US20090048314A1 - Treatment of duchenne muscular dystrophy - Google Patents

Treatment of duchenne muscular dystrophy Download PDF

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US20090048314A1
US20090048314A1 US12/192,053 US19205308A US2009048314A1 US 20090048314 A1 US20090048314 A1 US 20090048314A1 US 19205308 A US19205308 A US 19205308A US 2009048314 A1 US2009048314 A1 US 2009048314A1
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polymorphic form
ethylsulfonyl
oxazole
naphthalen
benzo
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Shabana Ahmed
Mark William Hooper
Karen June Etherington
Alexander Charles Weymouth-Wilson
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Summit Therapeutics Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D263/57—Aryl or substituted aryl radicals
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis

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  • polymorphic forms of a compound for the treatment of Duchenne muscular dystrophy are provided.
  • DMD Duchenne muscular dystrophy
  • DMD has been characterized as an X-linked recessive disorder that affects 1 in 3,500 males caused by mutations in the dystrophin gene.
  • the gene is the largest in the human genome, encompassing 2.6 million base pairs of DNA and containing 79 exons.
  • Approximately 60% of dystrophin mutations are large insertion or deletions that lead to frameshift errors downstream, whereas approximately 40% are point mutations or small frameshift rearrangements.
  • Becker muscular dystrophy is a much milder form of DMD caused by reduction in the amount, or alteration in the size, of the dystrophin protein.
  • the high incidence of DMD (1 in 10,000 sperm or eggs) means that genetic screening will never eliminate the disease, so an effective therapy is highly desirable.
  • the mdx mouse is the most widely used model due to availability, short gestation time, time to mature and relatively low cost (Bulfield, G., Siller, W. G., Wight, P. A. & Moore, K. J. X chromosome-linked muscular dystrophy (mdx) in the mouse. Proc. Natl. Acad. Sci. USA 81, 1189-1192 (1984)).
  • Pharmacological approaches for the treatment of muscular dystrophy differ from gene- and cell-based approaches in not being designed to deliver either the missing gene and/or protein.
  • the pharmacological strategies use drugs/molecules in an attempt to improve the phenotype by means such as decreasing inflammation, improving calcium homeostasis and increasing muscle progenitor proliferation or commitment.
  • These strategies offer the advantage that they are easy to deliver systemically and can circumvent many of the immunological and/or toxicity issues that are related to vectors and cell-based therapies.
  • investigations with corticosteroids and sodium cromoglycate, to reduce inflammation, dantrolene to maintain calcium homeostasis and clenbuterol to increase muscle strength have produced promising results none of these potential therapies has yet been shown to be effective in treating DMD.
  • Upregulation therapy is based on increasing the expression of alternative genes to replace a defective gene and is particularly beneficial when an immune response is mounted against a previously absent protein.
  • Upregulation of utrophin an autosomal paralogue of dystrophin has been proposed as a potential therapy for DMD (Perkins & Davies, Neuromuscul Disord, S1: S78 S89 (2002), Khurana & Davies, Nat Rev Drug Discov 2:379-390 (2003)).
  • DAPC dystrophin-associated protein complex
  • the equivalent reagents which would be used in the above method for the synthesis of 5-(ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole are 2-amino-4-ethylsulfonylphenol (rather than 2-amino-4-nitrophenol) and 2-naphthoyl chloride (rather than 2-phenylacetyl chloride).
  • polymorphs of the compound of formula I having advantageous properties and processes by which the polymorphs can be prepared.
  • X-ray powder diffraction pattern peaks are given as °2 ⁇ and Raman spectra peaks are given as cm ⁇ 1 .
  • a polymorphic form of the compound 5-(ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole (polymorphic form 1) characterised in that it provides an X-ray powder diffraction pattern comprising a peak at 14.5 ⁇ 0.2.
  • polymorphic form 1 of the compound 5-(ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole (polymorphic form 1) characterised in that it provides an X-ray powder diffraction pattern comprising a peak at 16.7 ⁇ 0.2.
  • polymorphic form 1 of the compound 5-(ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole (polymorphic form 1) characterised in that it provides an X-ray powder diffraction pattern comprising a peak at 19.1 ⁇ 0.2.
  • polymorphic form 1 of the compound 5-(ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole (polymorphic form 1) characterised in that it provides an X-ray powder diffraction pattern comprising a peak at 24.0 ⁇ 0.2.
  • polymorphic form 1 of the compound 5-(ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole (polymorphic form 1) characterised in that it provides an X-ray powder diffraction pattern comprising peaks at 14.5 ⁇ 0.2, 16.7 ⁇ 0.2, 19.1 ⁇ 0.2 and 24.0 ⁇ 0.2.
  • polymorphic form 2 of the compound 5-(ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole (polymorphic form 2) characterised in that it provides an X-ray powder diffraction pattern comprising peaks at 15.9 ⁇ 0.2, 18.5 ⁇ 0.2 and 23.3 ⁇ 0.2.
  • a polymorphic form of the compound 5-(ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole (polymorphic form 3) characterised in that it provides an X-ray powder diffraction pattern comprising peaks at 12.1 ⁇ 0.2, 17.4 ⁇ 0.2, 22.7 ⁇ 0.2, 25.0 ⁇ 0.2 and 26.5 ⁇ 0.2.
  • a polymorphic form of the compound 5-(ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole (polymorphic form 4) characterised in that it provides an X-ray powder diffraction pattern comprising peaks at 14.6 ⁇ 0.2, 16.1 ⁇ 0.2, 17.0 ⁇ 0.2, 19.3 ⁇ 0.2 and 29.2 ⁇ 0.2.
  • FIG. 1 shows the x-ray powder diffraction pattern for polymorphic form 1
  • FIG. 2 shows the differential scanning calorimetry trace for polymorphic form 1
  • FIG. 3 shows the thermogravimetric analysis trace for polymorphic form 1
  • FIG. 4 shows the Raman spectra for polymorphic form 1
  • FIG. 5 shows optical microscope images of polymorphic form 1
  • FIG. 6 shows the x-ray powder diffraction pattern for polymorphic form 2
  • FIG. 7 shows the differential scanning calorimetry trace for polymorphic form 2
  • FIG. 8 shows the thermogravimetric analysis trace for polymorphic form 2
  • FIG. 9 shows the raman spectra for polymorphic form 2
  • FIG. 10 shows optical microscope images of polymorphic form 2
  • FIG. 11 shows the x-ray powder diffraction pattern for polymorphic form 3.
  • FIG. 12 shows the differential scanning calorimetry trace for polymorphic form 3
  • FIG. 13 shows the thermogravimetric analysis trace for polymorphic form 3
  • FIG. 14 shows the raman spectra for polymorphic form 3.
  • FIG. 15 shows optical microscope images of polymorphic form 3
  • FIG. 16 shows the x-ray powder diffraction pattern for polymorphic form 4.
  • FIG. 17 shows the differential scanning calorimetry trace for polymorphic form 4.
  • FIG. 18 shows the thermogravimetric analysis trace for polymorphic form 4.
  • FIG. 19 shows the raman spectra for polymorphic form 4.
  • FIG. 20 shows optical microscope images of polymorphic form 4.
  • FIG. 21 shows a comparison of the x-ray powder diffraction patterns for polymorphic forms 1, 2, 3 and 4;
  • FIG. 22 shows a comparison of Raman spectra for polymorphic forms 1, 2, 3 and 4;
  • FIG. 23 shows the x-ray powder diffraction pattern of polymorphic form 1 before and after slurrying in methanol;
  • FIG. 24 shows the x-ray powder diffraction pattern of polymorphic form 2 before and after slurrying in methanol.
  • FIG. 25 shows the x-ray powder diffraction pattern of a mixture of polymorphic forms 1, 2 and 3 after slurrying in methanol.
  • FIG. 26 show a diagram of an immortalized mdx mouse H2K cell line that has been stably transfected with a plasmid containing ⁇ 5 kb fragment of the Utrophin A promoter including the first untranslated exon linked to a luciferase reporter gene.
  • FIG. 27 shows pharmacological dose response of compounds in the luciferase reporter assay.
  • FIG. 28 shows an example of TA muscle sections stained with antibody specific for mouse utrophin.
  • FIG. 29 shows increased levels of utrophin expression compared to control in mice exposed to CPD-A (V2 and V3).
  • the polymorphic form 1 having an x-ray powder diffraction pattern substantially in accordance with FIG. 1 .
  • polymorphic form 1 having a differential scanning calorimetry trace substantially in accordance with FIG. 2 .
  • polymorphic form 1 having a thermogravimetric analysis trace substantially in accordance with FIG. 3 .
  • polymorphic form 1 having a raman spectra substantially in accordance with FIG. 4 .
  • polymorphic form 2 having an x-ray powder diffraction pattern substantially in accordance with FIG. 6 .
  • polymorphic form 2 having a differential scanning calorimetry trace substantially in accordance with FIG. 7 .
  • polymorphic form 2 having a thermogravimetric analysis trace substantially in accordance with FIG. 8 .
  • polymorphic form 2 having a raman spectra substantially in accordance with FIG. 9 .
  • polymorphic form 3 having an x-ray powder diffraction pattern substantially in accordance with FIG. 11 .
  • polymorphic form 3 having a differential scanning calorimetry trace substantially in accordance with FIG. 12 .
  • polymorphic form 3 having a thermogravimetric analysis trace substantially in accordance with FIG. 13 .
  • polymorphic form 3 having a raman spectra substantially in accordance with FIG. 14 .
  • polymorphic form 4 having an x-ray powder diffraction pattern substantially in accordance with FIG. 16 .
  • polymorphic form 4 having a differential scanning calorimetry trace substantially in accordance with FIG. 17 .
  • polymorphic form 4 having a thermogravimetric analysis trace substantially in accordance with FIG. 18 .
  • polymorphic form 4 having a raman spectra substantially in accordance with FIG. 19 .
  • a compound of the formula 5-(ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole having a structure comprising greater than 60% of polymorphic form 1, in another embodiment comprising greater than 80% of polymorphic form 1 and in another embodiment greater than 95% of polymorphic form 1.
  • a compound of the formula 5-(ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole having a structure comprising polymorphic form 1 as the only polymorphic form.
  • a compound of the formula 5-(ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole having a structure comprising greater than 60% of polymorphic form 2, in another embodiment comprising greater than 80% of polymorphic form 2 and in another embodiment greater than 95% of polymorphic form 2.
  • a compound of the formula 5-(ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole having a structure comprising polymorphic form 2 as the only polymorphic form.
  • a compound of the formula 5-(ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole having a structure comprising greater than 60% of polymorphic form 3, in another embodiment comprising greater than 80% of polymorphic form 3 and in another embodiment greater than 95% of polymorphic form 3.
  • a compound of the formula 5-(ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole having a structure comprising polymorphic form 3 as the only polymorphic form.
  • a compound of the formula 5-(ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole having a structure comprising greater than 60% of polymorphic form 4, in another embodiment comprising greater than 80% of polymorphic form 4 and in another embodiment greater than 95% of polymorphic form 4.
  • a compound of the formula 5-(ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole having a structure comprising polymorphic form 4 as the only polymorphic form.
  • polymorphic form 1 exhibits increased stability over previously known forms of 5-(ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole. This property of polymorphic form 1 is relevant because it is important that a pharmaceutical product is supplied in a known form. Therefore, if a pharmaceutical is supplied as the most stable polymorph, it may remain in this form as supplied and taken by the patient.
  • polymorphic form 1 retains its structure before and after slurrying in methanol for four days at 25° C.
  • polymorphic form 2 is converted into polymorphic form 1
  • mixtures of polymorphoic forms 1, 2 and 3 are also converted into polymorphic form 1.
  • the polymorphic forms of the compound of formula I for use in the treatment of DMD will generally be administered in the form of a pharmaceutical composition.
  • a pharmaceutical composition including less than 80% w/w, in another embodiment less than 50% w/w, e.g. 0.1 to 20%, of the polymorphic form of the compound of formula I in admixture with a pharmaceutically acceptable diluent or carrier.
  • compositions which comprises mixing the ingredients.
  • suitable diluents or carriers are as follows:
  • microcrystalline cellulose for tablets, capsules and dragees—microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin;
  • the polymorphic form of the compound of formula I in one embodiment is in a form having a mass median diameter of from 0.01 to 10 ⁇ m.
  • the compositions may also contain suitable preserving, stabilising and wetting agents, solubilisers, e.g. a water-soluble cellulose polymer such as hydroxypropyl methylcellulose, or a water-soluble glycol such as propylene glycol, sweetening and colouring agents and flavourings. Where appropriate, the compositions may be formulated in sustained release form.
  • the content of the polymorphic form of the compound of formula I in a pharmaceutical composition is generally about 0.01-about 99.9 wt %, in one embodiment about 0.1-about 50 wt %, relative to the entire preparation.
  • the dose of the polymorphic form of the compound of formula I is determined in consideration of age, body weight, general health condition, diet, administration time, administration method, clearance rate, combination of drugs, the level of disease for which the patient is under treatment then, and other factors.
  • While the dose varies depending on the target disease, condition, subject of administration, administration method and the like, for oral administration as a therapeutic agent for the treatment of Duchenne muscular dystrophy in a patient suffering from such a disease is from 0.01 mg-10 g, in one embodiment 0.1-100 mg, is in certain embodiments administered in a single dose or in 2 or 3 portions per day.
  • the potential activity of the compound of formula I for use in the treatment of DMD may be demonstrated in the following predictive assay and screens.
  • the cell line used for the screen is an immortalized mdx mouse H2K cell line that has been stably transfected with a plasmid containing 5 kb fragment of the Utrophin A promoter including the first untranslated exon linked to a luciferase reporter gene (see FIG. 26 ).
  • the cells Under conditions of low temperature and interferon containing media, the cells remain as myoblasts. These are plated into 96 well plates and cultured in the presence of compound for three days. The level of luciferase is then determined by cell lysis and reading of the light output from the expressed luciferase gene utilising a plate luminometer.
  • Examples of pharmacological dose response of compounds in the assay is shown in FIG. 27 .
  • ADMET data Data obtained from the ADMET data was prioritised and the compounds with the best in vitro luciferase activity and reasonable ADMET data were prioritised for testing in the mdx proof of concept study where the outcome was to identify whether any of the compounds had the ability to increase the levels of utrophin protein in dystrophin deficient muscle when compared to vehicle only dosed control animals.
  • FIG. 28 shows an example of TA muscle sections stained with antibody specific for mouse utrophin. Comparison to the mdx muscle only injected with vehicle shows an increase in the amount of sarcolemmal bound utrophin.
  • Muscles from the above treated mice were also excised and processed for Western blotting and stained with specific antibodies (see FIG. 29 ). Again using muscle dosed with CPD-A shows a significant increase in the overall levels of utrophin present in both the TA leg muscle and the diaphragm. Both mice exposed to CPD-A (V2 and V3) showed increased levels of utrophin expression compared to control.
  • the H2K/mdx/Utro A reporter cell line was passaged twice a week until ⁇ 30% confluent. The cells were grown at 33° C. in the presence of 10% CO 2
  • the H2K/mdx/Utro A reporter cell line cells were plated out into 96 well plates (Falcon 353296, white opaque) at a density of approximately 5000 cells/well in 190 ⁇ l normal growth medium. The plates were then incubated at 33° C. in the presence of 10% CO 2 for 24 hrs.
  • Mdx from a breeding colony were selected for testing. Mice were injected daily with either vehicle or up to 50 mg/kg of compound using the intreperitoneal route (ip). Mice were weighed and compounds diluted in 5% DMSO, 0.1% tween in PBS.
  • mice were sacrificed by cervical dislocation at desired time points, and muscles excised for analysis
  • Tissues for sectioning were dissected, immersed in OCT (Bright Cryo-M-Bed) and frozen on liquid nitrogen cooled isopentane. Unfixed 8 ⁇ M cryosections were cut on a Bright Cryostat, and stored at ⁇ 80° C.
  • sections were blocked in 5% foetal calf serum in PBS for 30 mins.
  • the primary antibodies were diluted in blocking reagent and incubated on sections for 1.5 hrs in a humid chamber then washed three times for 5 mins in PBS.
  • Secondary antibodies also diluted in blocking reagent, were incubated for 1 hr in the dark in a humid chamber. Finally sections were washed three times 5 mins in PBS and coverslip Mounted with hydromount. Slides were analysed using a Leica fluorescent microscope.
  • a vessel was equipped with a retreat blade stirrer and downward pumping turbine, a five necked flange lid, seal and clamp, stirrer gland and overhead stirrer, thermometer pocket, Dean-Stark trap, dropping funnel and condenser. The water to the condenser was then switched on.
  • the sodium hydroxide and 0.80 L of water were then mixed (whilst cooling in an ice bath until all the sodium hydroxide has dissolved—caution exothermic). The resulting solution was then transferred to a scrubber appropriately attached to the vessel.
  • the temperature of the solution was gradually increased to 100° C. over a period of not less than 30 mins, and then maintained at that level for 10 mins. (Caution: HCl gas is evolved during this process through the gas scrubber).
  • the stirrer speed was then increased to 315 rpm and the temperature gradually increased over a period of 30 minutes until reflux (155° C.) at which level it was maintained for 90 mins. (Caution: HCl gas is evolved during this process through the gas scrubber).
  • the methanesulfonic acid was then added drop-wise over a period of 30 mins and relux was maintained until no further water was being collected in the Dean-Stark apparatus (approx 15 mins).
  • the product was then dried in a vacuum oven at 65° C. at a pressure of 10 mbar until constant weight was achieved (less than 0.5 g difference between consecutive measurements of mass which must be at least 1 h apart).
  • the product was obtained as a sandy-beige powder in a yield of 80%.
  • Tube anode Cu Generator tension: 40 kV Tube current: 40 mA Wavelength alpha1: 1.5406 A Wavelength alpha2: 1.5444 A Start angle [2 ⁇ ]: 5 End angle [2 ⁇ ]: 35 Time per step: 2.5 seconds Scan step size: 0.06
  • sample was weighed into an aluminium DSC pan and sealed using a non-hermetic lid. The sample was then loaded into a Perkin-Elmer Diamond DSC (equipped with a liquid nitrogen cooling unit) cooled and held at 0° C. Once a stable heat-flow response was seen, the sample was then heated from 0 to 200° C. at scan rate of 200° C./min and the resulting heat flow response was monitored. A 20 ml/min helium purge was used to prevent thermally induced oxidation of the sample during heating and also to reduce the thermal lag through the sample to increase the instrument sensitivity. Prior to analysis, the instrument was temperature and heat-flow calibrated using an indium reference standard.
  • sample was placed into a wire-mesh vapour sorption balance pan and loaded into an ‘IgaSorp’ vapour sorption balance (Hiden Analytical Instruments). The sample was then dried by maintaining a 0% humidity environment until no further weight change was recorded. Subsequently, the sample was then subjected to a ramping profile from 0-90% RH at 10% RH increments, maintaining the sample at each step until equilibration had been attained (99.5% step completion). Upon reaching equilibration, the % RH within the apparatus was ramped to the next step and the equilibration procedure repeated. After completion of the sorption cycle, the sample was then dried using the same procedure. The weight change during the sorption/desorption cycles were then monitored, allowing for the hygroscopic nature of the sample to be determined.
  • sample was accurately weighed into a platinum TGA pan and loaded into a TGA 7 gravimetric analyser held at room temperature. The sample was then heated at a rate of 10° C./min from 20° C. to 250° C. during which time the change in weight monitored.
  • the purge gas used was nitrogen at a flow rate of 20 ml/min. Prior to analysis the instrument was weight calibrated using a 100 mg reference weight and temperature calibrated using an alumel reference standard.
  • Polymorphic form 1 was prepared under the above conditions using following solvent combinations:
  • Polymorphic form 1 gives an x-ray powder diffraction pattern according to FIG. 1 having the following peaks:
  • Polymorphic form 1 gives a differential scanning calorimetry trace according to FIG. 2 .
  • Polymorphic form 1 gives a thermogravimetric analysis trace according to FIG. 3 .
  • Polymorphic form 1 gives a raman spectra according to FIG. 4 having the following peaks:
  • FIG. 5 shows optical microscope images of polymorphic form 1.
  • Polymorphic form 2 was prepared under the above conditions using following solvent combinations:
  • Polymorphic form 2 gives an x-ray powder diffraction pattern according to FIG. 6 having the following peaks:
  • Polymorphic form 2 gives a differential scanning calorimetry trace according to FIG. 7 .
  • Polymorphic form 2 gives a thermogravimetric analysis trace according to FIG. 8 .
  • Polymorphic form 2 gives a raman spectra according to FIG. 9 having the following peaks:
  • FIG. 10 shows optical microscope images of polymorphic form 2.
  • Polymorphic form 3 was prepared under the above conditions using following solvent combination:
  • Polymorphic form 3 gives an x-ray powder diffraction pattern according to FIG. 11 having the following peaks:
  • Polymorphic form 3 gives a differential scanning calorimetry trace according to FIG. 12 .
  • Polymorphic form 3 gives a thermogravimetric analysis trace according to FIG. 13 .
  • Polymorphic form 3 gives a raman spectra according to FIG. 14 having the following peaks:
  • FIG. 15 shows optical microscope images of polymorphic form 3.
  • Polymorphic form 4 was prepared by dissolving 100 mg of the compound of formula I in DMF and then removing the solvent by evaporation.
  • Polymorphic form 4 gives an x-ray powder diffraction pattern according to FIG. 16 having the following peaks:
  • Polymorphic form 4 gives a differential scanning calorimetry trace according to FIG. 17 .
  • Polymorphic form 4 gives a thermogravimetric analysis trace according to FIG. 18 .
  • Polymorphic form 4 gives a raman spectra according to FIG. 19 having the following peaks:
  • FIG. 20 shows optical microscope images of polymorphic form 4.
  • Polymorphic form 1 was slurried in methanol and then the solid product isolated using the above slurrying experiment (single form). The x-ray powder diffraction pattern of the solid product was obtained. The experiment was performed twice and the resulting diffraction patterns are illustrated by FIG. 23 . It can be seen that the diffraction pattern is the same before and after slurrying indicating that there is no change in the polymorphic form.
  • Polymorphic form 2 was slurried in methanol and then the solid product isolated using the above slurrying experiment (single form). The x-ray powder diffraction pattern of the solid product was obtained. The experiment was performed twice and the resulting diffraction patterns are illustrated by FIG. 24 together with the diffraction pattern for polymorphic form 1. It can be seen that the diffraction pattern of the product subsequent to slurrying is the same as that for polymorphic form 1, indicating that subsequent to slurrying, polymorphic form 1 has converted to polymorphic form 2.
  • the x-ray powder diffraction pattern of the solid products after slurrying were obtained.
  • the spectra are illustrated by FIG. 25 .

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KR101886788B1 (ko) 2017-02-07 2018-08-09 가톨릭대학교 산학협력단 MG53과 Orai1의 결합을 이용한 뒤시엔느 골격근 위축증 치료제 스크리닝 방법

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018236879A1 (en) 2017-06-19 2018-12-27 University Of Maryland, Baltimore Microtubule polymerization inhibitor prodrugs and methods of using the same
EP4403171A2 (en) 2017-06-19 2024-07-24 University of Maryland, Baltimore Microtubule polymerization inhibitor prodrugs and methods of using the same

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