2-(2,5-diethoxy-4-(ethylthio)phenyl)ethane-1-aminium chloride

Abstract

The disclosure relates to 2-[2,5-diethoxy-4-(ethylsulfanyl)phenyl]ethan-1-aminium chloride (2-(2,5- diethoxy-4-(ethylthio)phenyl)ethane-1-aminium chloride), crystalline 2-(2,5-diethoxy-4- (ethylthio)phenyl)ethane-1-aminium chloride, and specific crystalline forms thereof, including crystalline form 1 of 2-(2,5-diethoxy-4-(ethylthio)phenyl)ethane-l-aminium chloride, to compositions containing the same, and to methods of treatment using them.

Description

[0078] E8. A composition comprising crystalline 2-(2,5-diethoxy-4-(ethylthio)phenyl)ethane-l- aminium chloride according to any one of E2-E4 as a first component and a second component selected from at least one of (a) a serotonergic drug, (b) a purified psilocybin derivative, (c) a purified cannabinoid, (d) a purified terpene, (e) an adrenergic drug, (f) a dopaminergic drug, (g) a monoamine oxidase inhibitor, (h) a purified erinacine, and (i) a purified hericenone.

[0079] E9. A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a therapeutically effective amount of 2-(2,5-diethoxy-4-(ethylthio)phenyl)ethane-l-aminium chloride according to El.

[0080] E10. A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a therapeutically effective amount of crystalline 2-(2,5-diethoxy-4-(ethylthio)phenyl)ethane-l-aminium chloride according to any one of E2-E4.

[0081] Ell. A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to E5 or E7.

[0082] E12. A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to E6 or E8.

[0083] E13. A method of preventing or treating inflammation and / or pain comprising the step of: administering to a subject in need thereof a therapeutically effective amount of 2-(2,5-diethoxy-4-(ethylthio)phenyl)ethane-l-aminium chloride according to El.

[0084] E14. A method of preventing or treating inflammation and / or pain comprising the step of: administering to a subject in need thereof a therapeutically effective amount of crystalline 2-(2,5-diethoxy-4-(ethylthio)phenyl)ethane-l-aminium chloride according to any one of E2-E4.

[0085] E15. A method of preventing or treating inflammation and / or pain comprising the step of: administering to a subject in need thereof a composition according to E5 or E7.

[0086] E16. A method of preventing or treating inflammation and / or pain comprising the step of: administering to a subject in need thereof a composition according to E6 or E8. Examples

[0087] The preparation and characterization of crystalline form 1 of2-[2,5-diethoxy-4-(ethylsulfa nyl)phenyl]ethan-l-aminium chloride (2-(2,5-diethoxy-4-(ethylthio)phenyl)ethane-l-aminium chloride or 2CT2-2,5DiEtO chloride) is described below.

[0088] Single Crystal X-Ray Diffraction (SCXRD) Characterization: Data were collected on a Bruker D8 Venture CMOS Diffractometer equipped with an Oxford Cryosystems Cryostream cooling device and using Mo Ka radiation. Structures were solved using the Bruker SHELXTL program and refined with the SHELXTL program as part of the Bruker SHELXTL suite, or 0LEX2 software. Unless otherwise stated, hydrogen atoms attached to carbon were placed geometrically and allowed to refine with a riding isotropic displacement parameter. Hydrogen atoms attached to a heteroatom were located in a difference Fourier synthesis and were allowed to refine freely with an isotropic displacement parameter.

[0089] Preparation and Characterization of Crystalline form 1 of 2-(2,5-diethoxy-4-(ethylthio)phenyl)ethane-l-aminium chloride

[0090] Synthesis (1}                              (2.}                              (3)                                 (4}

[0091] Synthetic route for the preparation of 2CT2-2,5DiEtO hydrochloride: (i) 100% H2SO4 / ice, 33% NaOH; (ii) (CH3CH2O)2SO2, 33% NaOH; (ill) POCI3; (iv) Zn, 96% H2SO4 / ice, reflux; (v) Etl, KOH / EtOH; (vi) POCI3 / N-methylformanilide; (vii) NO2CH3, NH4CO2CH3; (viii) LAH / THF; (ix) IPA / HCI.

[0092] Preparation of 5-ethoxy-2-hydroxybenzenesulfonic acid

[0093] Step i: 20 g of 4-ethoxyphenol (1) and 12.9 mL of 100% sulfuric acid were mixed at room temperature and placed in a 30°C water bath and stirred. The temperature was raised at the rate of not more than l°C / minute with constant stirring until a bath temperature of 80° C was reached. The mixture was poured over 70 g of crushed ice to cool. The flask was washed out with 5-10 mL H2O. The mixture was stirred and 33% NaOH was slowly added until slightly basic. The mixture turned to a cottage cheese-like consistency. 50 mL of H2O and 10 mL more of the 33% NaOH solution were added to the mixture. The final temperature was 20°C and the volume was about 180 mL.

[0094] Step ii: The mixture was transferred to a 500 mL Erlenmeyer flask and the beaker was washed out with 15 mL of H2O. 10 mL of 33% NaOH and 10 mL of diethyl sulfate were added with swirling, then after a few minutes, another 10 mL of diethyl sulfate was added. The mixture was warmed to 60-65 °C with swirling to dissolve lumps and speed the reaction. The pH was kept above 10; but if it dropped below 10, then 10 mL of 33% NaOH solution was added. Another 10 mL of diethyl sulfate was added. After the mixture continued warming and swirling for a few minutes, 10 mL more of diethyl sulfate was added, for a total of 40 mL. The mixture was heated on a steam bath for one hour.

[0095] Preparation of 2,5-diethoxy-benzenesulfonyl chloride (2)

[0096] Step ill. The solution from the previous step was evaporated to dryness, then the flask was heated in an oil bath set at 125-130 °C or an air bath at 150-160 °C, with an occasional brief air sweep. When fumes appeared in the flask during the air sweep, heating was stopped and the flask was cooled. 75 mL of POCI3 was added to the foamy crust in the flask. The mixture was added to a reflux condenser and heated in a boiling water bath. HCI gas was evolved. After about 20 min, most of the crust was broken up with a thin, flat, stainless steel tool. The mixture was swirled occasionally as heating continued. After about 1.5 hours, the entire mass set up to a semi-solid. The mass was cooled and the semi-hard solids were broke up and added to crushed ice with stirring. More crushed ice was added as the hydrolysis continued. The flask was washed out with some of the cold aqueous material from the hydrolysis. When the hydrolysis was complete, the solid 2,5-diethoxy-benzenesulfonyl chloride was filtered and washed with ice water. The yield was about 24 g.

[0097] Preparation of 2,5-diethoxy-benzenethiol

[0098] Step iv: Damp 2,5-diethoxy-benzenesulfonyl chloride from the previous step was added to a mixture of 35 mL 96% sulfuric acid and 560 g crushed ice in a round bottom flask equipped with a condenser, heating mantle, and mechanical stirrer. 31 g Zn powder (325 mesh) was added with stirring. The mixture was heated to reflux with stirring for 1.5 hr. The reaction was cooled, decanted, and filtered, and the filter cake was washed with CH2CI2. The combined decant and filtrate were extracted with CH2CI2. The CH2CI2 extract was washed once quickly with 5% NaHCO3, dried, then the solvent was removed by distillation. The residue was vacuum distilled to yield about 7.8 g of a paleyellow oil (2,5-diethoxy-benzenethiol).

[0099] Preparation of (2,5-diethoxyphenyl)(ethyl)sulfane

[00100] Step v: 28 g of powdered KOH dissolved in 24 mL EtOH at ambient temperature, was added in rapid sequence to 2.5 g of 2,5-diethoxy-benzenethiol from the previous step, followed by 2.0 mL of iodoethane. There was a moderate exotherm and precipitation of KL The mixture was refluxed for 30 minutes, filtered, the solvent removed, and short-path vacuum distilled to yield about 2.74 g of a clear oil.

[00101] Preparation of 2,5-diethoxy-4-(ethylthio)-benzaldehyde (3)

[00102] Step vi: A round bottom flask was fitted with a CaCI2 drying tube, magnetic stirrer, and heating mantle. 10.3 g of freshly-distilled POCI3 and 14.5 mL N-methylformanilide was added to the flask and allowed to stand for 20 min. 7.5 g of (2,5-diethoxy-phenyl)(ethyl)sulfane from the previous step was added and the reaction was heated to 100 °C over 10-15 min with stirring. After 20 min of heating, the reaction was poured into 150 mL ice / water with stirring, then stirred for another 30 min until the original thick orange oil had hydrolyzed to a granular floc. The reaction was filtered and the filter cake was washed with water. The filter cake was triturated with 80:20 MeOH:H2O, filtered, washed with a little of the MeOH:H2O mixture, then dried. Melting point of 2,5-diethoxy-4-(ethylthio)-benzaldehyde (3) = 84-85 °C.

[00103] Preparation of (2,5-diethoxy-4-(2-nitrovinyl)phenyl)(ethyl)sulfane

[00104] Step vii: 5 g of the 2,5-diethoxy-4-(ethylthio)-benzaldehyde (3) from the previous step was mixed with 5 mL nitromethane and 2.5 g of ammonium acetate crystals. The mixture was refluxed for 15 min, cooled in ice / NaCI slush bath then washed twice with H2O. 30 mL EtOH was added and heated to boiling with stirring, and cooled. Crystals formed shortly and were filtered and dried to yield about 4.5 g. Melting point = 123-124 °C.

[00105] Preparation of 2-(2,5-diethoxy-4-(ethylthio)-phenyl)ethan-l-aminium chloride (2CT2- 2,5DiEtO chloride; (4))

[00106] Step viii: The (2,5-diethoxy-4-(2-nitrovinyl)phenyl)(ethyl)sulfane from the previous step, dissolved in 50 mL tetrahydrofuran (THF), was added dropwise over a 30 min period to a refluxing solution of 2.85 g lithium aluminum hydride in 75 mL THF. The reaction was refluxed overnight, then cooled and quenched by adding about 4.5 mL 33% NaOH solution dropwise with stirring. Additional THF was added as needed to maintain a consistency suitable for stirring. Diatomaceous earth was added to aid filtering, then the mixture as suction filtered and the filter cake washed with fresh THF. The THF solvent was removed by distillation, then the crude oil was distilled using a Kugelrohr to obtain a nearly colorless oil of the amine free base.

[00107] Step ix: The free base was dissolved in isopropyl alcohol then acidified with hydrochloric acid to a slightly acid pH. Diethyl ether or t-butyl methyl ether was added to initiate crystal formation. The crystals were harvested by suction filtration, washed with fresh ether, and then suctioned dry to yield 2CT2-2,5DiEtO (4). Melting point = 220-221 °C.

[00108] Crystallization

[00109] Single crystals suitable for X-ray diffraction studies were grown from the slow evaporation of a methanol solution.

[00110] Single Crystal Characterization

[00111] The single crystal data and structure refinement parameters for the crystalline form 1 structure of 2CT2-2,5DiEtO chloride are reported in Table 3, below. Table 3 Crystal data Chemical formula C14H24NO2S-CI Mr 305.85 Crystal system, space group monoclinic, Pl^c Temperature (K) 300(2) a, b, c (A) 22.0287(14), 8.6158(5), 9.1053(5) a(°) 90 P (°) 101.335(2) y (°) 90 V(A3) 1694.43(17) Z 4 F(000) 656 D< (Mg m'3) 1.199 Radiation type Mo Ka A (A) 0.71073 6(°) 2.83 -25.73 p (mm-1) 0.347 Crystal size (mm) 0.39x0.34x0.04 Crystal description block Crystal color colourless Data collection Diffractometer Bruker APEX-II CCD Absorption correction Multi-scan SADABS (Bruker, 2016) was used. wR2(int) was 0.0620 before and 0.0533 after correction. The Ratio of minimum to maximum transmission is 0.8983. The A / 2 correction factor is not present. Tmin / 7”max 0.6695, 0.7453 No. of measured, independent, and observed [1 > 2o( / )] reflections 40666, 3238, 2791 Pint 0.0369 6max, 0min (°) 25.757, 2.545 h, k, 1 -26^26,-10^ 10,-11-» 11 Refinement R[F2 > 2o(F2)], wR(F2), S 0.0481, 0.1218,1.126 No. of reflections 3238 No. of parameters 187 No. of restraints 3 H-atom treatment H atoms treated by a mixture of independent and constrained refinement w w=1 / [o2(Fo2)+(0.0343P)2+1.4149P] where P=(F02+2Fc2) / 3 (△ / o)max 0.000 △Pmax / △Pmin A ) 0.302, -0.227 Software Data collection Bruker APEX4 Cell refinement Bruker SAINT Data reduction Bruker SAINT Structure solution SHELXS-97 (Sheldrick, 2008) Structure refinement SHELXL 2018 / 3 (Sheldrick, 2015) Molecular graphics Olex2 1.3 (Dolomanov et aL, 2009) Publication material preparation Olex2 1.3 (Dolomanov et al., 2009)

[00112] FIG. 1 shows the molecular structure of crystalline form 1 of 2CT2-2,5DiEtO chloride, showing the atomic labeling.

[00113] FIG. 2 shows the unit cell of crystalline form 1 of 2CT2-2,5DiEtO chloride along the c-axis.

[00114] Simulated Powder X-ray Diffraction (PXRD) Pattern

[00115] FIG. 3 shows a simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 2CT2-2,5DiEtO chloride generated from its single crystal data. Table 4 lists the angles, °20 ± O.2°20, and d-spacing of the peaks identified in the experimental XRPD pattern of FIG. 3. The entire list of peaks, or a subset thereof, may be sufficient to characterize the cocrystal. For example, the cocrystal may be characterized by at least two peaks selected from the peaks at 8.2, 12.3, and 14.3 °20 ± O.2°20 or their corresponding d-spacing as well as by an XRPD pattern substantially similar to FIG. 3. Table 4 d-spacing (A) °20±O.2°20 Intensity 10.80 8.18 2384 8.00 11.05 4 7.20 12.28 10112 6.74 13.13 1114 6.20 14.27 15839 6.19 14.30 52954 5.75 15.39 873 5.72 15.47 6551 5.52 16.03 7314 5.40 16.40 685 5.09 17.42 11215 5.05 17.54 12845 4.58 19.38 16097 4.55 19.48 5943 4.46 19.87 352 4.45 19.96 1120 4.41 20.12 24493 4.38 20.26 404 4.32 20.54 25577 4.31 20.60 33553 4.22 21.01 61 4.21 21.08 13345 4.18 21.24 420 4.03 22.07 1523 4.00 22.20 85054 3.96 22.41 3384 3.95 22.49 3677 3.88 22.90 9650 3.88 22.92 47672 3.87 22.99 40 3.86 23.01 6514 3.83 23.21 11289 3.82 23.26 5559 3.80 23.42 45670 3.78 23.50 5388 3.76 23.62 8528 3.76 23.64 80 3.75 23.68 16076 3.70 24.05 81 3.60 24.71 11771 3.56 25.02 20794 3.54 25.10 102985 3.53 25.23 1003 3.50 25.43 21 3.50 25.44 29287 3.46 25.70 24092 3.37 26.45 12853 3.34 26.69 5344 3.32 26.82 25 3.32 26.87 8210 3.30 27.00 11 3.29 27.11 1993 3.24 27.49 85 3.21 27.74 3328 3.15 28.31 165 3.13 28.50 60780 3.12 28.61 11 3.10 28.78 9718 3.09 28.84 10541 3.09 28.91 2559 3.05 29.25 624 3.03 29.45 1432 3.02 29.58 1286 3.01 29.64 37364 3.00 29.76 30910 References Dolomanov, O. V., Bourhis, L J., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2009). J. Appl. Cryst. 42, 339-341. Sheldrick, G. M. (2015). Acta Cryst. C71, 3-8.

Claims

The claimed invention is:

1. 2-[2,5-diethoxy-4-(ethylsulfanyl)phenyl]ethan-l-aminium chloride (2-(2,5-diethoxy-4-(ethylthio)phenyl)ethane-l-aminium chloride).

2. Crystalline 2-[2,5-diethoxy-4-(ethylsulfanyl)phenyl]ethan-l-aminium chloride (2-(2,5-diethoxy-4-(ethylthio)phenyl)ethane-l-aminium chloride).

3. Crystalline form 1 of 2-[2,5-diethoxy-4-(ethylsulfanyl)phenyl]ethan-l-aminium chloride (2-(2,5-diethoxy-4-(ethylthio)phenyl)ethane-l-a minium chloride).

4. Crystalline form 1 of 2-(2,5-diethoxy-4-(ethylthio)phenyl)ethane-l-aminium chloride according to claim 3, characterized by at least one of:a monoclinic crystal system at a temperature of about 300 K;a P2i / c space group at a temperature of about 300 K;unit cell dimensions a = 22.0287(14) A, b = 8.6158(5) A, c = 9.1053(5) A, a = 90°, 0 = 101.335(2)°, and y = 90°;an X-ray powder diffraction pattern substantially similar to FIG. 3; oran X-ray powder diffraction pattern characterized by at least two peaks selected from 8.2,12.3, and 14.3 °20 ± 0.2 °26.

5. A composition comprising 2-(2,5-diethoxy-4-(ethylthio)phenyl)ethane-l-aminium chloride according to claim 1 and an excipient.

6. A composition comprising crystalline 2-(2,5-diethoxy-4-(ethylthio)phenyl)ethane-l-aminium chloride according to any one of claims 2-4 and an excipient.

7. A composition comprising 2-(2,5-diethoxy-4-(ethylthio)phenyl)ethane-l-aminium chloride according to claim 1 as a first component and a second component selected from at least one of (a) a serotonergic drug, (b) a purified psilocybin derivative, (c) a purified cannabinoid, (d) a purified terpene, (e) an adrenergic drug, (f) a dopaminergic drug, (g) a monoamine oxidase inhibitor, (h) a purified erinacine, and (i) a purified hericenone.

8. A composition comprising crystalline 2-(2,5-diethoxy-4-(ethylthio)phenyl)ethane-l-aminium chloride according to any one of claims 2-4 as a first component and a second component selectedfrom at least one of (a) a serotonergic drug, (b) a purified psilocybin derivative, (c) a purified cannabinoid, (d) a purified terpene, (e) an adrenergic drug, (f) a dopaminergic drug, (g) a monoamine oxidase inhibitor, (h) a purified erinacine, and (i) a purified hericenone.

9. A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a therapeutically effective amount of 2-(2,5-diethoxy-4-(ethylthio)phenyl)ethane-l-aminium chloride according to claim 1.

10. A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a therapeutically effective amount of crystalline 2-(2,5-diethoxy-4-(ethylthio)phenyl)ethane-l-aminium chloride according to any one of claims 2-4.

11. A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to claim 5 or claim 7.

12. A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to claim 6.

13. A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to claim 8.

14. A method of preventing or treating inflammation and / or pain comprising the step of: administering to a subject in need thereof a therapeutically effective amount of 2-(2,5-diethoxy-4-(ethylthio)phenyl)ethane-l-aminium chloride according to claim 1.

15. A method of preventing or treating inflammation and / or pain comprising the step of: administering to a subject in need thereof a therapeutically effective amount of crystalline 2-(2,5-diethoxy-4-(ethylthio)phenyl)ethane-l-aminium chloride according to any one of claims 2-4.

16. A method of preventing or treating inflammation and / or pain comprising the step of: administering to a subject in need thereof a composition according to claim 5 or claim 7.

17. A method of preventing or treating inflammation and / or pain comprising the step of: administering to a subject in need thereof a composition according to claim 6.

18. A method of preventing or treating inflammation and / or pain comprising the step of: administering to a subject in need thereof a composition according to claim 8.

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