Polymorphs of florbetapir precursor AV-105

Abstract

A novel polymorphic crystalline form of the following compound is disclosed: 18 F). TIFF2025535620000017.tif33128

Description

[Technical Field]

[0001] The present invention relates to novel polymorphs of precursors used to make florbetapir, pharmaceutical compositions containing the precursors, and methods of using the precursors to make florbetapir.

[0002] Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the formation of amyloid-β ("Aβ")-containing deposits in the brain. Detection of these deposits by postmortem histological examination has been used to confirm the diagnosis of AD. See U.S. Pat. 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. Because of its half-life of approximately 110 minutes, 18 F is a commonly used radioisotope in PET. For AD, one of the targets of greatest interest 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.

[0004] One commercially available PET radiopharmaceutical for amyloid imaging is florbetapir. Florbetapir is sold under the trade name Amyvid®. This drug was approved by the FDA in 2012 to estimate Aβ plaque density in adult patients. Florbetapir is administered to the patient, and then a PET scan is performed as a means of showing the physician the amyloid burden in the patient's brain.

[0005] 18 F-Florbetapir is (E)-4-(2-(6-(2-(2-(2[ 18 F]fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl-N-methylbenzamine, having the following structure:

[0006] [ka]

[0007] Florbetapir is described in US Pat. Nos. 7,687,052 and 8,506,929.

[0008] 18 Commercial distribution of F-labeled radiopharmaceuticals (including florbetapir) is complicated by the short half-life of the radioisotope. Specifically, it must be administered to patients within approximately 10 hours after delivery. Therefore, in some instances, the radiopharmaceutical supplier actually provides the precursor molecule to a PET imaging center, which converts it to florbetapir, which can then be rapidly administered to the patient so that a PET scan can be performed.

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

[0010] [ka]

[0011] This molecule is also known as "AV-105." AV-105, and 18Methods for using AV-105 to make F-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. 2011 Jul;41(4):300-4. AV-105 is commercially available or can be synthesized by one of skill in the art, for example, by using techniques to those found in US Pat. Nos. 7,687,052 and 8,506,929 (and / or similar techniques).

[0012] Alternative solid-state forms of florbetapir precursors with improved thermodynamic stability are needed for the manufacture of active pharmaceutical and drug products. [Brief explanation of the drawings]

[0013] [Figure 1] 1 shows the XRPD pattern of AV-105 form A (collected with Cu-Kα radiation). [Figure 2] 1 shows the XRPD pattern of AV-105 form B (collected with Cu-Kα radiation). [Figure 3] 1 shows the XRPD pattern of AV-105 form B+minor peak as described in Example 3. The top pattern is the pattern corresponding to form B+minor peak, and the arrow indicates an extra peak not present in pure form B (bottom pattern). [Figure 4]1 shows a comparison of DSC thermograms of AV-105 Form A (top line) and Form B (bottom line). DETAILED DESCRIPTION OF THE INVENTION

[0014] Form A In this embodiment, there is provided a crystalline form of the compound of Formula I, characterized by an X-ray powder diffraction pattern using CuKα radiation comprising one or more peaks selected from the group consisting of 3.8°, 15.1°, and 21.2°, and a peak at a diffraction angle 2θ of 20.9°, with a diffraction angle tolerance of ±0.2 degrees.

[0015] In some embodiments, the crystalline form of the compound of Formula I is characterized by an X-ray powder diffraction pattern using CuKα radiation comprising a peak at a diffraction angle 2θ of 20.9° and a peak at 3.8°.

[0016] In another embodiment, the crystalline form of the compound of Formula I is characterized by an X-ray powder diffraction pattern using CuKα radiation comprising a peak at a diffraction angle 2θ of 20.9° and a peak at 15.1°.

[0017] 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 comprising a peak at a diffraction angle 2θ of 20.9° and a peak at 21.2°.

[0018] 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 comprising a peak at a diffraction angle 2θ of 20.9° and one or more peaks selected from the group consisting of 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 2θ of 11.3°, with a tolerance on diffraction angles of ±0.2 degrees.

[0019] The present embodiments further provide a compound of Formula I that is crystalline and is characterized by an X-ray powder diffraction pattern using CuKα radiation that includes two peaks at diffraction angles 2θ, the two peaks being selected from the group consisting of 3.8, 7.5, 11.3, 15.1, 15.7, 16.8, 18.7, 19.1, 20.9, and 21.2, with a tolerance on the diffraction angles of 0.2 degrees.

[0020] The present embodiments also provide a compound of Formula I, which is a crystalline form of AV-105, characterized by an X-ray powder diffraction pattern using CuKα radiation including a peak at a diffraction angle 2θ of 11.3° and one or more peaks selected from the group consisting of 3.8° and 7.5°, with a diffraction angle tolerance of ±0.2 degrees.

[0021] 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 that includes the peaks shown in FIG.

[0022] Form B In this embodiment, there is provided a crystalline form of the compound of Formula I, characterized by an X-ray powder diffraction pattern using CuKα radiation comprising a peak at a diffraction angle 2θ of 20.7° and one or more peaks selected from the group consisting of 13.3° and 19.4°, with a diffraction angle tolerance of ±0.2 degrees.

[0023] In another embodiment, the crystalline form of the compound of Formula I is characterized by an X-ray powder diffraction pattern using CuKα radiation comprising a peak at a diffraction angle 2θ of 20.7° and a peak at 13.3°.

[0024] In another embodiment, the crystalline form of the compound of Formula I is characterized by an X-ray powder diffraction pattern using CuKα radiation comprising a peak at a diffraction angle 2θ of 20.7° and a peak at 19.4°.

[0025] The present embodiments also provide a compound of Formula I in crystalline form, characterized by an X-ray powder diffraction pattern using CuKα radiation comprising a peak at a diffraction angle 2θ of 20.7° and one or more peaks selected from the group consisting of 12.7°, 13.3°, 17.8°, 19.4°, and 23.7°, with a diffraction angle tolerance of ±0.2 degrees.

[0026] The present embodiments further provide a compound of Formula I that is crystalline and is characterized by an X-ray powder diffraction pattern using CuKα radiation comprising two peaks at diffraction angles 2θ, the two peaks being selected from the group consisting of 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, with a diffraction angle tolerance of ±0.2 degrees.

[0027] The present embodiments provide a crystalline form of the compound of Formula I, which can be characterized by an X-ray powder diffraction pattern using CuKα radiation comprising a peak at a diffraction angle 2θ of 13.3° and at least one additional peak selected from the group consisting of 13.5°, 9.2°, and 19.4°, with a diffraction angle tolerance of ±0.2 degrees.

[0028] 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 comprising a peak at a diffraction angle 2θ of 13.3° and a peak at 13.5°.

[0029] 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 comprising a peak at a diffraction angle 2θ of 13.3° and a peak at 19.4°.

[0030] 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 that includes the peaks shown in FIG.

[0031] The present invention further provides a pharmaceutical composition of florbetapir precursor comprising the compound of formula I. In certain embodiments, the composition further comprises a recrystallization of AV-105 form B.

[0032] The present invention provides pharmaceutical compositions comprising a compound of the present disclosure and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises a crystalline form of AV-105 and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises Form A of AV-105 and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises Form B of AV-105 and one or more pharmaceutically acceptable excipients.

[0033] Additionally, the present invention provides compounds of Formula I for use as precursors for florbetapir therapy. Any of the listed compounds can be used. In some embodiments, the present invention provides compounds of Formula I for use as precursors for use in PET diagnostic imaging. Any of the listed compounds can be used.

[0034] The present invention further provides the use of a compound of Formula I for the manufacture of a precursor of a medicament for the treatment or diagnosis of a disease or condition selected from AD or other diseases associated with amyloid-beta accumulation. Any of the listed compounds can be used.

[0035] This embodiment further includes: 18 Includes any of the compounds (and polymorphs) listed above for use as precursors to F-florbetapir.

[0036] This embodiment further includes: 18 F-Includes any of the compounds (and polymorphs) listed above for use as precursors for florbetapir therapy.

[0037] Embodiments of the present invention further include any of the above-listed compounds (and polymorphs) for use as precursors for use in PET diagnostic imaging.

[0038] This embodiment provides a method for preparing any of the compounds (and polymorphs) listed above. 18 reacting with a F source, 18 The present invention includes a method for making F-florbetapir.

[0039] Embodiments of the present invention include methods of preparing any of the compounds (and polymorphs) described herein.

[0040] The present embodiments further include the use of any of the above-listed compounds (and polymorphs) for the manufacture of a precursor to a medicament for the treatment or diagnosis of a disease or condition selected from AD or other diseases associated with amyloid beta accumulation.

[0041] The present invention further encompasses polymorphs of the compounds of Formula I that are thermodynamically more stable and provide better and / or more reliable properties than conventional crystalline forms.

[0042] [Table 1]

[0043] Example 1. Method for producing AV-105 Form B

[0044] [ka]

[0045] Scheme 1: Synthetic route to AV-105 The synthesis of AV-105 is a five-step process. According to a hypothetical example, this is step 5 of the synthesis method:

[0046] Compound 7 (basic material, 1.00 equiv.) is reacted with para-toluenesulfonyl chloride (pTsCl, 1.20 mol equiv.), triethylamine (TEA, 1.25 mol equiv.), and catalytic N,N-dimethylaminopyridine (DMAP, 0.0500 mol equiv.) in dichloromethane (DCM, 5.0 vol.) at 25 °C. The reaction is quenched with water (2.0 vol.), and crude AV-105 is isolated by extractive workup from DCM-water. Crude AV-105 is purified by column chromatography on silica gel using an ethyl acetate-heptane gradient. AV-105 column fractions meeting the purity criteria are combined and concentrated. AV-105 precursor is recrystallized from methanol with seeding using AV-105 Form A, filtered, washed with methanol, and dried.

[0047] A process flow chart for Step 5 of this process to AV-105 Form A is provided below in Scheme 2 and Scheme 3.

[0048] [Table 2]

[0049] Scheme 2: Flowchart, process for recrystallization of AV-105 form A

[0050] [Table 3]

[0051] Scheme 3: Flowchart, process for recrystallization of AV-105 form A According to a hypothetical example, this is the recrystallization protocol for Form A below. AV-105 (base material, 1.00 equiv.) was dissolved in MeOH (3.6 vol.) at 40 ± 3 °C and passed through a 0.45 μm in-line filter. The system was rinsed with MeOH (3.6 vol.) and the temperature was adjusted to 15–20 °C. The mixture was seeded with AV-105 Form A (1.0 wt% slurry in 0.025 vol. MeOH) and stirred at 15–20 °C for 30–45 min. The temperature was adjusted to –20 ± 3 °C (target 5 °C / 10 min) and held for 1–20 h before filtration.

[0052] Example 1A. XRPD Data of AV-105 Form A XRPD patterns were collected on a PANalytical X'Pert PRO MPD or Empyrean diffractometer using an incident beam of Cu radiation generated with an Optix long-narrow focus source. An elliptical tilted multilayer mirror was used to focus the CuKα X-ray radiation through the sample onto the detector. Prior to analysis, a silicon specimen (NIST SRM 640f) was analyzed to verify that the position of the observed Si 111 peak matched the NIST-certified position. Samples were sandwiched between 3 μm thick films and analyzed in transmission geometry. A beam stop, short anti-scatter extension, and an anti-scatter knife edge were used to minimize background generated by air. Soller slits for the incident and diffracted beams were used to minimize spread from the axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) positioned 240 mm from the sample and Data Collector software v.5.5. Data acquisition parameters for each pattern are displayed above the images in the data section of this report, including the divergence slit (DS) in front of the mirror.

[0053] [Table 4]

[0054] Example 2. Method for producing AV-105 Form B

[0055] [Table 5]

[0056] Scheme 4: Flowchart, process for recrystallization of AV-105 form B According to a hypothetical example, the recrystallization protocol for Form B is as follows: AV-105 (base material, 1.00 equiv.) was dissolved in MeOH (11.5 vol.) at 40-45°C and passed through a 0.45 μm in-line filter. The system was rinsed with MeOH (0.5 vol.) and the temperature was adjusted to 30-40°C. The mixture was seeded with AV-105 Form B (1.0 wt% slurry in 0.020 vol. MeOH) with stirring at 30-40°C for 1 hour. The temperature was adjusted to -10 ± 3°C (target 5°C / 10 min) and held for a minimum of 8 hours before filtration.

[0057] Example 2A. XRPD Data of AV-105 Form B XRPD patterns were collected as described in Example 1A.

[0058] [Table 6]

[0059] Example 3. Form B is the thermodynamically more stable form. As described above, AV-105 is suitable for administration to humans. 18 It is desirable to obtain a thermodynamically stable compound that supports localized PET imaging centers upon efficient and consistent conversion to F-florbetapir.

[0060] Experiments were conducted to determine whether Form A or Form B was the most thermodynamically stable. Long-term slurry and DSC experiments were performed. Based on the experiments described below, Form B was identified as the most thermodynamically stable form.

[0061] Long-term slurry A sample of the starting material was suspended in a specific solvent and ground at a specific 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 stirring continued for a total of two weeks. The solid was isolated as described above and analyzed by XRPD.

[0062] A measured aliquot of the supernatant isolated from the solid was placed in a pre-weighed TGA pan for evaporation. After the solvent was observed to evaporate to dryness, the pan was reweighed and the equilibrium solubility was calculated based on the weight of the remaining solid and the volume of the corresponding aliquot.

[0063] Unless otherwise stated, AV-105 solids consisted of Form A and were stirred in the specified solvent at the specified temperature. When possible, the solvent was exchanged after approximately 24 hours. After approximately two weeks, the solids were separated from the supernatant by centrifugation with filtration and analyzed by XRPD. Solubility was assessed as a single small-scale gravimetric measurement using the supernatant separated from the solid. The organic solvents used were anhydrous. The water activity provided in the tables does not account for the contribution of water in the starting materials and ambient RH. Approximate solvent ratios are expressed as volume percent. The temperature and duration of the experiments are approximate. The results are shown in Table 3 below.

[0064] [Table 7]

[0065] Slurrying Form A in various solvent systems resulted in conversion to Form B in all solvent systems tested, ranging from 2-8°C up to 45°C. Solvent conditions included anhydrous organic solvents as well as high water activity ACN / water mixtures. Based on XRPD data, all solids isolated from these experiments were consistent with Form B. These results confirm that Form B is the thermodynamically more stable form at these temperatures.

[0066] A single experiment performed in MeOH at freezer temperature resulted in Form B with a small additional peak not explained by the indexing solution of Form B and Form A (see, e.g., the arrow in Figure 3). Reslurrying the sample in MeOH at 2-8 °C for approximately 5 days resulted in phase-pure Form B with an additional peak that was no longer observed in the XRPD pattern (see, e.g., the bottom pattern in Figure 3). This suggests that solvates or cryoforms may exist, but are only stable at temperatures below 2-8 °C.

[0067] Differential scanning calorimetry (DSC) By DSC, Form B exhibits melting with an onset of 72.2°C and a heat of fusion of 102.5 J / g, while the previously known Form A exhibits melting at 61.3°C (onset) with a heat of fusion of 78.9 J / g (Figure 4). Based on the heat of fusion law (Bernstein, J. (2002). Polymorphism in Molecular Crystals. Clarendon Press, Oxford), phases with higher heats of fusion and melting are thermodynamically more stable than phases with lower heats of fusion and melting at all temperatures. 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 screening findings where the transformation from Form A to Form B was observed over a wide temperature range, from 2-8°C to 45°C.

Claims

1. The following formula: 【Chemical 1】 wherein the compound is a crystalline form of AV-105 and is characterized by an X-ray powder diffraction pattern using CuKα radiation including a peak at a diffraction angle 2θ of 20.7° and one or more peaks selected from the group consisting of 13.3° and 19.4°, the tolerance of said diffraction angles being ±0.2 degrees.

2. 2. The compound of claim 1, characterized by an X-ray powder diffraction pattern using CuKα radiation including a peak at a 2θ diffraction angle of 20.7° and a peak at 13.3°, the diffraction angles having a tolerance of ±0.2 degrees.

3. 2. The compound of claim 1, characterized by an X-ray powder diffraction pattern using CuKα radiation including a peak at a 2θ diffraction angle of 20.7° and a peak at 19.4°, the diffraction angles having a tolerance of ±0.2 degrees.

4. The following formula: 【Chemistry 2】 wherein the compound is a crystalline form of AV-105 and is characterized by an X-ray powder diffraction pattern using CuKα radiation including a peak at a diffraction angle 2θ of 20.7° and one or more peaks selected from the group consisting of 12.7°, 13.3°, 17.8°, 19.4°, and 23.7°, wherein the tolerance of said diffraction angles is ±0.2 degrees.

5. The following formula: 【Chemistry 3】 wherein the compound is a crystalline form of AV-105 and is characterized by an X-ray powder diffraction pattern using CuKα radiation comprising two peaks at diffraction angles 2θ, said two peaks being selected from the group consisting of 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, and the tolerance of said diffraction angles is ±0.2 degrees.

6. The following formula: 【Chemistry 4】 wherein the compound is a crystalline form of AV-105 and is characterized by an X-ray powder diffraction pattern using CuKα radiation comprising a peak at a diffraction angle 2θ of 13.3° and at least one additional peak selected from the group consisting of 13.5°, 9.2°, and 19.4°, wherein the tolerance of said diffraction angle is ±0.2 degrees.

7. 7. The compound of claim 6, characterized by an X-ray powder diffraction pattern using CuKα radiation including a peak at a 2θ diffraction angle of 13.3° and a peak at 13.5°, the diffraction angles having a tolerance of ±0.2 degrees.

8. 7. The compound of claim 6, characterized by an X-ray powder diffraction pattern using CuKα radiation including a peak at a 2θ diffraction angle of 13.3° and a peak at 19.4°, the diffraction angles having a tolerance of ±0.2 degrees.

9. The following formula: 【Chemistry 5】 2. A compound having the formula: embedded image wherein the compound is a crystalline form of AV-105, characterized by an X-ray powder diffraction pattern using CuKα radiation that includes the peaks shown in FIG.

10. １８ A compound according to any one of claims 1 to 9 for use as a precursor of F-florbetapir.

11. １８ A compound according to any one of claims 1 to 9 for use as a precursor for F-florbetapir therapy.

12. A compound according to any one of claims 1 to 9 for use as a precursor for use in PET diagnostic imaging.

13. The compound according to any one of claims 1 to 9 １８ reacting with a F source; １８ F - Methods for making florbetapir.

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

15. Use of a compound according to any one of claims 1 to 9 for the manufacture of a precursor of a medicament for the treatment or diagnosis of a disease or condition selected from Alzheimer's disease and diseases associated with amyloid-beta accumulation.

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

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