Polymorphic substance of flubetapir precursor AV-105

Abstract

Disclosed are novel polymorphic forms of the following compound: (I). And the compound # imgabs0 is used for preparing the flubetapir (18F).

Description

[0001] The present invention relates to novel polymorphs of precursors for preparing florbetapir, pharmaceutical compositions comprising the precursors, and methods for using the precursors to prepare florbetapir.

[0002] Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the formation of deposits containing amyloid-β ("Aβ") in the brain. Detection of these deposits by postmortem histological examination has been used to confirm the diagnosis of AD. See U.S. Patent No. 9,592,308 and WO 2009 / 059977.

[0003] PET imaging has significantly advanced the diagnosis of AD in living patients. In PET imaging, a positron-emitting radioisotope is incorporated into a compound that specifically binds to a target molecule. Since 18 the half-life of 18 F is approximately 110 minutes,

[0004] F is a commonly used radioisotope in PET. For AD, one of the most intensively studied targets for PET is Aβ. Specifically, using PET imaging to examine amyloid burden in the brain is an important tool for patient stratification and treatment monitoring.

[0005] 18 F-florbetapir is (E)-4-(2-(6-(2-(2-(2 18 F]fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl-N-methylbenzylamine and has the following structure:

[0006]

[0007] Florbetapir is described in U.S. Patent Nos. 7,687,052 and 8,506,929:

[0008] 18The commercial distribution of F-labeled radiopharmaceuticals (including florbetapir) is complicated by the short half-life of their radioisotopes. Specifically, once supplied, it must be administered to the patient within about 10 hours. Thus, in some cases, the radiopharmaceutical supplier will actually supply the PET imaging center with a precursor molecule, which the PET imaging center will convert to florbetapir, which can then be rapidly administered to the patient so that a PET scan can be performed.

[0009] A precursor molecule of florbetapir has the following chemical structure and is referred to herein as Compound I:

[0010]

[0011] This molecule is also referred to as “AV-105”. AV-105, and methods of using AV-105 to prepare 18 18F-florbetapir are known in the literature. See John Lister-James, Michael J Pontecorvo, Chris Clark, Abhinay D Joshi, Mark A Mintun, Wei Zhang, Nathaniel Lim, Zhiping Zhuang, Geoff Golding, Seok Rye Choi, Tyler E Benedum, Paul Kennedy, Franz Hefti, Alan P Carpenter, Hank F Kung, Daniel M Skovronsky, “Florbetapir f-18: a histopathologically validated Beta-amyloid positron emission tomography imaging agent,” Semin Nucl Med. July 2011; 41(4):300-4. AV-105 is commercially available and can also be synthesized by those skilled in the art, for example, by using the techniques (and / or similar techniques) found in U.S. Patent Nos. 7,687,052 and 8,506,929.

[0012] Alternative solid forms of the florbetapir precursor with improved thermodynamic stability are needed for the manufacture of pharmaceutical products and drug products. Brief Description of the Drawings

[0014] Figure 1Depicts the XRPD pattern of AV-105 Form A (collected with Cu-Kα radiation).

[0015] Figure 2 Depicts the XRPD pattern of AV-105 Form B (collected with Cu-Kα radiation).

[0016] Figure 3 Depicts the XRPD pattern of AV-105 Form B + minor peaks as described in Example 3. The top pattern corresponds to the pattern of Form B + minor peaks, where the arrows indicate the extra peaks not present in pure Form B (bottom pattern).

[0017] Figure 4 Depicts the comparison of DSC thermograms of AV-105 Form A (top line) and Form B (bottom line).

[0018] Detailed description

[0019] Form A

[0020] This embodiment provides a crystalline form of the compound of formula I, and the crystalline form of the compound of formula I is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern of which comprises a peak at a diffraction angle 2-θ of 20.9° and one or more peaks selected from 3.8°, 15.1° and 21.2°; wherein the tolerance of the diffraction angle is ±0.2 degrees.

[0021] In some embodiments, the crystalline form of the compound of formula I is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern of which comprises a peak at a diffraction angle 2-θ of 20.9° and a peak at 3.8°.

[0022] In other embodiments, the crystalline form of the compound of formula I is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern of which comprises a peak at a diffraction angle 2-θ of 20.9° and a peak at 15.1°.

[0023] In further embodiments, the crystalline form of the compound of formula I is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern of which comprises a peak at a diffraction angle 2-θ of 20.9° and a peak at 21.2°.

[0024] In a further embodiment, the crystalline form of the compound of formula I is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern of which comprises a peak at a diffraction angle 2-θ of 20.9° and one or more peaks selected from 3.8°, 15.1° and 21.2°, wherein the X-ray powder diffraction pattern using CuKα radiation further comprises a peak at a diffraction angle 2-θ of 11.3°; wherein the tolerance of the diffraction angle is ±0.2 degrees.

[0025] This embodiment also provides a compound of formula I which is crystalline, and the crystalline compound of formula I is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern of which comprises two peaks at a diffraction angle 2-θ, wherein the two peaks are selected from 3.8, 7.5, 11.3, 15.1, 15.7, 16.8, 18.7, 19.1, 20.9 and 21.2; wherein the tolerance of the diffraction angle is 0.2 degrees.

[0026] This embodiment also provides a compound of formula I which is a crystalline form of AV-105, and the crystalline form of the compound of formula I which is AV-105 is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern of which comprises a peak at a diffraction angle 2-θ of 11.3° and one or more peaks selected from 3.8° and 7.5°; wherein the tolerance of the diffraction angle is ±0.2 degrees.

[0027] In a further embodiment, the crystalline form of the compound of formula I is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern of which comprises the peaks depicted in Figure 1 thereof.

[0028] Crystalline Form B

[0029] This embodiment provides a crystalline form of the compound of formula I, and the crystalline form of the compound of formula I is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern of which comprises a peak at a diffraction angle 2-θ of 20.7° and one or more peaks selected from 13.3° and 19.4°; wherein the tolerance of the diffraction angle is ±0.2 degrees.

[0030] In other embodiments, the crystalline form of the compound of formula I is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern of which comprises a peak at a diffraction angle 2-θ of 20.7° and a peak at 13.3°.

[0031] In other embodiments, the crystalline form of the compound of formula I is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern of which comprises a peak at a diffraction angle 2-θ of 20.7° and a peak at 19.4°.

[0032] This embodiment also provides a compound of formula I which is a crystal, and the compound of formula I which is a crystal is characterized by an X-ray powder diffraction pattern using CuKα radiation, and its X-ray powder diffraction pattern includes a peak at a diffraction angle 2-θ of 20.7° and one or more peaks selected from 12.7°, 13.3°, 17.8°, 19.4° and 23.7°; wherein the tolerance of the diffraction angle is ±0.2 degrees.

[0033] This embodiment also provides a compound of formula I which is a crystal, and the compound of formula I which is a crystal is characterized by an X-ray powder diffraction pattern using CuKα radiation, and its X-ray powder diffraction pattern includes two peaks at a diffraction angle 2-θ, wherein the two peaks are selected from 9.0, 9.2, 10.3, 12.7, 13.3, 13.5, 17.8, 18.9, 19.4, 20.7, 22.7, 23.7 and 27.6; wherein the tolerance of the diffraction angle is ±0.2 degrees.

[0034] This embodiment provides a crystal form of a compound of formula I, and the crystal form of the compound of formula I can be characterized by an X-ray powder diffraction pattern using CuKα radiation, and its X-ray powder diffraction pattern includes a peak at a diffraction angle 2-θ of 13.3° and at least one additional peak selected from 13.5°, 9.2° and 19.4°; wherein the tolerance of the diffraction angle is ±0.2 degrees.

[0035] In a further embodiment, the crystal form of the compound of formula I is characterized by an X-ray powder diffraction pattern using CuKα radiation, and its X-ray powder diffraction pattern includes a peak at a diffraction angle 2-θ of 13.3° and a peak at 13.5°.

[0036] In a further embodiment, the crystal form of the compound of formula I is characterized by an X-ray powder diffraction pattern using CuKα radiation, and its X-ray powder diffraction pattern includes a peak at a diffraction angle 2-θ of 13.3° and a peak at 19.4°.

[0037] In a further embodiment, the crystal form of the compound of formula I is characterized by an X-ray powder diffraction pattern using CuKα radiation, and its X-ray powder diffraction pattern includes the peaks depicted in Figure 2 ...

[0038] The present invention further provides a flupetrapiprant precursor of a pharmaceutical composition comprising a compound of formula I. In a specific embodiment, the composition further comprises a recrystallization of AV-105 crystal form B.

[0039] The present invention provides a pharmaceutical composition comprising any compound of the present disclosure and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises a polymorph of AV-105 and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises polymorph A of AV-105 and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises polymorph B of AV-105 and one or more pharmaceutically acceptable excipients.

[0040] Furthermore, the present invention provides a compound of formula I that serves as a precursor for flubatine therapy. Any of the aforementioned compounds can be used. In some embodiments, the present invention provides a compound of formula I that serves as a precursor for PET diagnostic imaging. Any of the aforementioned compounds can be used.

[0041] Furthermore, the present invention provides the use of a compound of formula I in the manufacture of a pharmaceutical precursor for treating or diagnosing a disease or disorder selected from AD or other diseases associated with the accumulation of β-amyloid. Any of the aforementioned compounds can be used.

[0042] This embodiment also includes any of the above-listed compounds (and polymorphs) that serve as a precursor for 18 18F-flubatine.

[0043] This embodiment also includes any of the above-listed compounds (and polymorphs) that serve as a precursor for 18 18F-flubatine therapy.

[0044] This embodiment also includes any of the above-listed compounds (and polymorphs) that serve as a precursor for PET diagnostic imaging.

[0045] This embodiment includes a method for preparing 18 18F-flubatine, which comprises reacting any of the above-listed compounds (and polymorphs) with 18 an 18F source.

[0046] This embodiment includes a method for preparing any of the compounds (and polymorphs) described herein.

[0047] This embodiment also includes using any of the above-listed compounds (and polymorphs) to manufacture a pharmaceutical precursor for treating or diagnosing a disease or disorder selected from AD or other diseases associated with the accumulation of β-amyloid.

[0048] The present invention also includes polymorphs of the compound of formula I that are thermodynamically more stable than existing crystal forms and provide better and / or more reliable properties.

[0049] Abbreviations and Definitions

[0050]

[0051]

[0052] Example 1. Method for manufacturing AV-105 polymorph B

[0053]

[0054] Scheme 1: Synthetic route of AV-105

[0055] The synthesis of AV-105 is a five-step method. According to the prophetic example, this is the synthetic method for step 5:

[0056] At 25 °C, compound 7 (starting material, 1.00 equivalent) is reacted with p-toluenesulfonyl chloride (pTsCl, 1.20 mol equivalent), triethylamine (TEA, 1.25 mol equivalent), and catalytic N,N-dimethylaminopyridine (DMAP, 0.0500 mol equivalent) in dichloromethane (DCM, 5.0 volumes (vol.)). The reaction is quenched with water (2.0 volumes) and the crude AV-105 is separated from the DCM-water by extractive work-up. The crude AV-105 is purified by silica gel column chromatography using an ethyl acetate - heptane gradient. The AV-105 column fractions meeting the purity criteria are combined and concentrated. The AV-105 precursor is seeded with AV-105 polymorph A, recrystallized from methanol, filtered, washed with methanol, and dried.

[0057] The process flow diagrams for step 5 of the current process for AV-105 polymorph A are provided in Schemes 2 and 3 below:

[0058]

[0059] Scheme 2: Process flow diagram for the recrystallization of AV-105 polymorph A

[0060]

[0061] Scheme 3: Process flow diagram for the recrystallization of AV-105 polymorph A

[0062] According to the prophetic example, this is the recrystallization scheme for polymorph A:

[0063] Dissolve AV-105 (base material, 1.00 equivalent) in MeOH (3.6 volumes) at 40 ± 3 °C and pass through a 0.45-μm in-line filter. Rinse the system with MeOH (3.6 volumes) and adjust the temperature to 15 - 20 °C. Inoculate the mixture with AV-105 polymorph A (1.0 wt% slurry in 0.025 volume of MeOH) and stir at 15 - 20 °C for 30 - 45 minutes. Adjust the temperature to -20 ± 3 °C (target 5 °C / 10 minutes) and hold for 1 - 20 hours before filtration.

[0064] Example 1A. XRPD Data of AV-105 Polymorph A

[0065] XRPD patterns were collected using a PANalytical X'Pert PRO MPD or Empyrean diffractometer, which uses an incident beam of Cu radiation generated by an Optix long, fine-focus source. The CuKα X-rays were focused through the sample and onto the detector using an elliptically graded multilayer mirror. Prior to analysis, a silicon sample (NIST SRM 640f) was analyzed to verify that the position of the observed Si 111 peak was consistent with the position confirmed by NIST. The sample was sandwiched between 3-μm thick films and analyzed in transmission geometry. A beam-stop, short antiscatter extension, and antiscatter knife-edge were used to minimize the background generated by air. Both the incident beam and the diffracted beam used Soller slits to minimize broadening from axial divergence. The diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator), which was located 240 mm from the sample, and data collector software v.5.5. The data acquisition parameters for each pattern, including the divergence slit (DS) in front of the mirror, are shown above the image in the data section of this report.

[0066] Table 1. Peaks Observed for AV-105 Polymorph A in XRPD Using CuKα Radiation

[0067]

[0068]

[0069] Example 2. Method for Manufacturing AV-105 Polymorph B

[0070]

[0071] Scheme 4: Recrystallization Process Flow Chart of AV-105 Polymorph B According to the Predictive Example, this is the recrystallization scheme of Polymorph B:

[0072] Dissolve AV-105 (base material, 1.00 equivalent) in MeOH (11.5 volumes) at 40 - 45 °C and pass through a 0.45-μm in-line filter. Rinse the system with MeOH (0.5 volume) and adjust the temperature to 30 - 40 °C. Inoculate the mixture with AV-105 Polymorph B (1.0 wt% slurry in 0.020 volume of MeOH) and stir at 30 - 40 °C for 1 hour. Adjust the temperature to -10 ± 3 °C (target 5 °C / 10 minutes) and hold for at least 8 hours before filtration.

[0073] Example 2A. XRPD Data of AV-105 Polymorph B

[0074] The XRPD pattern was collected as described in Example 1A.

[0075] Table 2. Peaks Observed in XRPD of AV-105 Polymorph B Using CuKα Radiation

[0076]

[0077]

[0078] Example 3. Polymorph B is the thermodynamically more stable polymorph.

[0079] As discussed above, it is desirable to obtain a thermodynamically stable compound to assist local PET imaging centers in the efficient and consistent conversion of AV-105 to 18 F-fluorobetapir suitable for human administration.

[0080] Experiments were conducted to determine which of Polymorph A and Polymorph B is the thermodynamically most stable. Long-term slurry and DSC experiments were carried out. Based on the experiments described below, Polymorph B was determined to be the thermodynamically most stable polymorph.

[0081] Long-term slurry

[0082] Samples of the starting material were suspended in the designated solvent and milled at the designated temperature. After approximately 24 hours, the suspension was transferred to a Spin-X centrifuge tube equipped with a solid 0.45-μm nylon filter and centrifuged. The separated solid was resuspended in fresh solvent and stirred for a total of 2 weeks. The solid was separated as described above and analyzed by XRPD.

[0083] An aliquot of the supernatant separated from the solid is placed in a pre-weighed TGA pan for evaporation. Once it is observed that the solvent has evaporated to dryness, the pan is weighed again, and the equilibrium solubility is calculated based on the weight of the remaining solid and the volume of the corresponding aliquot.

[0084] Unless otherwise stated, the solid of AV-105 consists of polymorph A and is stirred in the specified solvent at the specified temperature. Where possible, the solvent is replaced after about 24 hours. After ~2 weeks, the solid is separated from the supernatant by centrifugation and filtration and analyzed by XRPD. Solubility is evaluated by gravimetry using the supernatant separated from the solid in a single small-scale measurement. The organic solvents used are anhydrous. The water activities provided in the table do not account for the contribution of water in the starting material and the ambient RH. The approximate solvent ratios are expressed in volume %. The temperature and duration of the experiment are approximate values. The results are depicted in Table 3 below.

[0085] Table 3. Results of long-term slurry experiments

[0086]

[0087]

[0088] a The starting material consists of a mixture of polymorph A / polymorph B

[0089] In all tested solvent systems from 2 - 8 °C to 45 °C, slurrying polymorph A in various solvent systems results in its conversion to polymorph B. The solvent conditions include anhydrous organic solvents and ACN / water mixtures with high water activity. Based on XRPD data, all solids isolated from these experiments are consistent with polymorph B. These results confirm that polymorph B is the thermodynamically more stable polymorph at these temperatures.

[0090] At freezer temperature, a single experiment in MeOH gave polymorph B with small additional peaks not accounted for by the indexing solutions of polymorph B and polymorph A (e.g., see the arrow in Figure 3 ). The sample was re-slurried in MeOH at 2 - 8 °C for ~5 days to give pure-phase polymorph B in which the additional peaks were no longer observed in the XRPD pattern (e.g., see the bottom pattern in Figure 3 ). This indicates that there may be a solvate or a low-temperature polymorph that is only stable at temperatures below 2 - 8 °C.

[0091] Differential scanning calorimetry (DSC)

[0092] By DSC, Form B shows a melting onset at 72.2 °C with a heat of fusion of 102.5 J / g, while the previously known Form A exhibits a melting onset at 61.3 °C with a heat of fusion of 78.9 J / g( Figure 4 ). Based on the heat of fusion rule (Bernstein, J. (2002). Polymorphism in Molecular Crystals. Clarendon Press, Oxford), at all temperatures, the phase with the higher melt and heat of fusion is thermodynamically more stable than the phase with the lower melt / heat of fusion. The DSC data indicate that Form B is more stable than Form A and that the two forms are monotropically related. This is consistent with the screening findings where, over the broad temperature range of 2 - 8 °C to 45 °C, the conversion of Form A to Form B has been observed.

Claims

1. A compound of the following formula which is a crystal form of AV-105, characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern of which comprises a peak at a diffraction angle 2-θ of 20.7° and one or more peaks selected from 13.3° and 19.4°; wherein the tolerance of the diffraction angle is ±0.2 degrees.

2. The compound according to claim 1, characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern of which comprises a peak at a diffraction angle 2-θ of 20.7° and a peak at 13.3°; wherein the tolerance of the diffraction angle is ±0.2 degrees.

3. The compound according to claim 1, characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern of which comprises a peak at a diffraction angle 2-θ of 20.7° and a peak at 19.4°; wherein the tolerance of the diffraction angle is ±0.2 degrees.

4. A compound of the following formula which is a crystal form of AV-105, characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern of which comprises a peak at a diffraction angle 2-θ of 20.7° and one or more peaks selected from 12.7°, 13.3°, 17.8°, 19.4° and 23.7°; wherein the tolerance of the diffraction angle is ±0.2 degrees.

5. A compound of the following formula which is a crystal form of AV-105, characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern of which comprises two peaks at a diffraction angle 2-θ, wherein the two peaks are selected from 9.0, 9.2, 10.3, 12.7, 13.3, 13.5, 17.8, 18.9, 19.4, 20.7, 22.7, 23.7 and 27.6; wherein the tolerance of the diffraction angle is ±0.2 degrees.

6. A compound of the following formula which is a crystal form of AV-105 and is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern of which comprises a peak at a diffraction angle 2-θ of 13.3° and at least one additional peak selected from 13.5°, 9.2° and 19.4°; wherein the tolerance of the diffraction angle is ±0.2 degrees.

7. The compound according to claim 6, which is characterized by an X-ray powder diffraction pattern using CuKα radiation, and the X-ray powder diffraction pattern includes peaks at diffraction angles 2-θ of 13.3° and 13.5°; wherein the tolerance of the diffraction angle is ±0.2 degrees.

8. The compound according to claim 6, which is characterized by an X-ray powder diffraction pattern using CuKα radiation, and the X-ray powder diffraction pattern includes peaks at diffraction angles 2-θ of 13.3° and 19.4°; wherein the tolerance of the diffraction angle is ±0.2 degrees.

9. A compound of the following formula which is a crystal form of AV-105 and is characterized by an X-ray powder diffraction pattern using CuKα radiation, and the X-ray powder diffraction pattern includes the peaks depicted in Figure 2.

10. The compound according to any one of claims 1-9, which is used as a 18 precursor for F-fluorobetapir.

11. The compound according to any one of claims 1-9, which is used as a 18 precursor for F-fluorobetapir therapy.

12. The compound according to any one of claims 1-9, which is used as a precursor for PET diagnostic imaging.

13. A method for preparing 18 F-fluorobetapir, which comprises reacting the compound according to any one of claims 1-9 with a 18 F source.

14. A method for preparing the compound according to any one of claims 1-9 via recrystallization.

15. Use of the compound according to any one of claims 1-9 in the manufacture of a drug precursor for treating or diagnosing a disease or disorder selected from Alzheimer's disease and diseases associated with the accumulation of β-amyloid.

16. A pharmaceutical composition comprising the compound according to any one of claims 1-9 and one or more pharmaceutically acceptable excipients.

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