US20160289245A1 - Crystalline Beta-Lactamase Inhibitor - Google Patents
Crystalline Beta-Lactamase Inhibitor Download PDFInfo
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- US20160289245A1 US20160289245A1 US15/035,176 US201415035176A US2016289245A1 US 20160289245 A1 US20160289245 A1 US 20160289245A1 US 201415035176 A US201415035176 A US 201415035176A US 2016289245 A1 US2016289245 A1 US 2016289245A1
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- HFZITXBUTWITPT-YWVKMMECSA-N [H][C@@]12CC(=O)N1[C@@H](C(=O)[O-])[C@](C)(CN1C=C[N+](C)=N1)S2(=O)=O Chemical compound [H][C@@]12CC(=O)N1[C@@H](C(=O)[O-])[C@](C)(CN1C=C[N+](C)=N1)S2(=O)=O HFZITXBUTWITPT-YWVKMMECSA-N 0.000 description 6
- 0 C[C@](C[n]1n*(C)cc1)([C@](C([O-])=O)N([C@]1C2)C2=O)S1(=O)=O Chemical compound C[C@](C[n]1n*(C)cc1)([C@](C([O-])=O)N([C@]1C2)C2=O)S1(=O)=O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/86—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with only atoms other than nitrogen atoms directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
- A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/87—Compounds being unsubstituted in position 3 or with substituents other than only two methyl radicals attached in position 3, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present invention relates to crystalline (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide, processes for the preparation thereof, pharmaceutical compositions comprising (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide and uses of the compound, including uses of compositions containing the compound, in particular use with an antibacterial agent in treatment or prevention of bacterial infection.
- Emergence and dissemination of resistance is an inevitable consequence of the evolutionary dynamic set in motion by the introduction of antibiotics, irrespective of structural class or mode of action (Shapiro S. 2013. Speculative strategies for new antibacterials: all roads should not lead to Rome. J. Antibiot. 66: 371-386).
- Spread of resistance amongst clinically relevant pathogens has had an especially strong impact on the value of ⁇ -lactam antibiotics, heretofore regarded as very safe and efficacious therapies for serious bacterial infections.
- WO 2008/010048 discloses the ⁇ -lactamase inhibitor (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide (formula I):
- WO 2008/010048 discloses formation of an amorphous compound of Formula (I) which is isolated by filtering and lyophilisation.
- the present inventors have found that the compound of formula (I) as prepared by the process of WO 2008/010048 is hygroscopic, and has limited stability when stored at room temperature.
- the present inventors have developed crystalline compounds of formula (I).
- the present inventors have surprisingly found that crystalline compounds of formula (I) have improved thermal stability, are less hygroscopic and easier to purify and handle than the compound of formula (I) in amorphous form.
- the XRPD spectrum of Form A has one, two, three, four or all five peaks selected from peaks with 2 ⁇ angles of: 8.82, 12.07, 14.43, 18.25 and 19.78 ⁇ 0.1 degrees 2 ⁇ .
- the XRPD spectrum of Form A has all ten peaks with 2 ⁇ angles of: 8.82, 12.07, 14.43, 14.92, 16.26, 18.25, 19.06, 19.78, 20.82 and 23.51 ⁇ 0.1 degrees 2 ⁇ , optionally ⁇ 0.05 degrees 2 ⁇ .
- Form A has a XRPD spectrum substantially as shown in FIG. 1 .
- Form A may be further characterised by its Thermo Gravimetric Analysis (TGA) curve showing an endothermic event at about 163° C. ⁇ 2° C.
- TGA Thermo Gravimetric Analysis
- the TGA curve may show a weight loss of about 6% up to 130° C. ⁇ 2° C. due to water loss.
- Form A has a TGA curve substantially as shown in FIG. 9 .
- Form A may be further characterized by its differential scanning calorimetry (DSC) curve showing an endothermic event with a maximum at about 163° C. ⁇ 2° C.
- the DSC curve may show an endothermic event starting at about 45° C. ⁇ 2° C. due to water loss.
- Form A has a DSC curve substantially as shown in FIG. 5 .
- the XRPD spectrum of Form B has one, two, three, four or all five peaks selected from peaks with 2 ⁇ angles of: 10.34, 15.00, 15.63, 18.51 and 23.93 ⁇ 0.1 degrees 2 ⁇ .
- the XRPD spectrum of Form B has all ten peaks with 2 ⁇ angles of: 9.37, 10.34, 12.59, 13.17, 15.00, 15.63, 18.51, 19.10, 20.79 and 23.93 ⁇ 0.1 degrees 2 ⁇ , optionally ⁇ 0.05 degrees 2 ⁇ .
- Form B has a XRPD spectrum substantially as shown in FIG. 2 .
- Form B may be further characterised by its Thermo Gravimetric Analysis (TGA) curve showing an endothermic event at about 155° C. ⁇ 2° C.
- TGA Thermo Gravimetric Analysis
- the TGA curve may show a weight loss of about 8% up to 120° C. ⁇ 2° C. correlated with water desorption.
- Form B has a TGA curve substantially as shown in FIG. 10 .
- Form B may be further characterized by its differential scanning calorimetry (DSC) curve showing an endothermic event with a maximum at about 180° C. ⁇ 2° C.
- the DSC curve may show an endothermic event starting at about 50° C. ⁇ 2° C. due to water loss.
- Form B has a DSC curve substantially as shown in FIG. 6 .
- the XRPD spectrum of Form C has one, two, three, four or all five peaks selected from peaks with 2 ⁇ angles of: 10.73, 14.85, 15.29, 20.12 and 23.22 ⁇ 0.1 degrees 2 ⁇ .
- the XRPD spectrum of Form C has all ten peaks with 2 ⁇ angles of: 9.33, 10.73, 14.85, 15.29, 15.77, 16.16, 18.60, 20.12, 21.00 and 23.22 ⁇ 0.1 degrees 2 ⁇ , optionally ⁇ 0.05 degrees 2 ⁇ .
- Form C has a XRPD spectrum substantially as shown in FIG. 3 or FIG. 20 .
- Form C may be further characterised by its Thermo Gravimetric Analysis (TGA) curve showing an endothermic event at about 149° C.
- TGA Thermo Gravimetric Analysis
- the TGA curve may show a weight loss of about 3% up to 120° C. ⁇ 2° C. correlated with water desorption.
- Form C has a TGA curve substantially as shown in FIG. 11 .
- Form C may be further characterized by its differential scanning calorimetry (DSC) curve showing an endothermic event with a maximum at about 185° C. ⁇ 2° C.
- DSC differential scanning calorimetry
- Form C has a DSC curve substantially as shown in FIG. 7 .
- the XRPD spectrum of Form D has one, two, three, four or all five peaks selected from peaks with 2 ⁇ angles of: 6.78, 16.39, 17.10, 20.63 and 23.23, ⁇ 0.05 degrees 2 ⁇ .
- the XRPD spectrum of Form D has all ten peaks with 2 ⁇ angles of 6.78, 15.45, 16.39, 17.10, 20.06, 20.63, 23.23, 23.68, 26.18 and 32.47 ⁇ 0.05 degrees 2 ⁇ .
- Form D has an XRPD spectrum substantially as shown in FIG. 25 .
- the XRPD spectrum of Form E has one, two, three, four or all five peaks selected from peaks with 2 ⁇ angles of: 15.04, 15.68, 16.47, 20.69 and 23.88 ⁇ 0.05 degrees 2 ⁇ .
- the XRPD spectrum of Form E has all ten peaks with 2 ⁇ angles of: 6.82, 15.04, 15.68, 16.47, 17.17, 18.44, 20.69, 23.34, 23.88 and 25.38 ⁇ 0.05 degrees 2 ⁇ .
- Form E has an XRPD spectrum substantially as shown in FIG. 27 .
- the XRPD spectrum of Form F has one, two, three, four or all five peaks selected from peaks with 2 ⁇ angles of: 12.73, 15.36, 15.95, 16.42 and 20.48 ⁇ 0.5 degrees 2 ⁇ .
- the XRPD spectrum of Form F has all eleven peaks with 2 ⁇ angles of: 12.73, 15.36, 15.95, 16.42, 18.12, 20.48, 22.85, 23.22, 27.04, 27.69 and 32.47 ⁇ 0.05 degrees 2 ⁇ .
- Form F has an XRPD spectrum substantially as shown in FIG. 29 .
- the invention provides a process for preparing crystalline compound of formula (I):
- the process comprising the steps of: forming a formulation by dissolving or suspending an amorphous compound of formula (I) in a solvent or solvent mixture; and crystallising the compound of formula (I) from the formulation.
- the amorphous compound of formula (I) in the formulation may substantially all be dissolved in the formulation; may substantially all be dispersed in the formulation; or may partly be dissolved and partly dispersed in the formulation.
- the quantity of the amorphous compound of formula (I) used in the process of the second aspect of the invention may be below a solubility limit of the amorphous compound in the solvent or solvent mixture, in which case the formulation is a solution, or may be above the solubility limit, in which case the formulation is a suspension.
- Solvents for dissolving the amorphous compound of formula (I) may be selected from solvents in which the amorphous compound of formula (I) has a solubility at 20° C. of greater than 200 mg/ml, optionally greater than 400 mg/ml.
- Solvents may be polar, protic or dipolar aprotic solvents.
- Exemplary polar, protic solvents are water, primary alcohols, preferably methanol, ethanol and 1-propanol.
- Further exemplary dipolar aprotic solvents are dimethylsulfoxide and N,N-dimethylformamide, N-methylpyrrolidone and the alike.
- Primary alcohols are preferred. Methanol and ethanol are particularly preferred. Water content of a primary alcohol solvent is preferably less than 4 wt %, more preferably less than 2 wt %. When the primary alcohol is methanol the water content is preferably less than 1%.
- Crystallisation of a crystalline compound of formula (I) may be induced by adding an antisolvent to a formulation containing dissolved amorphous compound of formula (I).
- Antisolvents may be solvents in which the amorphous compound of formula (I) has a solubility at 20° C. of less than 50 mg/ml, optionally less than 30 mg/ml.
- Antisolvents may be aprotic materials.
- Exemplary antisolvents are acetone, ethyl acetate, methyl-tert-butyl ether, heptane, 2-propanol, isopropyl acetate, diisopropyl ether, methylethyl ketone, tetrahydrofuran, anisole, and tert-butyl acetate.
- the amorphous compound of formula (I) may have little or no solubility in the solvent or solvent mixture used to form the formulation, in which case the formulation is a suspension.
- a nucleating agent may be added to the formulation.
- the nucleating agent may be a crystalline seed of a compound of formula (I).
- the purity of the solvent may affect solubility of the compound of formula (I) in the solvent, either in its amorphous form or in one or more of its crystalline forms.
- the temperature of the formulation may be lowered following formation of the formulation.
- the solvent or solvent mixture may be heated during formation of the formulation, and may be cooled following formation of the formulation.
- the invention provides crystalline compounds of formula (I) prepared by a process according to the second aspect of the invention.
- the invention further provides crystalline compounds of formula (I) preparable by a process according to the second aspect of the invention.
- the crystalline compound of formula (I) according to the first or third aspects of the invention comprises more than 90% of a single crystalline polymorph of the compound, preferably more than 95%, more preferably more than 99%, even more preferably more than 99.5% and most preferably more than 99.8% as measured by XRPD or DSC, preferably as measured by XRPD.
- the single polymorph is one of Form A, Form B, Form C, Form D, Form E, and Form F.
- the crystalline compound of formula (I) according to the first or third aspects of the present invention has a chemical purity of at least 95 wt %, more preferably at least 98%, more preferably at least 99%, more preferably at least 99.5%, even more preferably at least 99.8%, and most preferably at least 99.9%, preferably as measured by HPLC.
- the crystalline compound of formula (I) may be suitable for reconstitution with a pharmaceutically acceptable vehicle for administration.
- a pharmaceutical composition comprising an antibiotic and the crystalline compound of formula (I) according to the first or third aspects of the present invention.
- the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
- the invention provides a pharmaceutical composition according to the fourth aspect for treatment of bacterial infection.
- the invention provides a method of treating a bacterial infection comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition according to the fourth aspect of the present invention.
- the invention provides a method of forming a pharmaceutical composition comprising a compound of formula (I), the method comprising the step of dissolving or dispersing the crystalline compound of formula (I) in a carrier liquid.
- the carrier liquid is a pharmaceutically acceptable vehicle for intravenous injections such as Dextrose, Sodium chloride & Dextrose 5 mixture. Sodium chloride, Sodium lactate, etc.
- the carrier liquid is an aqueous saline solution.
- the concentration of a compound of formula (I) in the pharmaceutical composition range from 1 mg/ml to 700 mg/ml, preferably from 100 to 500 mg/ml, more preferably from 150 to 250 mg/ml.
- FIG. 1 is a X-ray powder diffraction pattern of Form A of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide;
- FIG. 2 is a X-ray powder diffraction pattern of Form B of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide;
- FIG. 3 is a X-ray powder diffraction pattern of Form C of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide;
- FIG. 4 is a X-ray powder diffraction pattern of amorphous form of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide;
- FIG. 5 is a differential scanning calorimetric thermogram of Form A of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide;
- FIG. 6 is a differential scanning calorimetric thermogram of Form B of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide;
- FIG. 7 is a differential scanning calorimetric thermogram of Form C of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide;
- FIG. 8 is a differential scanning calorimetric thermogram of amorphous form of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide;
- FIG. 9 is a thermogravimetric curve of Form A of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide;
- FIG. 10 is a thermogravimetric curve of Form B of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide;
- FIG. 11 is a thermogravimetric curve of Form C of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide;
- FIG. 12 is a plot of HPLC response area vs. concentration for solutions or suspensions of amorphous (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide;
- FIG. 13 is a 25 ⁇ magnified optical microscope image of Form A of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide;
- FIG. 14 is a 25 ⁇ magnified optical microscope image of Form B of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide;
- FIG. 15 is a 25 ⁇ magnified optical microscope image of Form C of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide.
- FIG. 16 is a Raman spectrum of Form A of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide.
- FIG. 17 is a FT-RT spectrum of Form A of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide.
- FIG. 18 is a Raman spectrum of Form C of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide.
- FIG. 19 is a FT-RT spectrum of Form C of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide.
- FIG. 20 is a X-ray powder diffraction pattern of Form C of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide, obtained according to Example 13;
- FIG. 21 is a thermogravimetric curve of Form C of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide, obtained according to Example 13;
- FIG. 22 is a 25 ⁇ magnified optical microscope image of Form C of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide, obtained according to Example 13;
- FIG. 23 is an 1 H-NMR spectrum of Form C of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide.
- FIG. 24 shows particle size distribution curves of Form C of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide, obtained according to Example 13;
- FIG. 25 is a X-ray powder diffraction pattern of Form D of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide;
- FIG. 26 is a Raman spectrum of Form D of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide.
- FIG. 27 is a X-ray powder diffraction pattern of Form E of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide;
- FIG. 28 is a Raman spectrum of Form E of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide.
- FIG. 29 is a X-ray powder diffraction pattern of Form F of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide;
- FIGS. 30 and 31 are Raman spectra of three bathes of Form F of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide.
- FIGS. 32-39 are scanning electron microscopy images of samples of a first batch of Form F of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide;
- FIGS. 40-46 are scanning electron microscopy images of samples of a second batch of Form F of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide;
- FIGS. 47-50 are scanning electron microscopy images of samples of a third batch of Form F of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide;
- FIG. 51 is a FT-RT spectrum of Form F of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide.
- FIG. 52 is a differential scanning calorimetric thermogram of Form F of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide;
- FIG. 53 is a thermogravimetric curve of Form F of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide;
- FIG. 54 is a gas evolution image of Evolved Gas Analysis (EGA) of Form F of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide;
- EVA Evolved Gas Analysis
- FIG. 55 is a plot of Dynamic Vapor Sorption (DVS) change in mass of Form F of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide; and
- FIG. 56 shows Dynamic Vapor Sorption (DVS) isotherm plots of Form F of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide.
- DFS Dynamic Vapor Sorption
- the present invention provides crystalline (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide which is non-hygroscopic, thermally stable and has beneficial properties that avoid problems associated with the prior art forms.
- the present invention further provides a process for forming crystalline (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide.
- the process allows formation of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide in high polymorphic purity.
- Suitable crystallization techniques for forming crystalline compounds of formula (I) include, without limitation, precipitation and re-crystallization (including antisolvent crystallization) processes, with or without seeding with nucleating agents. In a preferred embodiment, antisolvent crystallization processes are used.
- Diluted, saturated or super-saturated solutions may be used for crystallization.
- a solution of an amorphous compound of formula (I) may be cooled to promote crystallization of crystalline compounds of formula (I).
- An amorphous compound of formula (I) may be dissolved at a temperature in the range of 20-50° C.
- the solution may be cooled down to about 0° C. or about 10° C. to promote the crystallization.
- Methods of preparing crystalline forms of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide include, without limitation, the following methods:
- Forms D, E and F may be formed by crystallization from dimethylformamide solution.
- the present inventors have found that Forms D and E may crystallize initially from DMF solution but do not form once form F has formed. Without wishing to be bound by any theory, this may be due to Form F having greater stability than either Form D or Form E.
- a pharmaceutical composition as described herein may be in an injectable form for intravenous injection.
- the composition may contain stabilizing agents.
- the composition may be in suitable sterile solid form ready for reconstitution to form an injectable solution.
- a pharmaceutical composition containing a crystalline compound of formula (I) as described herein may be administered either alone or may be co-administered with therapeutically effective amount of an antibiotic.
- a pharmaceutical composition as described herein may comprise an antibiotic and may comprise one or more conventional pharmaceutically acceptable excipient(s).
- antibiotics are ⁇ -lactam antibiotics, in particular penicillins and cephalosporins and may be selected from Amoxicillin, Ampicillin, Apalcillin, Azlocillin, Bacampicillin, Carbenacillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Lenampicillin, Mecillinam, Methacillin, Mezlocillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Temocillin, Ticarcillin, Aztreonam, BAL30072, Carumonam, PTX2416, Tigemonam, Cefaclor, Cefadroxil, Cefalexin, Cefalotin, Cefamandole, Cefapirin, Cefazolin, Cefbuperazone, Cefdinir, Cefepime, Cefetamet, Cefixime, Cefmenoxime, Cefmetazole, Cefminox
- the antibiotic may be selected from aminoglycosides: Amikacin, Arbekacin, Apramycin, Dibekacin, Gentamicin, Isepamicin, Kanamycin, Neomycin, Netilmicin, Plazomicin, Sisomicin, Spectinomyin, Streptomycin, Tobramycin or derivatives thereof.
- the antibiotic may be selected from quinolones: Cinoxacin, Ciprofloxacin, Enofloxacin, Gatifloxacin, Gemifloxacin, Levofloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Oxafloxacin, or derivatives thereof.
- the antibiotic may be selected from antimicrobial peptides, for example Colistin, Polymyxin B or derivatives thereof.
- a pharmaceutical composition as described herein may comprise only one or more than one antibiotic.
- a pharmaceutical composition containing a crystalline compound of formula (I) may contain or be co-administered with bactericidal or permeability-increasing-g protein product (BPI) or efflux pump inhibitors to improve activity against gram negative bacteria and bacteria resistant to antimicrobial agents.
- BPI permeability-increasing-g protein product
- Antiviral, antiparasitic, antifungal agents may also be administered in combination with the inhibitor compounds.
- the pharmaceutical composition may contain complexing agents or anticoagulants, antioxidants, stabilizers, aminoglycosides, pharmaceutically acceptable salts or the like or mixtures thereof.
- the pharmaceutical composition may contain ⁇ -lactam antibiotics, preferably penicillins, cephalosporins, carbapenem, monobactams, more preferably piperacillin, cefepime; ceftriaxone; meropenem, aztreonam.
- ⁇ -lactam antibiotics preferably penicillins, cephalosporins, carbapenem, monobactams, more preferably piperacillin, cefepime; ceftriaxone; meropenem, aztreonam.
- the pharmaceutical composition may contain buffers, for example sodium citrate, sodium acetate, sodium tartrate, sodium carbonate, sodium bicarbonate, morpholinopropanesulfonic acid, other phosphate buffers and the like and chelating agents like ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid, hydroxyethylenediaminetriacetic acid, nitrilotriacetic acid, 1,2-diaminocyclohexanetetraacetic acid, bis(2-aminoethyl)ethyleneglycoltetraacetic acid, 1,6-hexamethylenediaminetetraacetic acid and the like or pharmaceutically acceptable salts thereof.
- buffers for example sodium citrate, sodium acetate, sodium tartrate, sodium carbonate, sodium bicarbonate, morpholinopropanesulfonic acid, other phosphate buffers and the like and chelating agents like ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic
- a pharmaceutical composition as described herein may be administered to a human or warm-blooded animal by any suitable method, and preferably by intravenous injection.
- TGA analyses were run on a TA Q5000 instrument. The data were evaluated using Universal Analysis software.
- FIG. 13 An optical microscope image of Form A is shown in FIG. 13 .
- the addition of the antisolvent resulted in a solid formation.
- the mixture was cooled down to 10° C. over 1 hour. During the cooling ramp the material became sticky and the majority of the material adhered to the vessel walls.
- the mixture was stirred overnight and the solid obtained was discharged from the vessel by mechanical removal of the sticky solid from the vessel wall.
- the obtained mixture was filtered under vacuum; the cake was dried at room temperature in a vacuum oven for 60 hours to afford 2.75 g of a white solid.
- the solid recovered was crystalline Form A characterized by XRPD concordant with XRPD pattern given in Example 1.
- FIG. 14 An optical microscope image of Form B is shown in FIG. 14 .
- TGA thermal curve is shown in FIG. 11 .
- FIG. 15 An optical microscope image of Form C is shown in FIG. 15 .
- Solubility values of solvents were calculated with respect to the HPLC response factor, set out in FIG. 12 .
- HPLC response factor was calculated for the amorphous compound of formula (I) using samples dissolved in acetonitrile/water 9/1 with the following method:
- the solid residual were isolated and analyzed by XRPD.
- Solubility of amorphous compound of formula (I) Solubility (mg/ml) Solvent 20° C. 40° C.
- FIG. 17 shows the FT-IR spectrum of Form A with the related peak bands list in Table 6.
- Form A is a hydrate form with a rapid water exchange with the ambient and Form C is a more stable anhydrous form. Therefore, Form C was selected for further optimisation and scale-up of the crystallization process, and assessments as described below.
- Form C material 27 mg was added to the solution as seed; the seed was not dissolved and promoted the product crystallization.
- the mixture was cooled to 15° C. over 3.5 hours.
- the slurry was aged overnight and then was filtered under vacuum; the cake was dried at 30° C. in a vacuum oven for 40 hours to afford 3.7 g of a white solid.
- the solid showed an XRPD pattern for Form C.
- the quality of the ethanol system was also investigated in the production of Form C material using 96% ethanol instead of ethanol HPLC grade 99.8% as described in Example 11.
- Form C material 28 mg was added to the solution as seed. After 10 minutes at 35° C. was dissolved. The temperature was lowered to 30° C. over 15 minutes and more Form C material (27 mg) was added as seed. The seed was dissolved after 15 minutes. The solution was heated up to 35° C. and a pinch of Form B material was added to the solution but was dissolved after few minutes. A pinch of Form A material was added as seed; this time the seed did not dissolve and promoted the product crystallization. The mixture was cooled to 15° C. over 3.5 hours. The slurry was aged overnight and then was filtered under vacuum; the cake was dried at 30° C. in a vacuum oven for 18 hours to afford 3.1 g of a white solid. The solid showed an XRPD pattern concordant to Form A.
- Examples 10 and 11 procedures demonstrate that the water content in the ethanol system can affect production of Forms A and C by a seeded approach.
- the formation of Form A material is possible in ethanol 96%, whereas the formation of Form C from a Form C crystal required use of ethanol HPLC grade 99.8%.
- the cake was further dried at 35° C. in the vacuum oven for 6 hours. A new sample was taken and analyzed by 1 H-NMR for solvent content. The ethanol residual was comparable to the first sample.
- the product was stored at ⁇ 20° C. for the week-end and then put in the vacuum oven at 40° C. for 24 hours to yield 6 g of the product.
- the solid showed an XRPD pattern concordant with Form C.
- 1 H-NMR confirmed the presence of ⁇ 1.3% w/w of ethanol residual in the cake.
- the solid was analyzed by XRPD, TGA, optical microscopy (OM) and 1 H-NMR.
- the TGA analysis for the product shows a weight loss of circa 2% up to 120° C. probably due to adsorbed water and solvent residual.
- the OM analysis in FIG. 22 shows Form C crystals. Birefringent particles using polarized light could be seen.
- the 1 H-NMR spectrum ( FIG. 23 ) is consistent with the structure of (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide.
- the ethanol residue was calculated comparing the ethanol signal at 1.06 ppm and the API signal at 1.40 ppm. Considering integrals values, number of protons and the molecular weight of the reference signals the estimated ethanol residue is equal to 0.4% w/w respect to the API.
- the Form C solubility was calculated by HPLC employing a dedicated walk-up method.
- the product obtained by the scaled up procedure described in Example 13 was used to perform the experiments.
- the obtained solid is filtered and washed with 50 mL of N,N-dimethylformamide pre-cooled to 0/+5° C.
- the wet product is then suspended in 300 mL of dichloromethane and the temperature is adjusted to +30/32° C.
- the suspension is stirred for 45 minutes then the solid is filtered and washed with 100 mL of dichloromethane pre-heated to +30/32° C.
- the product is dried under vacuum at +40° C. until constant weight is achieved.
- the obtained product (19.3 g) was crystalline form D which was characterized by an XRPD pattern as shown in FIG. 25 and summarized in the following Table 11.
- the Raman spectrum of Form D is shown in FIG. 26 with the related peak band list in the following Table 12 (using Raman Jasco RFT-600 instrument, light source Nd-YAG, 1064 nm: exciting wavelength).
- the obtained solid is filtered and washed with 12.5 mL of N,N-dimethylformamide.
- the wet product is then suspended in 100 mL of ethyl acetate and the temperature is adjusted to +40/45° C. The suspension is stirred for 60 minutes then the solid is filtered and washed with 50 mL of ethyl acetate pre-heated to +40/45° C.
- the obtained product (2.4 g) was crystalline form E which was characterized by an XRPD pattern as shown in FIG. 27 and summarized in the following Table 13.
- the Raman spectrum of Form E is shown in FIG. 28 with the related peak band list in the following Table 14 (using Raman Jasco RFT-600 instrument, light source Nd-YAG, 1064 nm: exciting wavelength).
- the obtained solid is filtered and washed with 300 mL of N,N-dimethylformamide pre-cooled to 0/+5° C.
- the wet product is then suspended in 700 mL of ethyl acetate and the temperature is adjusted to +40/45° C.
- the suspension is stirred for 30 minutes then the solid is filtered and washed with 150 mL of ethyl acetate pre-heated to +40/45° C.
- the procedure with the suspension in Ethyl acetate is repeated twice. Finally the product is dried under vacuum at +40° C. till constant weight is achieved.
- the obtained product (65-66 g, molar yield about 76%, with an assay of 98-99% was crystalline form F, which was characterized by an XRPD pattern as shown in FIG. 29 and summarized in the following Table 15.
- FIGS. 32-50 Scanning electron microscopy images of samples of the three batches of Form F are shown in FIGS. 32-50 .
- the SEM images of the samples were obtained using a JEOL JSM 5500 LV scanning electron microscope, operating at 30 kV in low vacuum (30 Pa) with the backscattered electron technique.
- FIG. 51 shows the FT-IR spectrum of Form F with the related peak bands list in Table 16.
- the DSC profile of form F is presented in FIG. 52 .
- the DSC profile shows an exothermic peak at approximately 184° C. (Onset 175° C.) associated with the degradation of the sample.
- TGA Thermo Gravimetric Analysis
- EGA Evolved Gas Analysis
- DVS isotherms plots are reported in FIG. 56 , wherein the red line depicts the first sorption phase, the blue line depicts the first desorption phase, the green line depicts the second sorption phase and the pink line depicts the second desorption phase.
- the DVS analyses show that Form F is stable at up to approximately 50% RH and that at 90% RH, the sample showed a weight increase that is greater than 50% w/w. After this event the sample releases and takes water reversibly.
- the sample becomes a viscous liquid after a day at 25° C. and 60% RH and after a day at 60° C. and 75% RH.
- the hygroscopicity was calculated using the following equation:
- W1 is weight of sample at the start of the experiment; and W2 is weight of sample at 25° C. and 80% RH in the first absorption cycle.
- Variable number of scans (16-256) was applied, using standard acquisition parameters.
- the pre-acquisition delay was set to 10 sec whenever NMR quantification was carried out. Appropriate phasing and baseline corrections were applied in processing the spectra.
- the XRPD spectra were collected in transmission mode on an analytical X'pert Pro instrument with X'celerator detector using a standard Aptuit method. The data were evaluated using the HighScore Plus software. The instrumental parameters used are listed below.
- Instrumental parameter Value 2-theta range 2-45 Step size [°2-theta] 0.0170 Time per step [sec] 60.7285 sec Wavelength [nm] 0.154060 (Cu K-Alpha1) Rotation [Yes/No] Yes Slits divergence/ Incident Mask fixed 10 mm; Divergence slits antiscatter. 1 ⁇ 2, Antiscat.slits 1 ⁇ 2 on incident beam; 1/32 on diffracted X-ray Mirror Inc.
- the TGA analyses were run on a TA Q5000 instrument or on Mettler Toledo Star System (Form F analysis).
- the DSC analyses were run on the TA Q2000 MDSC or on the DSC 200 F3 Maia (Form F analysis) instruments. DSC and TGA method details are listed below:
- TGA Balance purge gas [mL/min] 10 Sample purge gas [mL/min] 25 Gas Nitrogen Temperature-Time-Rate Typically from room temperature to 250/350° C. at 10° C./min (TA Q5000 instrument); or to 450° C. at 10°K/min (Mettler Toledo Star System) Typical sample amount [mg] Usually from 2 mg to 20 mg Pan [Pt/Al] Hermetically sealed Al (punched) DSC Cooling [ON/OFF] ON Gas Nitrogen Temperature-Time-Rate From 0° C. to ⁇ 160° C. Ramp at 10° C./min (TA Q2000 MDSC); or from 25° C. to ⁇ 350° C. Ramp at 10°K/min (DSC 200 F3 Maia). Typical sample amount [mg] Usually from 0.5 mg to 2.5 mg Pan Not hermetic Al (TA Q2000 MDSC); or hermetically sealed Al ((DSC 200 F3 Maia)
- Instrumental Parameter Value Probe N Objective 50x, 50x LWD, 10x Exposure [sec] Typically 0.5-1 Laser Power [mW] 50-400 Autofocus [Y/N] Typically N Accumulation Typically 10 Cosmic ray filter [Y/N] Y Intensity calibration [Y/N] Y Dark subtract [Y/N] Y
- FT-IR analyses were performed with a Thermo Nicolet Nexus 470 FT-IR or with a Thermo Nicolet 6700 FT-IR (Form F analyses).
- Particle Size Distribution by laser light scattering was performed after developing a wet dispersion method using Malvern Mastersizer 2000 instrument. The method parameters are listed below.
- the EGA analysis was carried out on the gas produced during the TGA analysis.
- the kinetic moisture sorption measurement was performed at 25° C. and in a RH % range described in the following:
- the experiment is performed on 10-15 mg of sample and the equilibrium criterion is set as dm/dt ⁇ 0.002% w/w in 10 min with a maximum step time of 240 min.
- the sample was positioned on the sample holder and stored in the following conditions:
- the samples were analyzed after the test by XRPD.
- the hygroscopicity of the sample was determined using the method reported in the academic article “ Efficient throughput method for hygroscopicity classification of an active and inactive pharmaceutical ingredients by water vapor sorption analysis ” V. Murikipudi et al., Pharmaceutical Development and Technology, 2013, 18(2): 348-358.
- the hygroscopicity was calculated using the following equation:
- W1 is a weight of sample at the start of the experiment; and W2 is a weight of sample at 25° C. and 80% RH in the first absorption cycle.
- Non hygroscopic increase in mass is less than 0.2%
- Slightly hygroscopic increase in mass is less than 2% and equal to or greater than 0.2%
- Hygroscopic increase in mass is less than 15% and equal to or greater than 2%
- Very Hygroscopic increase in mass is equal to or greater than 15%
- Deliquescent sufficient water is absorbed to form a liquid.
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US20080015156A1 (en) * | 2006-07-12 | 2008-01-17 | Orchid Chemicals & Pharmaceuticals Ltd. | Novel 2-substituted methyl penam derivatives |
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US7273935B2 (en) * | 2003-08-21 | 2007-09-25 | Orchid Chemicals & Pharmaceuticals, Ltd. | Process for the preparation of 3-methylcepham derivatives |
US7417143B2 (en) * | 2004-04-07 | 2008-08-26 | Orchid Chemicals & Pharmaceuticals Limited | Process for the preparation of Tazobactam in pure form |
KR101933084B1 (ko) * | 2010-11-25 | 2018-12-28 | 알레크라 테라퓨틱스 게엠베하 | 화합물 및 그의 용도 |
AU2013260057A1 (en) * | 2012-05-07 | 2014-11-27 | The Regents Of The University Of California | Novel oxysterol analogue, Oxy149, induces osteogenesis and hedgehog signaling and inhibits adipogenesis |
CA2911205A1 (en) * | 2013-05-02 | 2014-11-06 | The Regents Of The University Of California | Bone-selective osteogenic oxysterol-bone targeting agents |
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EP3617217B1 (en) * | 2014-12-09 | 2022-09-07 | Warsaw Orthopedic, Inc. | Process for the production of oxysterols |
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US6770759B2 (en) * | 1997-12-29 | 2004-08-03 | Research Corporation Technologies, Inc. | Penicillanic acid derivative compounds and methods of making |
US20080015156A1 (en) * | 2006-07-12 | 2008-01-17 | Orchid Chemicals & Pharmaceuticals Ltd. | Novel 2-substituted methyl penam derivatives |
US7687488B2 (en) * | 2006-07-12 | 2010-03-30 | Orchid Chemicals & Pharmaceuticals Ltd. | 2-substituted methyl penam derivatives |
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WO2015067787A1 (en) | 2015-05-14 |
US11124526B2 (en) | 2021-09-21 |
IL245386A0 (en) | 2016-06-30 |
EP3066103A1 (en) | 2016-09-14 |
CN105873935B (zh) | 2019-03-19 |
AU2014345507B2 (en) | 2018-11-22 |
AU2014345507A1 (en) | 2016-05-19 |
CA2929199A1 (en) | 2015-05-14 |
EA031348B1 (ru) | 2018-12-28 |
US20190071456A1 (en) | 2019-03-07 |
EA201690963A1 (ru) | 2016-10-31 |
PE20160890A1 (es) | 2016-08-25 |
CA2929199C (en) | 2023-01-03 |
JP7045795B2 (ja) | 2022-04-01 |
MX2016005869A (es) | 2017-01-05 |
JP7346485B2 (ja) | 2023-09-19 |
JP2016535054A (ja) | 2016-11-10 |
GB201408643D0 (en) | 2014-07-02 |
KR20160081964A (ko) | 2016-07-08 |
CL2016001097A1 (es) | 2016-12-02 |
JP2021102642A (ja) | 2021-07-15 |
GB201319776D0 (en) | 2013-12-25 |
CN105873935A (zh) | 2016-08-17 |
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