ("Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically", Approved standard, 7th ed., Clinical and Laboratory Standards Institute (CLSI) Document M7-A8, Wayne, Pa., USA, 2009.). While the compounds of this invention were serially diluted as described above, a constant concentration of the beta- lactamase inhibitors of 4 ⁇ g/mL was used.
  • Bacterial strains that were used to evaluate the antimicrobial acitivity using the MIC determination included but were not limited to E. coli ATCC25922, K. pneumoniae 60, E. cloacae 34654, C. freundii K21/3034, M. morganii 126/3048, P. aeruginosa PAOl, P. aeruginosa 2297 (AmpC wt), P. aeruginosa 2297-con (AmpC derepressed), A. baumannii ATCC15308, S. maltophilia ICB7569, S. aureus 133, M. catarrhalis ICB489, H. influenzae ATCC 49247, S. pneumoniae 113, B. fragilis 6688, C. perfringens DSM756, E. coli J62, and E. coli J62-TEM-3.
  • HPLC analysis HPLC grade solvents were used for all operations. HPLC analysis was performed with samples of a concentration around 1 mg/mL under the following conditions.
  • Step 1 Dicyclohexylcarbodiimide (DCC, 0.94 g, 4.56 mmol) and 1-hydroxybenzotriazole (HOBT, 0.62 g, 4.59 mmol) were added to a solution of compound Step 1 Intermediate (4.5 g, 4.56 mmol) in N,N-dimethylformamide (50 mL) at room temperature. After stirring at room temperature for lh, (3S)-3-amino-4,4-dimethyl-l-(sulfooxy)-2-azetidinone (0.96 g, 4.57 mmol) was added followed by sodium bicarbonate (0.38 g, 4.52 mmol). The resulting mixture was stirred at room temperature overnight and concentrated under reduced pressure at 40°C. The residue was purified by column chromatography eluting with a gradient of 1-5% methanol in dichloromethane to give Step 2 Intermediate (3.0 g, 60% yield) as a yellow solid.
  • DCC dicyclohexylcarbodi
  • Step 2 Intermediate (3.0 g, 2.75 mmol) in 90 % formic acid (20 mL) was stirred at 35°C for 15 min. After concentrating to dryness under reduced pressure, the residue was suspended in dichloromethane (100 mL) and anisole (3 mL). TFA (3 mL) was added at 0 °C; the mixture was allowed to warm to room temperature and stirred until no more starting material was detected by mass spectroscopy. The mixture was concentrated under reduced pressure at 20°C and dried under vacuum. The material was suspended in dichloromethane and filtered. The filter residue was purified by prep HPLC to afford compound of formula (I) (0.46 g, 25% yield) as colorless amorphous solid.
  • Example 2
  • step 3 (39 g, crude) was alternatively purified by reverse phase column chromatography on a Biotage SPF1 using a KP-C18-HS-400 column and a gradient of 8-12% acetonitrile in 0.2% aqueous formic acid as eluent.
  • the crude compound (1.5 g of crude per injection/run) was taken up in 10 mL of 0.2%> aqueous formic acid and loaded onto the column, 50 mL fractions were collected and the product containing combined fractions were freeze dried to give compound of formula (I) (10.5 g, 27%> yield) as off-white amorphous solid with some residual amounts of formic acid and trifluoroacetic acid.
  • the amorphous material obtained was characterized by XRPD, DSC, TGA, lH-nmr, IR, Raman, UV, PSD, DVS, microscopy, HPLC and optical rotation. Representative results are shown in the figures 1 to 11 and tables below.
  • Amorphous material (10 mg) of compound of formula (I) was suspended at room temperature in 0.2 mL of the corresponding solvent and successive additions (initially 0.2 mL and finally 0.5 mL) of solvent were performed until the solid was completely dissolved or up to a maximum of 6 mL. After each solvent addition the suspension was vigorously stirred for 5-10 minutes and visually inspected to determine if the solid was completely dissolved.
  • a salt screening program of amorphous compound of formula (I) was carried out using nine acidic and two basic counter-ions in one solvent system.
  • the starting material was liquid dosed in 1.8 mL or 8 mL scale experimental vials depending on volume of counter-ion to be added (stock solution of compound of formula (I) with water/acetone and concentration 66.4 mg/rnL).
  • the ratios of counter-ions used are given in the table below.
  • the different solutions of the acidic counter-ions were added in one step. However the basic counter-ions were added drop-wise in order to control the pH and avoid the hydrolysis of the parent compound (at pH>7-8).
  • a salt screening program for the formation of crystalline salts of compound of formula (I) using two acidic (p-toluenesulfonic acid and methanesulfonic acid) and two basic (sodium acetate and sodium bicarbonate) counter-ions in four solvent systems was carried out.
  • the salt formation experiments were followed by cooling-evaporative re-crystallization method and slurry using five solvents (water, ethyl acetate, ethanol, iso-propanol and THF) in an attempt to crystallize the samples.
  • the amorphous starting material was solid dosed in 1.8 mL scale experimental vials.
  • the salt formation was carried out with four counter-ions (p-toluenesulfonic acid, methanesulfonic acid, sodium acetate and sodium bicarbonate) and two ratios (1 : 1 and 1 :2).
  • the acidic counter-ion solutions were added in one step. However the basic counter-ions were added drop-wise in order to control the pH and avoid the hydrolysis of the molecule (at pH>8).
  • the experimental vials were capped and stirred at room temperature for 1 hour.
  • the salt and co-crystal screening was further extended by investigating equimolar mixtures of compound of formula (I) amorphous form and a set of 19 acidic counter ions (pKa range 2-6) at 50 mg scale in THF, water and iso-propanol; three crystallisation techniques were used:
  • Amorphous material (Compound of formula (I), 38.8 mg, 97.2% HPLC purity) was suspended in 1.0 mL 2,2,2-trifluoroethanol. The suspension was sonicated for 1 minute and stirred at room temperature. After stirring at room temperature for 1 hour a sticky material adhered to the glass wall of the vial. The system was sonicated for 1 minute and stirred at room temperature for 1 day. Still a sticky material adhered to the glass wall of the vial. The system was sonicated for 1 minute and stirred at room temperature. After 4 days and 6 days: a sticky material adhered to the glass wall of the vial. Sample was stored in a refrigerator.
  • Example 10 A suspension and precipitate formed on standing at room temperature for 2-16 h.
  • the precipitate contained API crystalline Form A and other components.
  • Suitable API Form A seed crystals can be selected from the precipitate.
  • the amorphous starting material (14.6 mg) was solid dosed in 1.8 mL scale experimental vials and acetone/water (50:50, 400 ⁇ ) was added. Following, the experimental vials were capped and stirred at 25 °C for 1 hour. Then they were cooled down to 5°C with an ageing time of 24 hours with no solid precipitating. The solution was removed by evaporation till dryness and the dry solid identified as amorphous material by XRPD. The solid was mixed with 1 mL of water, stirred at 25 °C for 2 hours, and cooled down to 5°C with an ageing time of 3 days.
  • the obtained solid was identified as amorphous material by XRPD.
  • the material was slurried in water (400 ⁇ ) at 25 °C for 5 days and the obtained solid was identified as crystalline Form A by XRPD.
  • the solid was then exposed to accelerated ageing conditions (40 °C / 75% RH for 24 hours), followed by re-analysis by XRPD, which confirmed crystalline Form A.
  • amorphous starting material about 1.797 g water- free material
  • 50 mL of acetone/water 50:50 v/v were added at room temperature.
  • the system was stirred with a paddle stirrer (250 rpm). After about 15 minutes a yellow solution was formed but a brown, sticky lump remained undissolved.
  • the rotation speed of the stirrer was increased (450 rpm) and an additional 20 mL of acetone/water 50:50 v/v were added in 5mL steps over about 1 hour (in total 70 mL of acetone/water 50:50 v/v). Most of the sticky lump was then dissolved.
  • the remaining undissolved sticky lump was removed from the system with a spatula.
  • the pH of the solution was 4.6.
  • the solution was seeded with 10 mg of crystalline compound of formula (I) and the very weak suspension formed was stirred at room temperature. After 1 hour a small aliquot of the weak suspension was taken. Microscopy confirmed the presence of some small particles which showed birefringence.
  • the rotation speed of the stirrer was reduced (300 rpm). After stirring at room temperature for an additional 1 hour the suspension was still very weak and again microscopy showed some small particles which showed birefringence.
  • To an aliquot of 1 mL of the weak suspension about 1 mg of crystalline compound of formula (I) was added. The sample was sonicated for 1 minute and stirred at 5°C for 5 minutes.
  • the suspension formed was used to seed the weak solution a second time. However, after about 20 minutes there was still only a very weak suspension present. Therefore, the gas phase of the reactor was purged with dry nitrogen in order to remove acetone slowly. After about 0.5 hour the still relatively weak suspension was seeded again using a sonicated suspension of 16 mg of crystalline compound of formula (I) in 1 mL of the supersaturated solution. After stirring for 2 hours at room temperature microscopy showed an increased number of particles which showed birefringence. However, the suspension was still relatively weak. Stirring the suspension and purging the gas phase of the reactor was continued overnight. After 13 hours about 35 mL of the solvent was evaporated. Off-white solid material adhered to the glass wall.
  • a white, thick suspension was formed and it was necessary to increase the rotation speed of the stirrer to 600 rpm in order to effectively stir the suspension. After stirring for 25 minutes and 55 minutes microscopy still showed mainly needle-like particles and some agglomerates or sticky particles.
  • An aliquot of the white suspension of about 20 mL was transferred to a sintered glass funnel (porosity P4) for vacuum filtration. The suspension was easy to filter (filtration time about 20 seconds). For air drying air was drawn through the filter cake (23°C / 50% r.h.). After 12 minutes vacuum was stopped and 5 mL of water/THF 80:20 v/v were added to the filter cake. After 2 minutes the solvent was drawn through the filter cake. The washing procedure was carried out twice. Then the filter cake was air dried by drawing air through the filter cake. After about 5 minutes the filter cake was carefully broken in with a spatula.
  • Amorphous material (1.996 g) was dissolved in THF/water 50:50 mixture (10 mL) at room temperature (concentration of 0.20 g/mL). After stirring for one hour at that temperature the resulting clear solution was seeded with crystalline Form A (30 mg, 1.5 wt%). The resulting weak suspension was stirred at room temperature for one hour, and water (2.5 mL) was added at a rate of 83 ⁇ / ⁇ until a final ratio of THF/water 40:60 (concentration of 0.16 g/mL). Once completed the addition, the resulting suspension was stirred at room temperature for 2 hours, cooled to 7 °C and kept at that temperature for 15 hours.
  • Amorphous material (20 g) was dissolved in THF/water 50:50 mixture (60.8 mL) at 35 °C (concentration of 0.33 g/mL). The resulting solution was cooled to 20 °C and seeded with crystalline Form A (0.2 g, 1.0 wt%) under stirring (200 rpm). After stirring for one hour at that temperature, water (15.2 mL) was added in 45 minutes to the resulting weak suspension until a final ratio of THF/water 40:60 (concentration of 0.26 g/mL). Once completed the addition, the resulting suspension was cooled to 5 °C in one hour and stirred (300 rpm) at that temperature for 16 hours. The solid obtained was filtered off, washed with THF/water 40:60 mixture (20 mL) and air-dried to give crystalline compound of formula (I) as off-white solid (20.7 g, 91 % yield)
  • the crystalline material obtained was characterized by XRPD, variable temperature XRPD, single crystal x-ray structure determination, DSC, TGA, IH-nmr, IR, Raman, UV, PSD, DVS, microscopy, HPLC and optical rotation. Representative results are shown in the figure 13 to 29 and tables below. Selection ofXRPD peaks (Fig. 13)
  • the single crystal structure obtained confirms the identity of compound of formula (I).
  • the sample crystallizes in the monoclinic chiral space group P2i.
  • the asymmetric unit is formed by one double-zwitterion of compound of formula (I) and ten water molecules, indicating that the material corresponds to a decahydrate.
  • the absolute configuration could be determined reliably with a Flack value of 0.046 and a Flack value based on Parsons' quotients of 0.014 (Reference: Flack H.D., Acta Cryst. A39 (1983) 876 and Parsons S., Flack H., Acta Cryst. A39 (2004) S61).
  • the Flack parameter value for the correct absolute configuration determination should be 0; the inverted structure would give 1.
  • the structure is of high quality with a Rl value of 3.9% at 100 K.
  • the XRPD pattern calculated from the single crystal data shows a good correspondence to the experimentally measured XRPD pattern of compound of formula (I) Form A, indicating that they correspond to the same crystalline phase (Fig. 15 to 29).
  • Crystalline material Form A (10 mg) of compound of formula (I) was suspended at room temperature in 0.2 mL of the corresponding solvent and successive additions (initially 0.2 mL and finally 0.5 mL) of solvent were performed until the solid was completely dissolved or up to a maximum of 6 mL. After each solvent addition the suspension was vigorously stirred for 5-10 minutes and visually inspected to determine if the solid was completely dissolved.
  • Crystalline material Form A (1 g) of compound of formula (I) was slurried in a THF/water (40:60) solvent mixture (50 mL) at room temperature for 1 hour and filtered through a glass fritted funnel to obtain a starting material containing 47% residual water. This material was dried under different temperature, pressure and relative humidity conditions for up to 48 hours. Obtained material was analysed by XRPD (solid form), TGA (water content) and HPLC (purity).
  • the brownish-green solution was stirred at room temperature with a paddle stirrer (250 rpm) and 90 mL of water (LiChrosolv Merck 1.15333) were added in 5 mL steps in about 15 minutes (final ratio water/tetrahydrofuran about 80:20 v/v).
  • the greenish-brown, turbid solution was seeded with a sonicated suspension of 0.154 g of crystalline compound of formula (I) in 3 mL of the turbid solution from the glass reactor [sonication for 1 minute at room temperature of the suspension for seeding is important and should produce a greenish, off-white suspension].
  • the weak suspension produced after seeding was stirred for 10 minutes at room temperature [some brown material adhered to the glass wall of the reactor].
  • Microscopy showed the presence of needle-like, birefringent particles.
  • the suspension was cooled with a cooling rate of about 12 K/hour to about 8°C in 85 minutes. At 15°C a greenish-brown suspension was present; the suspension was easy to stir and microscopy again showed the presence of needle-like particles, without sticky lumps. At 10°C a greenish, off- white suspension was present; the suspension was easy to stir and microscopy showed the presence of needle-like particles, without sticky lumps.
  • the suspension was then stirred between 8°C and 7°C for 16 hours. A greenish, off-white suspension was present, the suspension was easy to stir and microscopy showed the presence of needle-like particles, without sticky lumps.
  • Sample dispersion is a mixture of coarse and fine particles with wide particle distribution and increased result variability.
  • Optical rotation of crystalline material Three separate solutions in DMSO with a concentration of 0.01 g/mL were prepared, filtered in order to remove any particles in suspension and then analyzed at 24 °C (Na line at 589 nm). Choice of the solvent used has a strong impact on the result and consequently some variability is caused by differences in water content and assay of the analysed material. #: Each result is obtained as the average of ten measurements with an interval of two seconds. ⁇ : Each result is obtained from the average of three specific optical rotation values.

Abstract

L'invention concerne la première forme cristalline de l'acide (2S)-2-[[(Z)-[1-(2-amino-4-thiazolyl)-2-[[(3S)-2,2-diméthyl-4-oxo-1-(sulfooxy)-3-azétidinyl]amino]-2-oxoéthylidène]amino]oxy]-3-[4-[imino[(3R)-3-pipéridinylamino]méthyl]phénoxy]-propanoïque, c'est-à-dire un composé de formule (I).
PCT/EP2018/070475 2017-07-28 2018-07-27 Forme cristalline de l'acide (2s)-2-[[(z)-[-1-(2-amino-4-thiazolyl)-2-[[(3s)-2,2-diméthyl-4-oxo-1-(sulfooxy)-3-azétidinyl]amino]-2-oxoéthylidène]amino]oxy]-3-[4-[imino[(3r)-3- pipéridinylamino]méthyl]phénoxy]-propanoïque WO2019020810A1 (fr)

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WO2022011626A1 (fr) * 2020-07-16 2022-01-20 Ningxia Academy Of Agriculture And Forestry Sciences Nouveaux composés monobactam, leur préparation et leur utilisation en tant qu'agents antibactériens
WO2022027439A1 (fr) * 2020-08-06 2022-02-10 Ningxia Academy Of Agriculture And Forestry Sciences COMPOSÉS DE β-LACTAME, LEUR PRÉPARATION ET LEUR UTILISATION COMME AGENTS ANTIBACTÉRIENS
WO2023091438A1 (fr) * 2021-11-18 2023-05-25 Merck Sharp & Dohme Llc Antibiotiques monobactams de chromane amidine

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CN111592536A (zh) * 2020-06-04 2020-08-28 宁夏农林科学院农业资源与环境研究所（宁夏土壤与植物营养重点实验室） 单环β-内酰胺化合物及其制备方法和应用
CN111592536B (zh) * 2020-06-04 2023-11-03 宁夏农林科学院农业资源与环境研究所（宁夏土壤与植物营养重点实验室） 单环β-内酰胺化合物及其制备方法和应用
WO2022011626A1 (fr) * 2020-07-16 2022-01-20 Ningxia Academy Of Agriculture And Forestry Sciences Nouveaux composés monobactam, leur préparation et leur utilisation en tant qu'agents antibactériens
CN115210231A (zh) * 2020-07-16 2022-10-18 宁夏农林科学院 新型单环内酰胺类化合物、其制备方法及其作为抗菌药的用途
WO2022027439A1 (fr) * 2020-08-06 2022-02-10 Ningxia Academy Of Agriculture And Forestry Sciences COMPOSÉS DE β-LACTAME, LEUR PRÉPARATION ET LEUR UTILISATION COMME AGENTS ANTIBACTÉRIENS
CN114728953A (zh) * 2020-08-06 2022-07-08 宁夏农林科学院 β-内酰胺类化合物，及其制备方法以及其作为抗菌素的应用
CN114728953B (zh) * 2020-08-06 2024-04-09 宁夏农林科学院 β-内酰胺类化合物，及其制备方法以及其作为抗菌素的应用
WO2023091438A1 (fr) * 2021-11-18 2023-05-25 Merck Sharp & Dohme Llc Antibiotiques monobactams de chromane amidine
US11932637B2 (en) 2021-11-18 2024-03-19 Merck Sharp & Dohme Llc Chromane amidine monobactam compounds for the treatment of bacterial infections

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