A novel sulfate form of an alpha-2A adrenergic receptor agonist of isochroman-imidazole structure

Abstract

The present disclosure relates to a novel sulfate salt form of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). Compound (I) is a selective alpha2A adrenergic receptor agonist and is useful in the treatment of anxiety, and for use as a sedative or analgesic, and in other disorders in which alpha2A agonism is desired.

Description

[Technical field]

[0001] The present disclosure relates to novel sulfate salt forms of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I) and methods for preparing same. Additionally, the present disclosure relates to pharmaceutical compositions comprising at least one sulfate salt form of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). [Background technology]

[0002] Tacipimidine has the following structural formula (I): [ka] is the International Nonproprietary Name (INN) of the compound 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole,

[0003] Tacipimidine and its derivatives are disclosed in US Patent No. 5,999,633. Tacipimidine exhibits agonist activity at adrenergic alpha 2 receptors, particularly alpha 2A receptors, and therefore can be used in the treatment of disorders, conditions or diseases in which alpha 2A agonists have been shown to be useful, for example, for use as a sedative or analgesic, and for use in the treatment of anxiety.

[0004] Besides therapeutic efficacy, drug developers strive to provide suitable forms of therapeutic agents that have properties related to processing, manufacturing, storage stability and / or pharmaceutical utility. Thus, the discovery of forms that retain some or all of these desired properties is essential for drug development. Tacipimidine and its sulfate salts can be prepared, for example, using the methods described in US Pat. No. 5,399,633. However, neither US Pat. No. 5,399,633 nor US Pat. No. 5,399,633 provide any information about possible crystalline modifications of tacipimidine sulfate. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2013 / 150173 [Patent Document 2] International Publication No. 2019 / 106238 Summary of the Invention

[0006] It has been found that 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I) can exist in a sulfate salt form that is suitable for use in the manufacture of stable pharmaceutical products. In particular, the crystalline polymorph of the sulfate salt has been found to be chemically and physically stable under various manufacturing and storage conditions. Additionally, an amorphous form has also been identified.

[0007] The novel Sulfate Salt forms of the present disclosure can be reproducibly produced by specially selected selection of process conditions, e.g., selection of solvent system, crystallization time, etc., and they also exhibit properties that make them suitable for use in pharmaceutical development formulations.

[0008] Thus, the present disclosure relates to novel crystalline sulfate forms (Forms 1, 2, 3, and 4) and amorphous forms of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I), and novel methods for their preparation.

[0009] The present disclosure also relates to pharmaceutical compositions comprising at least one novel sulfate salt form of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I) and the use of said novel forms in the treatment of anxiety, and as a sedative or analgesic, and in other disorders in which alpha2A agonism is desired.

[0010] These and other features and advantages of the present teachings will become more fully understood from the following specification and claims. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 shows an X-ray powder diffraction (XRPD) pattern of crystalline form 1 of the sulfate salt of Compound (I). [Diagram 2] FIG. 2 shows an X-ray powder diffraction (XRPD) pattern of crystalline form 2 of the sulfate salt of Compound (I). [Diagram 3] FIG. 2 shows X-ray powder diffraction (XRPD) patterns of crystalline form 1+crystalline form 3 of the sulfate salt of Compound (I). [Figure 4] FIG. 2 shows an X-ray powder diffraction (XRPD) pattern of crystalline form 4 of the sulfate salt of Compound (I). [Diagram 5] FIG. 2 shows an X-ray powder diffraction (XRPD) pattern of an amorphous form of the sulfate salt of Compound (I). [Figure 6] FIG. 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline Form 1 of the sulfate salt of Compound (I). [Figure 7] FIG. 2 shows a differential scanning calorimetry (DSC) thermogram of crystalline Form 2 of the sulfate salt of Compound (I). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The present disclosure relates to a novel sulfate salt form of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). In particular, the present disclosure relates to a crystalline form of the sulfate salt of compound (I). Furthermore, the present disclosure relates to an amorphous form of the sulfate salt of compound (I).

[0013] The novel forms (Forms 1, 2, 3, 4 and Amorphous) of the sulfate salt of Compound (I) have been characterized by X-ray powder diffraction (XRPD) studies.

[0014] Thus, in one embodiment, the present disclosure relates to crystalline Form 1 of the sulfate salt of Compound (I) having an X-ray powder diffraction pattern comprising peaks at 5.8, 11.5, 13.9, 17.2, and 18.9 degrees 2-theta.

[0015] In one embodiment, the present disclosure relates to crystalline Form 1 of the sulfate salt of Compound (I) having an X-ray powder diffraction pattern including peaks at 5.8, 11.5, 13.9, 15.7, 17.2, 18.9, 23.8, 26.0, 27.2, and 28.3 degrees 2-theta.

[0016] In one embodiment, crystalline Form 1 of the sulfate salt of Compound (I) is further characterized by the X-ray powder diffraction pattern shown in FIG.

[0017] In one embodiment, the present disclosure relates to crystalline Form 2 of the sulfate salt of Compound (I), having an X-ray powder diffraction pattern comprising peaks at 4.7, 9.3, 13.9, 14.6, and 18.7 degrees 2-theta.

[0018] In one embodiment, the present disclosure relates to crystalline Form 2 of the sulfate salt of Compound (I), having an X-ray powder diffraction pattern including peaks at 4.7, 9.3, 11.5, 12.0, 13.9, 14.6, 18.7, 21.7, 22.0, 25.3 and 26.5 degrees 2-theta.

[0019] In one embodiment, crystalline Form 2 of the sulfate salt of Compound (I) is further characterized by the powder X-ray diffraction pattern shown in FIG.

[0020] In one embodiment, the present disclosure relates to crystalline Form 3 of the sulfate salt of Compound (I), having an X-ray powder diffraction pattern including peaks at 11.6, 17.7, and 23.6 degrees 2-theta.

[0021] In one embodiment, the present disclosure relates to a mixture of crystalline forms 1 and 3 of the sulfate salt of Compound (I) having an X-ray powder diffraction pattern including peaks at 5.8, 11.5, 11.6, 13.9, 17.2, 17.7, 18.9 and 23.6 degrees 2-theta.

[0022] In one embodiment, the mixture of crystalline forms 1 and 3 of the sulfate salt of Compound (I) is further characterized by the powder X-ray diffraction pattern shown in FIG.

[0023] In one embodiment, the present disclosure relates to crystalline Form 4 of the sulfate salt of Compound (I), having an X-ray powder diffraction pattern including peaks at 5.8, 11.5, 15.5, 16.2, 17.0, and 17.2 degrees 2-theta.

[0024] In one embodiment, the present disclosure relates to crystalline Form 4 of the sulfate salt of Compound (I), having an X-ray powder diffraction pattern including peaks at 5.8, 8.5, 11.5, 15.5, 16.2, 17.0, 17.2, 18.8, 19.0, 24.1, 25.2, 25.6 and 32.5 degrees 2-theta.

[0025] In one embodiment, crystalline Form 4 of the sulfate salt of Compound (I) is further characterized by the powder X-ray diffraction pattern shown in FIG.

[0026] In one embodiment, the present disclosure relates to an amorphous form of the sulfate salt of Compound (I).

[0027] In one embodiment, the amorphous form of the sulfate salt of Compound (I) is further characterized in that its powder X-ray diffraction pattern lacks distinguishable or sharp peaks and is substantially the same as that shown in FIG.

[0028] The XRPD peak positions given above are those as measured using CuKα radiation (λ=1.5418 Å). It will be appreciated by those skilled in the art that the peak positions of the powder X-ray diffraction patterns referred to herein may be subject to variation of ±0.2 degrees 2-theta due to various factors such as temperature, sample handling and the instrument used.

[0029] The sulfate salt of compound (I) can be prepared, for example, as described in WO 02 / 04396.

[0030] Crystalline Form 1 of the sulfate salt of Compound (I) can be prepared, for example, by i) dissolving 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole sulfate salt in a suitable solvent at room temperature or elevated temperature, ii) cooling the mixture, and iii) isolating the crystalline product. Suitable solvents include, for example, a mixture of acetone and water, a mixture of acetonitrile and water, a mixture of tetrahydrofuran (THF) and water, a mixture of methanol and ethyl acetate, a mixture of methanol and acetone, a mixture of methanol and heptane, a mixture of methanol, acetone and methyl acetate, a mixture of methanol and tert-butyl methyl ether (TBME), and a mixture of methanol and dichloromethane (DCM); for example, a mixture of acetone and water. In particular, crystalline form 1 can be prepared by dissolving 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole sulfate in a mixture of acetone and water at elevated temperature, e.g., 50-70°C, preferably 55-65°C. The ratio of acetone to water is suitably about 30:70% by volume. The solution is cooled to about room temperature over a period of one to several hours, e.g., about 2 hours. The mixture is further cooled to about 5°C and then aged at about 5°C for several hours, e.g., 72 hours. The precipitated crystalline form 1 can then be isolated, e.g., by filtration or decantation, followed by slow solvent evaporation at about room temperature.

[0031] Alternatively, crystalline form 1 can be prepared, for example, by dissolving 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole sulfate in a suitable solvent at about room temperature and then adding an anti-solvent. Suitable solvents include, for example, a mixture of ethanol and water, and methanol; for example, a mixture of ethanol and water. The ratio of ethanol to water is suitably about 96:4% by volume. Suitable anti-solvents include, for example, TBME, heptane, acetone, and isopropyl acetate; for example, TBME. The anti-solvent can be added to the solution, for example, in four steps, at about room temperature under constant stirring. A suitable stirring time between additions is, for example, about 5 minutes. After the addition of the anti-solvent, the mixture is cooled to about 5° C. Or, alternatively, the anti-solvent can be pre-cooled to about 5° C. before mixing with the solution. After the addition of the anti-solvent, the mixture is aged at about 5° C. for several hours, for example, about 72 hours. The precipitated crystalline form 1 can then be isolated, for example, by filtration or decantation, followed by slow solvent evaporation at about room temperature.

[0032] Crystalline form 2 of the sulfate salt of compound (I) can be prepared, for example, by i) dissolving 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole sulfate in a suitable solvent at about room temperature, ii) heating the mixture, iii) cooling the mixture, and iv) isolating the crystalline product. Suitable solvents include, for example, water, a mixture of ethanol and water, a mixture of methanol and water; for example, water. In particular, crystalline form 2 can be prepared by dissolving 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole sulfate in water at room temperature and then stirring at an elevated temperature, for example, 50-70°C, preferably 55-65°C. The solution is cooled to about room temperature over several hours, for example, about 2 hours. The mixture is further cooled to about 5°C and then aged at about 5°C for several hours, for example, about 72 hours. Crystalline Form 2 can then be isolated, for example, by filtration or decantation, followed by slow solvent evaporation at about room temperature.

[0033] Alternatively, crystalline form 2 can be prepared, for example, by dissolving 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole sulfate in a suitable solvent at about room temperature, followed by addition of an anti-solvent. Suitable solvents include, for example, 2,2,2-trifluoroethanol (TFE), and water; for example, TFE. Suitable anti-solvents include, for example, TBME, acetone, acetonitrile, 2-propanol, and THF; for example, TBME. The anti-solvent may be pre-cooled to about 5° C. before mixing with the solution. After addition of the anti-solvent, the mixture is suitably aged at about 5° C. for several hours, for example, 72 hours. The precipitated crystalline form 2 can then be isolated, for example, by centrifugation, decantation, and drying at room temperature.

[0034] Crystalline Form 3 of the sulfate salt of Compound (I) can be prepared, for example, by stirring a slurry containing 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole sulfate and a mixture of THF and water. The ratio of THF to water is suitably about 90:10% by volume. Suitably, the slurry is stirred at about room temperature for a period of time sufficient for the starting material to be converted to its crystalline form 3, for example, one week. The presence of crystalline Form 3 of the sulfate salt of Compound (I) can be confirmed by XRPD analysis.

[0035] Crystalline Form 4 of the sulfate salt of Compound (I) can be prepared, for example, by stirring a slurry containing 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole sulfate and 2-ethoxyethanol. Suitably, the slurry is stirred at about room temperature or at an elevated temperature, for example at about 30-50° C., preferably 35-45° C., for a period of time sufficient for the starting material to be converted to its crystalline form 4, for example one week. The presence of crystalline Form 4 of the sulfate salt of Compound (I) can be confirmed by XRPD analysis.

[0036] The amorphous form of the sulfate of compound (I) can be conveniently prepared by dissolving the sulfate of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I) in TFE, then freezing the resulting clear solution in liquid nitrogen and then lyophilizing, for example, for about 2 days. The sulfate of compound (I) can thus be obtained in amorphous form.

[0037] The crystalline form of the sulfate salt of Compound (I) can be formulated into pharmaceutical dosage forms such as tablets, capsules, powders, suspensions or solutions together with excipients known in the art.

[0038] In one embodiment, the disclosure relates to a pharmaceutical composition comprising at least one crystalline form 1, 2, 3, 4 or amorphous form of the sulfate salt of Compound (I), preferably crystalline form 1, and a pharma- ceutically acceptable carrier or excipient. In one embodiment, the disclosure relates to such compounds for use in the treatment or prevention of disorders, conditions or diseases in which alpha2A agonists have been shown to be useful, such as anxiety or conditions in which sedation or analgesia is required.

[0039] In one embodiment, the present disclosure relates to the use of at least one crystalline form 1, 2, 3, 4 or amorphous form of the sulfate salt of Compound (I), preferably crystalline form 1, as an active ingredient in the manufacture of a medicament for the treatment or prevention of a disorder, condition or disease in which alpha2A agonists have been shown to be useful, such as anxiety or conditions in which sedation or analgesia is required.

[0040] In one embodiment, the present disclosure relates to a method for the treatment of a disorder, condition or disease for which alpha2A agonists have been shown to be useful, such as anxiety or conditions in which sedation or analgesia is required, comprising administering to a mammal in need of such treatment a therapeutically effective amount of at least one of crystalline Forms 1, 2, 3, 4 or an amorphous form of the sulfate salt of Compound (I), preferably crystalline Form 1.

[0041] The present disclosure will be explained in more detail by the following examples, which are for illustrative purposes only and are not intended to limit the scope of the invention as defined in the claims.

[0042] Polymorphs of Compound (I) may be characterized using the following procedures.

[0043] XRPD measurements were performed at room temperature on a Bruker D8 Advance powder X-ray diffractometer using a copper-filled X-ray tube (40 kV × 40 mA), CuKα (λ = 1.5418 Å) as the X-ray source, a 0.6 mm divergence slit, 2.5° Soller slits above both the primary and secondary beams, and a one-dimensional LynxEye detector with an aperture angle of 2.91593°. Data collection was performed in the range of 3.8–33° 2θ with a scan rate of 0.3° / s and 0.02° increments.

[0044] Differential scanning calorimetry (DSC) measurements were performed using a Shimadzu DSC-60 calorimeter in a bonded aluminum sample cell with a nitrogen flow rate of 60 ml / min, over the range of 20-300° C., at a heating rate of 10° C. / min.

[0045] Single crystal measurements were performed on a Nonius Kappa-CCD diffractometer. Data were collected at 296 K. Data reduction was performed with HKL Scalepack and cell parameters were obtained within the θ range 1-32.5° with Denzo and Scalepak. The structure was solved by direct methods using SHELXT-2014 / 7. The structure was refined by full matrix refinement with least-squares method using SHELXL-2014 / 7. All H atoms were found in Fourier difference maps and refined isotropically. EXAMPLES

[0046] Example 1: Preparation of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole sulfate crystalline form 1 15 mg of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole sulfate was dispersed in 200 μl of a mixture of acetone and water (30:70% by volume) at room temperature (22-25° C.). The solution was stirred (600-1000 rpm) at room temperature and then heated to 60° C. for 30 minutes. The solution was then cooled to room temperature over 2 hours and then aged at 5° C. for 72 hours. Finally, a solid was obtained by slow evaporation of the solvent at room temperature for 3 days in an open vial. The product was analyzed by XRPD and found to be crystalline form 1 (Table 1). The powder X-ray diffraction pattern of form 1 is shown in FIG. 1 and the differential scanning calorimetry (DSC) thermogram is shown in FIG. 6. The DSC analysis shows an endotherm with an onset temperature of approximately 205° C.

[0047] [Table 1]

[0048] Example 2: Preparation of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole sulfate crystalline form 2 15 mg of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole sulfate was dispersed in 200 μl of water at room temperature (22-25° C.). The solution was stirred (600-1000 rpm) at room temperature and then heated to 60° C. for 30 minutes. The solution was then cooled to room temperature over 2 hours and then aged at 5° C. for 72 hours. Finally, a solid was obtained by slow evaporation of the solvent at room temperature for 3 days in an open vial. The product was analyzed by XRPD and found to be crystalline form 2 (Table 2). The powder X-ray diffraction pattern of form 2 is shown in FIG. 2 and the differential scanning calorimetry (DSC) thermogram is shown in FIG. 7. The DSC analysis shows an endotherm with an onset temperature of approximately 197° C.

[0049] [Table 2]

[0050] Example 3: Preparation of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole sulfate crystalline form 3 15 mg of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole sulfate was dispersed in 200 μl of a mixture of THF and water (90:10% by volume) under magnetic stirring (600-1000 rpm) at room temperature (22-25°C). The resulting suspension was aged for 1 week at room temperature under magnetic stirring. After completion of the aging period, the solid was harvested and the wet powder was analyzed by XRPD, which showed the presence of Form 3 in a mixture with Form 1 (Table 3). The powder X-ray diffraction pattern of Form 1 + Form 3 is shown in Figure 3.

[0051] [Table 3] TIFF2025502480000005.tif38155

[0052] Example 4: Preparation of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole sulfate crystalline form 4 15 mg of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole sulfate was dispersed in 200 μl of 2-ethoxyethanol under magnetic stirring (600-1000 rpm) at room temperature (22-25° C.). The resulting suspension was aged for 1 week at room temperature and 40° C. under magnetic stirring. After completion of the aging period, the solid was harvested and the wet powder was analyzed by XRPD, which showed the presence of Form 4 (Table 4). The powder X-ray diffraction pattern of Form 4 is shown in FIG. 4.

[0053] [Table 4]

[0054] Example 5: Preparation of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole sulfate in amorphous form 15 mg of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole sulfate was mixed with 1 ml of 2,2,2-trifluoroethanol (TFE) at room temperature. The mixture was stirred for 2-3 min and the resulting clear solution was frozen in liquid nitrogen and then freeze-dried for about 2 days. The freeze-drying conditions were: 1) primary drying: 0.20 mbar, -36 °C, about 47 h, 2) final drying: 6 mbar, 0 °C, 1 h. The resulting white powder was harvested and analyzed by XRPD, which showed the presence of an amorphous form. The powder X-ray diffraction pattern of the amorphous form is shown in Figure 5.

[0055] Test 1: Slurry test initiated with 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole sulfate crystalline form 1 Slurry studies (SLC, SL and SLT) were carried out with crystalline form 1 under different conditions. 15 mg of starting material was mixed with 200 μl of solvent or solvent mixture (at a concentration of about 75 mg / ml). The mixture was vortexed for 10 seconds to homogenize. The resulting suspension was aged under different conditions: a) 5° C. under magnetic stirring (SLC), b) room temperature under magnetic stirring (SL) and c) 40° C. in a shaker at 700 rpm (SLT). During the aging period, samples were checked periodically and solvent was added if necessary. After completion of the aging period, the vials were placed in an open system and the wet powder was analyzed by XRPD. The results are shown in Table 6.

[0056] [Table 5] TIFF2025502480000008.tif40155

[0057] Most studies showed the presence of forms 1, 2 and their mixtures. Crystalline form 2 is favored under higher water activity conditions (about 0.9). Furthermore, forms 4 and 3 were detected in the wet solid obtained from 2-ethoxyethanol and THF / water, respectively.

[0058] Test 2: Single crystal X-ray diffraction data of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole sulfate crystalline form 1 The unit cell parameters of the crystalline form 1 of the sulfate salt of compound (I) were determined from single crystal X-ray diffraction data and are summarized below: T=296(2)K, radiation wavelength MoKα (λ=0.71073 Å), crystal size 0.3×0.15×0.06 mm 3 , empirical formula [(C 13 H 17 N2O2)(HSO4)]

[0059] [Table 6]

[0060] Test 3: Short-term accelerated stability test The two crystalline forms (Form 1 and Form 2) were exposed openly to conditions of 40°C and 75% RH for one week to evaluate their physical stability upon storage at elevated temperature and relative humidity. After exposure, the solids were reanalyzed by XRPD. The results are shown in Table 7.

[0061] [Table 7]

[0062] The results show that crystalline form 1 exhibits good stability against the partial transformation of crystalline form 2 into crystalline form 1. In addition, crystalline forms 3 and 4 were found to be unstable already at room temperature and showed transformation into crystalline form 1.

[0063] Those skilled in the art will appreciate that the embodiments described herein can be modified without departing from the concept of the present invention. Those skilled in the art will appreciate that the present disclosure is not limited to the specific embodiments disclosed, but is intended to cover modifications of the embodiments that are within the scope of the present disclosure.

Claims

1. A compound which is crystalline form 1 of the sulfate salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I), characterized by a powder X-ray diffraction pattern containing peaks at 5.8±0.2, 11.5±0.2, 13.9±0.2, 17.2±0.2 and 18.9±0.2 degrees 2-theta.

2. 2. The compound of claim 1 having an X-ray diffraction pattern substantially the same as that shown in FIG.

3. A compound which is crystalline form 2 of the sulfate salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I), characterized by a powder X-ray diffraction pattern containing peaks at 4.7±0.2, 9.3±0.2, 13.9±0.2, 14.6±0.2 and 18.7±0.2 degrees 2-theta.

4. 4. The compound of claim 3 having an X-ray diffraction pattern substantially the same as that shown in FIG.

5. A compound which is crystalline form 3 of the sulfate salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I), characterized by a powder X-ray diffraction pattern containing peaks at 11.8±0.2, 17.7±0.2 and 23.6±0.2 degrees 2-theta.

6. The compound according to claim 5 in a mixture with crystalline form 1 according to claim 1 or 2.

7. 7. The mixture of claim 6 having an X-ray diffraction pattern substantially the same as that shown in FIG.

8. A compound which is crystalline form 4 of the sulfate salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I), characterized by a powder X-ray diffraction pattern containing peaks at 5.8±0.2, 11.5±0.2, 15.5±0.2, 16.2±0.2, 17.0±0.2 and 17.2±0.2 degrees 2-theta.

9. 9. The compound of claim 8 having an X-ray diffraction pattern substantially the same as that shown in FIG.

10. A compound which is an amorphous form of the sulfate salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I).

11. 11. The compound of claim 10 having an X-ray diffraction pattern substantially the same as that shown in FIG.

12. A process for the preparation of the compound of claim 1 or 2, which comprises dissolving the sulfate salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I) in a mixture of acetone and water, cooling the mixture and isolating the crystalline product.

13. A process for the preparation of the compound of claim 3 or 4, which comprises dissolving the sulfate salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I) in water, cooling the mixture and isolating the crystalline product.

14. A process for the preparation of a compound according to any one of claims 5 to 7, comprising preparing a slurry of the sulfate salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I) in a mixture of THF and water and inducing crystallization of the product for a sufficient period of time.

15. A process for the preparation of a compound according to claim 8 or 9, comprising preparing a slurry of the sulfate salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I) in 2-ethoxyethanol and inducing crystallization of the product for a sufficient period of time.

16. A process for the preparation of the compound according to claim 10 or 11, comprising dissolving the sulfate salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I) in 2,2,2-trifluoroethanol, freezing the mixture and removing the solvent by lyophilization to obtain an amorphous product.

17. A pharmaceutical composition comprising as an active ingredient a compound according to any one of claims 1 to 11 together with one or more excipients.

18. A compound according to any one of claims 1 to 11 for use in the treatment of a disorder, condition or disease in which alpha2A agonists have been shown to be useful, for example for use as a sedative or analgesic, and for use in the treatment of anxiety.

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