Crystalline polymorph of the selective androgen modulators (r) or (s)-n-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide

Description

FIELD OF THE INVENTION

The present invention relates to the crystalline form (R) or (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide and methods for its preparation.

BACKGROUND OF THE INVENTION

[0002] The androgen receptor (AR) is a ligand-activated transcriptional regulatory protein that mediates the induction of male sexual development and sexual function through its activity with endogenous androgens. Androgens are generally known as male sex hormones. Androgenic hormones are steroids produced in the body by the testes and the cortex of the adrenal glands, or they can be synthesized in a laboratory. Androgenic steroids play an important role in many physiological processes, including the development and maintenance of male sexual characteristics such as muscle and bone mass, prostate growth, spermatogenesis, and male hair type (Matsumoto, Endocrinol, Met. Clin. N. Am. 23: 857-75 (1994)). Endogenous steroid androgens include testosterone and dihydrotestosterone (DHT). Testosterone is the major testicular secreted steroid and is the major circulating androgen detected in male plasma. In many peripheral tissues, testosterone is converted into DHT with the participation of the enzyme 5-alpha reductase. DHT is believed to serve as an intracellular mediator for most androgen effects (Zhou et al., Molec. Endocrinol. 9: 20818 (1995)). Other steroidal androgens include testosterone esters such as cypionate, propionate, phenylpropionate, cyclopentylpropionate, isocaproate, enanthate and decanoate esters, and other synthetic androgens such as 7-methylnortestosterone (MENT) and its acetate ester (Sundaram et al., 7 Alpha-Methyl). -Nortestosterone (MENT): The Optimal Androgen For Male Contraception, Ann. Med., 25: 199-205 (1993) (Sundaram). Since AR is involved in male sexual development and function, AR is the likely target for achieving male contraception or other forms of hormone replacement therapy. Selective androgen receptor modulators for the treatment of muscle loss are described in US Patent Application 2007/0161608 A1 (Dalton & Miller).

[0003] Both at the level of basic science and clinical research there is a great need for new innovative approaches to develop compounds useful in a) male contraception; b) treating various hormone-related conditions, for example conditions associated with androgen depletion in aging men (ADAM) such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostatic hyperplasia, changes in mood and cognition, and prostate cancer; c) treatment of ADIF-related conditions such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, changes in cognitive processes and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine and ovarian cancer ; d) treatment and / or

Preventing acute and / or chronic states of muscle loss; e) preventing and / or treating dry eye conditions; f) oral androgen replacement therapy; and / or g) reducing the incidence, arresting or causing regression of a prostate cancer.

[0004] Polymorphs, solvates and salts of various drugs have been described in the literature as imparting new properties to drugs. Organic small molecules of a drug tend to self-assemble into different polymorphic forms depending on the environment that drives self-assembly. Heat and solvent mediated activities can also lead to changes that convert one polymorph to another.

[0005] Determining which polymorph is most stable under each of the conditions of interest tested, and identifying the processes that lead to changes in the polymorphic form, is key to designing the drug manufacturing process to ensure that the end product is in the preferred polymorphic form. . Different polymorphs of the active pharmaceutical ingredient (API) can lead to changes in drug solubility, dissolution rate, pharmacokinetics, and ultimately its bioavailability and efficacy in patients.

SUMMARY OF THE INVENTION

The present invention relates to a crystalline form of the compound (R) or (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide and methods for its preparation . Such compounds are useful for their androgenic and anabolic activities. The (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide compounds are selective androgen receptor modulators (SARMs) which are useful in the manufacture of medicaments for the treatment of a variety of hormone related conditions such as androgen deprivation conditions in aging men (ADAM); the treatment of conditions associated with lowering androgen levels in women (ADIF); treating and / or preventing chronic loss of muscle mass; as a medicament in oral androgen replacement therapy and / or in other clinical therapeutic and / or diagnostic areas.

The present invention provides a crystalline D-form of the compound (R) or (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide that characterizes yourself:

a) X-ray powder diffraction pattern with characteristic reflections at ° 2 ° angles (distance dw A value); with angles of 4.4 (19.9), 8.5 (10.4), 8.8 (10.0), 11.3 (7.8), 12.7 (6.9), 13, 8 (6.4), 14.4 (6.1), 14.6 (6.0), 15.1 (5.8), 16.1 (5.5), 16.6 (5.3 ), 16.9 (5.2), 18.0 (4.9), 18.7 (4.7), 19.0 (4.6), 19.4 (4.55), 20.8 (4.25), 22.1 (4.0), 22.7 (3.9), 23.1 (3.8), 23.4 (3.8), 24.7 (3.6) , 24.9 (3.56), 25.3 (3.51), 27.8 (3.2) and 29.3 (3.0) which were obtained using a copper anode lamp with K-alpha radiation; and b) a melting point of 130 ° C.

The invention also provides a composition comprising crystalline form D of compound (R) or (S) N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide and an appropriate carrier or diluent.

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[0009] In one embodiment, the present invention provides a method of making the crystalline form D of the compound (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy. -2-methylpropanamide, the method comprising mixing the amorphous compound (R) or (S) N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide in solvent / anti-solvent mixture at 50 ° C under conditions allowing crystallization, thus obtaining said crystalline form, wherein the solvent / anti-solvent mixture is an ethyl acetate / cyclohexane mixture.

[0010] In another embodiment, the invention also provides a method of making crystalline form D of the compound (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2- hydroxy-2-methylpropanamide, the method comprising heating a sample of the polymorphic forms A and / or B of the compound (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2 -hydroxy-2-methylpropanamide in the presence of polymorph D up to a temperature of 110 ° C.

[0011] In another embodiment, the invention also provides a method of making the crystalline form D of the compound (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2- hydroxy-2-methylpropanamide, the method comprising inoculating a sample of other polymorphs of compound (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide with a small amount of D and storing the sample at 110 ° C / 0% relative humidity for 7 days or in water at 50 ° C for 24 hours, followed by drying.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

[0012] The subject matter of the invention is indicated and expressly claimed at the end of the description. The invention, together with its objects, features and advantages, may be better understood by reference to the following detailed description when read with the accompanying drawing figures, in which:

Fig. 1 schematically shows the synthesis of racemic mixtures of compound 1.

Fig. 2 schematically shows the synthesis of the (S) -enantiomer of the compound S-1.

Fig. 3 schematically shows the synthesis of the (R) -enantiomer of the compound R-1.

Figures 4A - 4D show XRPD patterns for solid forms of Compound S-1. 4A - constant form A series P1 of the compound S-1; 4B - solid form A - series P2 of the compound S-1; 4C - constant form A - series P3 of compound S-1; 4D - constant form B '- P4 series of compound S-1.

Figures 5A-5D show Raman spectra of the sample series P1-P4 of compound S-1, respectively. The laser power was 100 mW with a resolution of 2 cm-¹.

Figures 6A-6D are TG-FTIR spectra for S-1 sample series P1-P4, respectively. The conditions covered the temperature range of the dynamic operation of 25 ° C / 10.0 / 250 ° C, under the N2 atmosphere.

Figures 7A-7D are DSC patterns for the sample series P1-P4 of compound S-1, respectively. The asterisk indicates the effect of heat absorption, an artifact resulting from the machine used.

Figures 8A, 8B, and 8C are SEM micrographs for sample series P1, P2, and P4 of S-1, respectively.

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Figures 9A, 9B and 9C are spectra from the dynamic method of determination of sorption isotherms (DVS) for the sample series P1, P2 and P4 of the compound S-1, respectively. 9A is DVS for Form A. 9B is DVS for Form A. 9C is DVS for Form B '.

Fig. 10 shows the XRPD spectrum of the compound obtained after changing the concentration of S-1 in the given solvents, changing the solvents, or a combination thereof. A - shows the XRPD pattern of compound S-1, Form A, suspended in n-heptane, 108 mg / 2.0 mL. B - shows the XRPD spectrum of S-1, Form B 'suspended in ethyl acetate + n-heptane 1: 2 (v / v), 81 mg / 1.7 ml. C - shows the XRPD spectrum of S-1, Form B 'suspended in ethyl acetate + n-pentane 1: 2 (v / v), 101 mg / 1.0 mL. D - shows the XRPD spectrum for S-1, Form A, suspended in ethyl acetate + nentane 1: 2 (v / v), 128 mg / 2.0 mL. E - shows the XRPD spectrum of S-1, Form A, suspended in ethyl acetate + n-pentane 1: 2 (v / v), 112 mg / 2.0 mL. F - shows the XRPD spectrum for compound S-1, Form A, suspended in methyl acetate + n-pentane 1: 2 (v / v), 126 mg / 2.0 mL.

Fig. 11 is an XRPD pattern showing the results of vapor diffusion experiments performed with compound S-1. A - shows the XRPD spectrum of S-1 in toluene in hexane at 23 ° C recorded for 2 days. B - shows the superimposed XRPD pattern for the series P1 (Form A) and XRPD obtained in Fig. 11A. C- shows the XRPD spectrum obtained for compound S-1 in acetic acid and water at 23 ° C recorded for 7 days. D - shows the superimposed XRPD spectrum of series P1 (Form A) and XRPD obtained in Fig. 11B.

Fig. 12 is an XRPD pattern showing the results of an evaporation experiment in which the compound solutions were dried at room temperature (dry N2 flow conditions) without agitation. 12A shows the XRPD pattern obtained for compound S-1 (lot P1) in ethyl acetate solution. 12B shows the superimposed XRPD pattern for the series P1 (Form A) and the XRPD pattern obtained in Fig. 12A. 12C shows the XRPD pattern obtained for compound S-1 (lot P1) with THF to give Form C. 12D shows the XRPD pattern of a mixture of Form A (red, top) and Form C (blue, bottom) which is shown in Fig. 12C.

Fig. 13 is an XRPD spectrum showing the results of a solution recrystallization experiment in which compound S-1 was dissolved in another solvent system at room temperature and cooled to + 5 ° C or -20 ° C. 13A - shows the XRPD pattern obtained for compound S-1 (P1 series) in ethyl acetate + n-heptane 1: 1 (v / v). 13B - Shows the superimposed XRPD pattern for the series P1 (Form A) and XRPD obtained in Fig. 13A. 13C - shows the XRPD spectrum obtained for the compound S-1 (P1 series) in acetonitrile + toluene 1: 3 v / v. 13D - shows the superimposed XRPD pattern of the P1 (Form A) and XRPD series obtained in Fig. 13B.

Fig. 14 is an XRPD spectrum showing the results of a lyophilization experiment. 14A - shows the XRPD pattern obtained for compound S-1 (lot P-1) in 1-4-dioxane and cooled to -50 ° C. 14B - shows the superimposed XRPD pattern of P1 series (Form A) and the XRPD pattern obtained in Fig. 14A.

Fig. 15 is a DSC thermogram showing the results of a drying experiment where compound S-1 (lot P4) was dried overnight under an atmosphere of dry N2. The asterisk indicates the effect of heat absorption, an artifact resulting from the machine used.

Fig. 16 is an XRPD spectrum showing the results from the relative stability experiments, where the slurry experiments were performed with mixtures for the Compound S-1 lot. 16A - shows the XRPD spectrum obtained from the mixture for lot S-1 (P1, P18, P24, P30, P37 and P38, all lots have XRPD characteristics for Form A) in ethyl acetate + n-heptane 1: 2 (v / v / v / v) 130 mg / 2.0 ml. 16B

PZ / 5402 / AG shows the superimposed XRPD spectrum of the P1 (Form A) and XRPD series obtained in Fig. 16A. 16C - shows the XRPD spectrum obtained from the mixture obtained for the Compound S-1 series (P1 and P52 where series P1 is Form A and P52 is Form A + C) in ethyl acetate + n-heptane 1: 2 (v / v. ); (81 + 64) mg / 2.0 ml. 16D shows the superimposed XRPD pattern of the P1 series (Form A) and the XRPD pattern obtained in Fig. 16B.

Fig. 17 is a DSC thermogram and XRPD diffractogram showing the results of water vapor sorption, with compound S-1 (Lot P1) stored in a glass tube at 96% RH (relative humidity) at room temperature. 17A - shows the DSC results obtained for S-1 lot P1 without solvent after 11 weeks. 17B - Shows the XRPD of Compound S-1 series P1 (Form A) in water after 19 hours at 37 ° C resulting in Form B '. 17C - shows the XRPD pattern for compound S-1 of the P1 series (form A) in acetic acid + water 1: 2 (v / v) after 20 hours at 23 ° C. 17D - Shows DSC thermogram of heating a sample of A (black), cooling the sample after melting (gray), and reheating the sample (white). The heating rate was 10 ° C / min and the cooling rate was 1 ° C / min. Heating Form A above its melting point produces Form B which does not revert to Form A even after the sample is cooled to ambient temperature. 17E 1 ° C / min DSC course for form A (gray), B (black), mixtures of forms A and D (white) and mixtures of B and D (dark gray): A and B can crystallize to form D, but only in the presence of D to form nuclei for crystallization. 17F - DSC graphs for Form A stored at ambient / 100% Relative Humidity (WW) for 7 days (light gray), 50 ° C / 0% RH for 7 days (dark gray) and 50 ° C / 75% RH for 6 hours (white) together with the DSC trace for the original sample (black). 17G - (a) DSC plots for polymorph A inoculated with Form D and stored at 50 ° C / 75% RH (b) DSC plots for polymorph A seeded with Form D and stored at 50 ° C in water.

Fig. 18 shows the XRPD pattern of an overlaid XRPD pattern of form A (top) and form D (bottom) of S-1.

Fig. 19 shows the DSC thermograms for forms A and D.

Fig. 20 Plot of thermogravimetric analysis (TGA) for the toluene solvate (red) and form D (black).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a crystalline form D of the compound (R) or (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide, characterized by X-ray powder diffraction pattern with characteristic reflections at ° 2 angles (dw A distance value); with angles of 4.4 (19.9), 8.5 (10.4), 8.8 (10.0), 11.3 (7.8), 12.7 (6.9), 13, 8 (6.4), 14.4 (6.1), 14.6 (6.0), 15.1 (5.8), 16.1 (5.5), 16.6 (5.3 ), 16.9 (5.2), 18.0 (4.9), 18.7 (4.7), 19.0 (4.6), 19.4 (4.55), 20.8 (4.25), 22.1 (4.0), 22.7 (3.9), 23.1 (3.8), 23.4 (3.8), 24.7 (3.6) , 24.9 (3.56), 25.3 (3.51), 27.8 (3.2) and 29.3 (3.0), which were obtained using a copper anode lamp with Kalfa radiation and melting point 130 ° C, and methods of its preparation. The invention also provides pharmaceutical compositions containing the crystalline form D of the compound (R) or (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide and their use .

Compounds (R) or (S) - N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide are androgen receptor targeting agents (ARTA). .androgen

PZ / 5402 / AG 6 EP 2 205 552 B1 receptor targeting agents) that exhibit androgenic and anabolic activity. In some embodiments, the methylpropanamides as described herein are selective androgen receptor modulators (SARMs). selective androgen receptor modulators), which in some embodiments are useful for treating a variety of hormone-mediated conditions, for example, conditions associated with androgen depletion in aging men (ADAM) such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostatic hyperplasia, changes in mood and cognition, and prostate cancer; the treatment of conditions associated with low levels of androgens in women (ADIF) such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, changes in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer , uterine cancer and ovarian cancer; for treating and / or preventing chronic loss of muscle mass; oral androgen replacement and / or other clinical therapeutic and / or diagnostic areas.

[0015] Solid polymorphs of compounds (R) or (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide are disclosed. In one embodiment, the term polymorph refers to a specific form of the SARM compounds of this invention, for example, polymorphs may have crystalline forms that may differ in pharmaceutically relevant physical properties from one form to another, for example under the influence of different conditions. crystallization, environmental conditions, activity of hygroscopic compounds, etc.

[0016] Thus, crystalline forms of the anhydrous compound (R) or (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide are disclosed, including the crystalline form of the anhydrous compound (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide.

[0017] One disclosed crystalline form of the compound (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide (compound S-1) is characterized by:

a.X-ray powder diffraction pattern with reflections at ° 2θ angles (dw A distance value) of approximately 5.6 (15.9), 7.5 (11.8), 8.6 (10.3), 9.9 ( 8.9), 12.4 (7.1), 15.0 (5.9), 16.7 (5.3), 17.3 (5.1), 18.0 (4.9), 18.5 (4.8), 19.3 (4.6), 19.8 (4.5), 20.6 (4.3), 21.8 (4.1), 22.3 (4 .0), 23.4 (3.8), 23.9 (3.7), 24.6 (3.6), 24.9 (3.6), 25.4 (3.5), 26 .0 (3.4), 26.5 (3.4), 27.8 (3.2) and b. A melting point of 80 ° C.

[0018] Such a crystalline form of the compound S-1, having all or part of the characteristics listed in (a) and (b) immediately above, is referred to herein as crystalline Form A. The solubility of Form A in water is 20-30 mg / l at 22 ° C or 23-27 mg / l at 22 ° C.

Also disclosed is a crystalline form of (R) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide (compound R-1), said a crystalline form is obtained by methods similar to those described in the present invention for the S-isomer. Such a crystalline form of the compound R-1 is structurally related and / or has properties similar to those of the compound S-1.

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[0020] Also disclosed is a paracrystalline compound (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide.

The paracrystalline form of (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide (compound S-1) is characterized by:

a.X-ray powder diffraction pattern showing a broad halo reflex with two harmonic reflections between 15-25 ° 2θ, and

b. A glass transition temperature of 55 ° C.

[0022] Such a paracrystalline form of the compound S-1 having all or part of the characteristics mentioned in (a) and (b) is referred to in the present specification as paracrystalline form B '. [0023] Paracrystalline refers to the state of a material exhibiting a short range order without a long range order, such as liquid crystals or other type of lamellar structures. The paracrystalline form may be a liquid crystal. The S-1 form B 'may be paracrystalline. The A form of the compound S-1 may convert wholly or in part to the paracrystalline form B 'of the compound S-1.

[0024] The water solubility of Form B 'is 20-30 mg / L at 22 ° C or 23-27 mg / L at 22 ° C.

[0025] Also disclosed is a paracrystalline form B of the compound (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3 (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide, characterized by:

a.X-ray powder diffraction pattern showing a broad halo reflex with two harmonic reflections between 15-25 ° 2θ, and

b. A glass transition temperature of 55 ° C.

[0026] Also disclosed is a crystalline Form C of the compound (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide, characterized by:

a.X-ray powder diffraction pattern with characteristic reflections at angles ° 2θ (dw A distance value) of 6.9 (12.8), 9.5 (9.3), 13.5 (6.6), 16.0 ( 5.6), 22.8 (3.9).

Crystalline form C of S-1 can be obtained as a mixture of forms A and C by evaporation of form A with THF.

The present invention provides a crystalline form D of the compound (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide, characterized by:

and. X-ray powder diffraction pattern with characteristic reflections at ° 2 ° angles (dw A distance value) of 4.4 (19.9), 8.5 (10.4), 8.8 (10.0), 11.3 (7, 8), 12.7 (6.9), 13.8 (6.4), 14.4 (6.1), 14.6 (6.0), 15.1 (5.8), 16, 1 (5.5), 16.6 (5.3), 16.9 (5.2), 18.0 (4.9), 18.7 (4.7), 19.0 (4.6 ), 19.4 (4.55), 20.8 (4.25), 22.1 (4.0), 22.7 (3.9), 23.1 (3.8), 23.4 (3.8), 24.7 (3.6), 24.9 (3.56), 25.3 (3.51), 27.8 (3.2) and 29.3 (3.0) , which were obtained using a copper anode lamp with K-alpha radiation; and

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b. a melting point of 130 ° C.

The Crystalline Form D of S-1 is stable at 50 ° C / 75% RH (Relative Humidity) as well as under other conditions such as ambient temperature / 75% RH, ambient temperature / 100% RH, 30 ° C / 75% RH and 50 ° C / 0% RH.

[0029] Characterization of the various solid forms of S-1 is shown in Example 2 and Figures 4-20.

[0030] The solid forms of this invention can be analyzed by any method known in the art, for example by X-ray powder diffraction. Other techniques may be used to analyze the solid forms of this invention, such as Raman spectroscopy, TG-FTIR (Fourier Infrared Thermogravimetry), FT-Raman (Fourier Transform Raman Spectroscopy), DSC (Differential Scanning Calorimetry), DVS ( dynamic vapor sorption) or SEM (scanning electron microscopy).

[0031] In one embodiment, the crystalline form D may be present in a polymorphic mixture comprising crystalline forms A, B ', and D in a ratio of from 5:90 to 10:10:80, respectively, or in a ratio of about 10:10, respectively. : 80 to 10:15:75 or in the ratio of 2: 3: 95 to 3: 7: 90 or in the ratio of 10:15:75 to 15:20:65 or in the ratio of 10:20:70 to 20: 20:60.

[0032] In one embodiment, the crystalline form D may be present in a polymorphic mixture containing the crystalline forms A and D in a ratio of 2:98 to 5:95 or in a ratio of 5:95 to 10:90 or in a ratio of 10, respectively. : 90 to 15:85 or in the ratio of 15:85 to 20:80 or in the ratio of 50:50.

[0033] In one embodiment, the crystalline form D may be present in the polymorphic mixture containing the crystalline forms B 'and D in a ratio of from 2:98 to 595 or in a ratio of from 5:95 to 10:90 or in a ratio of from 10, respectively. : 90 to 15:85 or in the ratio of 15:85 to 20:80 or in the ratio of 50:50.

[0034] In one embodiment, the sample of (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide may comprise a mixture of solid form A, B ' , B, C and D. The percentage of several solids in a sample can be determined by performing modulated DSC (Differential Scanning Calorimetry) at a heating rate of 3 ° C / min, at a temperature of 10 ° C to 130 ° C, followed by linear integration solid forms to obtain the enthalpy of each of them.

[0035] In one embodiment, the present invention provides a method of making the crystalline form D of the compound (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy- 2-methylpropanamide, which involves dissolving an amorphous (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide in a solvent / anti-solvent mixture in temperature of 50 ° C in conditions allowing for crystallization, thus obtaining a crystalline form wherein the solvent / anti-solvent mixture is an ethyl acetate / cyclohexane mixture.

A method of producing crystalline form A of the compound (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide is disclosed which comprises dissolving amorphous ( S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide in at least one organic solvent at a temperature of -20 ° C to + 30 ° C at conditions allowing crystallization, thus obtaining a crystalline form.

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Form A (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide (compound S-1) can be obtained by crystallization from an organic solvent containing a mixture of solvents. The mixture may contain two solvents in a ratio of 1: 2 v / v respectively. or in a ratio of 1: 3 v / v. or in a ratio of 1: 4 v / v. The mixture may contain ethyl formate and pentane in a ratio of 1: 2 v / v respectively. The mixture may contain methyl acetate and pentane in a ratio of 1: 2 v / v respectively. The mixture may contain ethyl acetate n-hexane or the mixture may contain toluene n-hexane or dichloromethane n-hexane or the mixture may contain acetic acid and water in a ratio of 1: 2 v / v. Form A can be prepared by crystallization from a solvent / anti-solvent mixture at ambient temperature. As solvents, ethyl acetate, ethanol, dichloromethane, or acetonitrile can be used, and as anti-solvents, n-hexane, n-pentane, n-heptane, and cyclohexane, etc. can be used. The solvent / anti-solvent ratio can be from 1: 2 to 1: 3.

[0038] Crystalline form A of the compound S-1 can be prepared by suspending the paracrystalline form of the compound of formula S-1 in a solvent / anti-solvent mixture. The solid form A can be prepared by suspending the paracrystalline form of the compound of formula S-1 in a mixture of ethyl acetate and heptane in a ratio of 1: 2 v / v, respectively. or by suspending the paracrystalline form of the compound of formula S-1 in a mixture of ethyl acetate and pentane in the proportion of 1: 2 v / v respectively. or by suspending Form B 'in a solvent / anti-solvent mixture at concentrations above the saturation limit at 23 ° C for several hours, followed by drying to obtain Form A.

[0039] In another embodiment of the present invention, the D form of the compound (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide (Compound S- 1) is prepared by crystallization from a solvent / anti-solvent mixture at 50 ° C using acetate and cyclohexane as solvent and anti-solvent, respectively. In another embodiment, Form D is prepared from other polymorphic forms by inoculating a sample with a small amount of Form D and storing at 110 ° C / 0% RH for 7 days or at 50 ° C in water for 24 hours and then drying. In another embodiment, heating form A and / or B to 110 ° C in the presence of form D causes forms A and B to convert to form D. In another embodiment, form D in the presence of moisture acts as a seed for the crystallization process and converts forms A and B 'to form D.

[0040] Figure 17G shows the progress over time of polymorph A seeded with a small amount of form D at 50 ° C / 75% RH. The amount of polymorph D initially added to the sample is very small as it is not detectable by DSC at a heating rate of 10 ° C / min. After 24 hours, most of the polymorphic form A was converted to form B ', but a small amount of the sample was also converted to form D, and the amount of sample in form D increased with time. The conversion process is accelerated as shown in Fig 17G by storing the sample in water at 50 ° C. Form A converts to both Form B and D after 6 hours, but the sample is predominantly D after 24 hours.

Also disclosed is a method for producing a paracrystalline compound (R) or (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide which comprises stirring the suspension of the crystalline form of the compound (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4

PZ / 5402 / AG

Cyanophenoxy) -2-hydroxy-2-methylpropanamide in water at ambient temperature of about 20-30 ° C for at least 0.5 hours to form a paracrystalline compound.

Also disclosed is a method of producing paracrystalline form B 'of the compound (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide which comprises mixing suspension of the crystalline form of (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide in water at an ambient temperature of about 20 ° C-30 ° C by which at least 0.5 hours to form a paracrystalline compound.

[0043] Further disclosed is a process for preparing paracrystalline form B 'of the compound (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide which comprises mixing a suspension of crystalline form A of (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide in water at an ambient temperature of 20 ° C-30 ° C for at least 0.5 hours to form a paracrystalline compound. Paracrystalline form B 'can be prepared by stirring a suspension of crystalline form A at 50 ° C in water for 24 h or by stirring a suspension of crystalline form A at 37 ° C overnight to obtain paracrystalline form B'.

[0044] The solid form B 'of the compound (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide can be prepared by storing the solid form A at 40 ° C. C and 75% RH for 1-2h or 40 ° C and 75% RH for 2-4h or 40 ° C and 75% RH for 410h or 40 ° C and 75% RH for 10-15h or at 40 ° C and 75% r.h. for 15-24h, or at 40 ° C and 75% r.h. for 24h, or by storage of solid form A at 40 ° C and 75% r.h. for 30 days.

Solid form B 'of the compound (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide can be prepared by storing solid form A at 40 ° C. C and 75% relative humidity (ww) or at 30-40 ° C and 50-75% relative humidity or at 40-50 ° C and 60-80% relative humidity or at 40-50 ° C and relative humidity 60-80%.

Form B 'can be assigned a liquid crystal lyotropic form due to solvent mediated formation of this form.

The liquid crystal form B of the compound (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide can be prepared by melting or heating the solid form A of the compound ( S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide to 80 ° C followed by cooling.

[0047] Form B of the compound (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide can be made by melting or heating to 130 ° C of the solid form Compound (S) N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide, followed by cooling.

[0048] Evaporation of (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide from solvents such as ethanol without anti-solvent can form B.

[0049] Form B can be assigned a thermotropic liquid crystal form because of its thermal preparation method.

Also disclosed is a method of preparing the solid form C of the compound (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide which comprises dissolving a crystalline A form of the compound (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4

PZ / 5402 / AG

Cyanophenoxy) -2-hydroxy-2-methylpropanamide in THF followed by evaporation to give the solid form C.

[0051] Form C may be obtained as a mixture with Form A.

[0052] Crystalline forms of the SARM compounds of the invention include the change of a given crystal form to another structurally similar, but not identical to, form. Such alterations in the crystalline forms can produce those that are more structurally stable than the original form. In some embodiments, the crystal forms of the present invention contain altered crystal forms as well as the starting forms in a single preparation. Such altered crystal forms may constitute a small percentage of the total SARM compound preparation, for example, up to 1%, or up to 5%, or up to 10%, or up to 15% or up to 25% of the preparation. Such altered forms may constitute the bulk of a SARM compound formulation, and may constitute 55%, or 65%, or 75%, or 80%, or 85%, or 90%, or 95%, or up to 100% of a SARM compound formulation. In one embodiment, the preferred crystalline form is the thermodynamically preferred form. The crystalline preferred form may result from a change in humidity as a result of a change in temperature or as a result of a change in solvents.

[0053] The methods of obtaining polymorphs of compounds (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide can lead to the formation of various crystalline forms . In one embodiment, the process produces a mixture of crystalline / paracrystalline forms A, B ', C, and D. In one embodiment, the process produces a mixture of crystalline / paracrystalline forms A, B', B, C, and D. In another embodiment, the method produces a mixture of crystalline forms A and D. In another embodiment, the method produces a mixture of crystalline / paracrystalline forms B 'and D. In another embodiment, the method produces a mixture of crystalline / paracrystalline forms B and D. In another embodiment, the method produces a mixture of crystalline forms C and D. In another embodiment, the process produces a mixture of crystalline / paracrystalline forms A, D, and B. In another embodiment, the method produces a mixture of crystalline / paracrystalline forms D, B ', and B.

[0054] In one embodiment, the solid compounds of this invention are dried from the solution by applying a vacuum at room temperature followed by gradually increasing the temperature. In another embodiment, the solid compounds of the present invention are filtered from the solution.

[0055] In one embodiment, the term ambient temperature refers to room temperature. In another embodiment, the term ambient temperature refers to 20-25 ° C. In another embodiment, ambient temperature refers to a temperature of 25-30 ° C.

[0056] In another embodiment, Form D is the thermodynamically most stable polymorph both under dry conditions and in the presence of water at ambient temperature up to a melting point of 130 ° C. Fig. 19 is a Differential Scanning Calorimeter (DSC) thermogram for Form A and Form D where Form A melts at 80 ° C and Form D melts at 130 ° C. Typically, Form A has a melting enthalpy of 40 5 J / g, while Form D has a melting enthalpy of 75 5 J / g.

In one embodiment, the compound (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide is obtained by chiral synthesis .

PZ / 5402 / AG

EP 2 205 552 B1

In one embodiment, (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide can be prepared according to the following scheme:

<img file="PL2205552T3_D0001.tif" />

<img file="PL2205552T3_D0002.tif" />

Level 1

4N NaOH / Acetone

-------*0-5^aboutC / Room temperature / 3h

<img file="PL2205552T3_D0003.tif" />

<img file="PL2205552T3_D0004.tif" />

Stage 3

24% HBr Reflux 100-110 ° C

Ϊ ⁵HcrSi h₃c 'oh

VIII

<img file="PL2205552T3_D0005.tif" />

<img file="PL2205552T3_D0006.tif" />

<img file="PL2205552T3_D0007.tif" />

Stage 5

<img file="PL2205552T3_D0008.tif" />

[0059] In one embodiment, the method described in the above scheme comprises reacting the acylanilide in step 5 with a cyanophenol, and the reaction may be carried out in the presence of potassium carbonate, sodium carbonate, or cesium carbonate. The reaction in the presence of potassium carbonate surprisingly resulted in a product with fewer impurities compared to the reaction in the presence of cesium carbonate. This represents an improved and more efficient synthetic method for producing the end product that minimizes the need for additional purification steps. This finding is also beneficial in the preparation of other compounds such as 6, 9, 12 and 14 below.

[0060] A method of producing (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide is disclosed, the process comprising the following steps:

a) Preparation of the carboxylic acid of formula 1 by ring opening of the cyclic compound of formula 2 in the presence of HBr

<img file="PL2205552T3_D0009.tif" />

b) reacting the amine of formula 3:

<img file="PL2205552T3_D0010.tif" />

PZ / 5402 / AG with a carboxylic acid of formula 2 in the presence of a coupling reagent to give the amide of formula 4

<img file="PL2205552T3_D0011.tif" />

and

c) reacting an amide of formula 4 with a compound of formula 5:

<img file="PL2205552T3_D0012.tif" />

wherein step (c) is carried out in the presence of potassium carbonate and tetrahydrofuran.

[0061] A method of producing a compound of Formula 6 is disclosed:

<td>^NCThese ones— the process comprises the steps of: a) production of carboxylic acid of Formula 2 in the presence of HBr / - \ H⁰ / &lt;^ Br CHf 1 b) reacting the amine of formula 7:</td><td>h₃c ^{% OH}of formula 1 by ring opening of cyclic 0 HBr * ΗΟ ^ Χ ^ Βγ h₃c ^oh2 CL _Λ\ ^^ NH₂ 7</td>

with a carboxylic acid of formula 2 in the presence of a coupling reagent to give the amide of formula 8

PZ / 5402 / AG

EP 2 205 552 B1

<img file="PL2205552T3_D0013.tif" />

and

c) reacting an amide of formula 8 with a compound of formula 5:

<img file="PL2205552T3_D0014.tif" />

wherein step (c) is carried out in the presence of potassium carbonate and tetrahydrofuran.

[0062] Also disclosed herein is a method of making a compound of Formula 9:

<img file="PL2205552T3_D0015.tif" />

the method comprising the steps of:

a) Preparation of the carboxylic acid of formula 1 by ring opening of the cyclic compound of formula 2 in the presence of HBr

<img file="PL2205552T3_D0016.tif" />

b) reacting the amine of formula 3:

<img file="PL2205552T3_D0017.tif" />

with a carboxylic acid of formula 2 in the presence of a coupling reagent to give the amide of formula 4 and

<img file="PL2205552T3_D0018.tif" />

PZ / 5402 / AG

EP 2 205 552 B1

c) reacting an amide of formula 4 with a compound of formula 10:

<img file="PL2205552T3_D0019.tif" />

wherein step (c) is carried out in the presence of potassium carbonate and tetrahydrofuran.

<img file="PL2205552T3_D0020.tif" />

b) reacting the amine of formula 3:

with a carboxylic acid of formula 2 in the presence of a coupling reagent to give the amide of formula 4

<img file="PL2205552T3_D0021.tif" />

and

c) reacting an amide of formula 4 with a compound of formula 13:

<img file="PL2205552T3_D0022.tif" />

wherein step (c) is carried out in the presence of potassium carbonate and tetrahydrofuran.

[0063] Also disclosed is a method of producing a compound of Formula 14:

<img file="PL2205552T3_D0023.tif" />

X is O, NH, Se, PR or NR;

T is OH, OR, NHCOCH3 or NHCOR;

Z is NO2, CN, COOH, COR, NHCOR or CONHR;

Y is CF3, F, I, Br, Cl, CN, CR3, or SnR3;

Q is alkyl, halogen, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR,

NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R,

PZ / 5402 / AG

EP 2 205 552 B1

OR, COR, OCOR, OSO2R, SO2R, SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by the structure A, B or C:

<img file="PL2205552T3_D0024.tif" />

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl or OH group; and

R1 is CH3, CH2F, CHF2, CF3, CH2CH3 or CF2CF3;

wherein the method comprises the following steps:

a) Preparation of the carboxylic acid of formula 15 by ring opening of the cyclic compound of formula 16 in the presence of HBr

<img file="PL2205552T3_D0025.tif" />

wherein L, R1 and T are as defined above and Ti is oxygen or NH;

b) reacting the amine of formula 17:

<img file="PL2205552T3_D0026.tif" />

where Z and Y are as defined above, with the carboxylic acid of formula 17 in the presence of a coupling reagent to give the amide of formula 18

<img file="PL2205552T3_D0027.tif" />

and

c) coupling an amide of formula II with a compound of formula 19:

<img file="PL2205552T3_D0028.tif" />

wherein Q and X are as defined above and wherein step (c) is carried out in the presence of potassium carbonate and tetrahydrofuran.

[0064] Crystalline Form D according to the invention can be produced by the method set out herein.

PZ / 5402 / AG 17 EP 2 205 552 B1

The crystalline polymorph D of the compound (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide can be converted into its analog, isomer , polymorph, polymorphic form A, paracrystalline form B ', solvate, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, N-oxide, hydrate, hemihydrate, or any combination thereof.

[0066] The term isomer includes optical isomers, structural isomers and conformational isomers. [0067] In one embodiment, the SARM compounds are pure (R) -enantiomers. In another embodiment, the SARM compounds are pure (S) enantiomers. In another embodiment, the SARM compounds are a mixture of the (R) and (S) enantiomers. In another embodiment, the SARM compounds are a racemic mixture containing an equal amount of the (R) and (S) enantiomers. In one embodiment, the method of the invention further provides the step of converting the SARM compound into an optically active isomer thereof.

[0068] In one embodiment, the separation of the optically active (R) enantiomer or (S) enantiomer from the racemic SARMs of the invention comprises crystallization techniques. The crystallization techniques may include the discriminatory crystallization of enantiomers, or may include the discriminatory crystallization of diastereoisomeric salts (tartar or quinine salts) or the discriminatory crystallization of chiral auxiliary derivatives (menthol esters etc.). In other embodiments, the separation of the optically active (R) enantiomer or (S) enantiomer from the racemic SARMs of the present invention may involve reacting the racemic mixture with another chiral group, forming a diastereomeric mixture, followed by separating the diastereoisomers and removing the additional chiral group to obtain pure enantiomers, chiral synthesis, biological separation, enzymatic separation, chromatographic separation using a chiral stationary phase, affinity chromatography, capillary electrophoresis or by formation of an ester group of a hydroxyl group of a chiral carbon atom with an optically active acid, for example (-) camphanic acid, separation of the diastereomeric esters thus obtained by fractional crystallization or preferably by the technique of flash chromatography followed by hydrolysis of each individual ester to an alcohol.

[0069] In another embodiment, the S-enantiomer of a SARM compound of the present invention can be converted to the R-enantiomer or its racemate. In another embodiment, the R-enantiomer of a SARM compound of the present invention can be converted to the S-enantiomer or its racemate. One enantiomer may be converted to another enantiomer, or a racemic mixture thereof, using a chiral reagent, solvent, biocatalyst, chiral catalyst, asymmetric hydrogenation, an enzyme, or a combination thereof.

[0070] In some embodiments, the solid compounds of polymorph D of the invention include solvates. In one embodiment, the term solvate refers to solvents associated with SARM compounds, for example, an ethyl acetate solvate that is part of the polymorphic structure of a SARM compound. Such solvents include ethanol, acetone, ethyl acetate, THF, acetonitrile, dichloromethane, 1,4-dioxane, acetic acid, toluene, water, n-heptane, toluene, TBME n-pentane, or any combination thereof.

[0071] In another embodiment, the method of the present invention further provides the step of converting the D polymorph of the SARM compound into a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutically acceptable salts include the salts of the amino substituted compounds with organic and inorganic acids, e.g.

PZ / 5402 / AG with citric and hydrochloric acid. The invention also includes N-oxides of the amine substituents of the compounds described herein. Pharmaceutically acceptable salts can also be prepared from the phenolic compounds by treatment with inorganic bases, for example sodium hydroxide. Esters of phenolic compounds with aliphatic and aromatic carboxylic acids, for example acetic acid esters and benzoic acid esters, can also be prepared.

[0072] The invention includes pharmaceutically acceptable salts of the compounds of the invention, which can be prepared by reacting a compound of the invention with an acid or a base.

[0073] Suitable pharmaceutically acceptable amine salts of polymorph D can be prepared from an inorganic acid or from an organic acid. In one embodiment, inorganic amine salts are bisulfates, borates, bromides, chlorides, hemisulfates, hydrobromides, hydrochlorides, 2-hydroxyethylsulfonates (hydroxyethanesulfonates), iodates, iodides, isothionates, nitrates, persulfates, phosphates, sulfates, sulfanates, sulfanates, alkylsulfonates, arylsulfonates, halogen substituted alkylsulfonates, halogen substituted arylsulfonates), sulfonates and thiocyanates.

[0074] Examples of the organic amine salts include the classes of organic acids of aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic character, examples of which are acetates, arginines, aspartates, ascorbates, adipates, anthranilate, algenate, alkanedic carboxylates, alkanes and substituted carboxylates. , alginates, benzene sulfonates, benzoates, bisulfates, butyrates, bicarbonates, hydrogenates, carboxylates, citrates, camphorates, camphorsulfonates, cyclohexylsulfamates, cyclopentanopropionates, calcium edithates, camsylates, carbonates, clavulanates, cinnamates, dicarboxylates, digluconates, dodecylsulfonates, dihydrochlorides, decanoates, enanthates, ethanesulfonates, edylates, edithates, glutamates, edithates , glycolates, glucorates, glucoheptanates, glycerophosphates, glucoheptonates, glycolylarsanilates, glutarates, glutamates, heptanates, hexanates, hydroxymaleates, hydroxycarboxylic acids, hexylresorcinates, hydroxybenzoates, hydroxynaphthoates, hydrofluorate, lactates, lactobionates, laurates, malates, maleates, methylene bis (beta-oxynaphthoesan), malonates, mandelates, methylsulfonates, methosulfonates, methylsulfonates, mesylsulfates mucic acid salts, monocarboxylates, mitranates, naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, sputters, N-methylglucamines, oxalates, octanoates, oleates, pamoates, phenylacetates, picrates, phenylbenzoates, pivalonates, propionates, phthalates, phenylacetate, pectates, phenylpropionates, palmitate, panthotenates, polygalacturates, pyruvates, quinates, salicylates, tartarates, succinates, alkanoates , p-toluenesulfonates (tosylates), trifluoroacetates, terephthalates, tannins, theoclates, trihaloacetates, triethiodide, tricarboxylates, undecanoates or valerates.

[0075] Examples of inorganic salts of carboxylic acids or phenols include ammonium, alkali metals including lithium, sodium, potassium, cesium; alkaline earth metals, including calcium, magnesium, aluminum; zinc, barium, choline or quaternary ammonium salts.

[0076] Examples of organic salts of carboxylic acids or phenols include arginine, organic amines including aliphatic organic amines, alicyclic organic amines, aromatic organic amines, benzathines, t-butylamines, benetamines (N-benzylphenethylamine), dicyclohexylamines, dimethylamines, diethanolamines, ethanolamines, ethylenediamines , hydrabamines, imidazoles, lysines, methylamines, meglamines, N-methyl-D-glucamine, N, N'-dibenzylethylenediamines, nicotinamide, organic amines, ornithine, pyridine,

PZ / 5402 / AG

Picolinates, piperazines, procaine, tris (hydroxymethyl) methylamine, triethylamine, triethanolamine, trimethylamine, tromethamine or ureas.

[0077] Salts may be prepared by conventional methods, such as by reacting the free base form or the free acid form with one or more equivalents of an appropriate acid or base in a solvent or medium in which the salt is insoluble, or in a solvent such as water, which is removed under reduced pressure or by freeze drying or by ion exchange from the salt present with another ion or a suitable ion exchange resin.

[0078] N-oxides of the amine substituents of polymorph D crystalline compounds described herein are disclosed. Esters of phenolic compounds with aliphatic and aromatic carboxylic acids, for example esters with acetic acid and benzoic acid, can also be prepared.

[0079] Also disclosed are derivatives of SARM compounds with crystalline polymorph form D. The term derivative includes ether derivatives, acid derivatives, amide derivatives, ester derivatives. Derivative processes are known to those skilled in the art. For example, ether derivatives are prepared by coupling the appropriate alcohols. The amide and ester derivatives are prepared from the corresponding carboxylic acid by reaction with amines and alcohols, respectively.

[0080] Also disclosed are SARM compounds hydrates of crystalline polymorph D form. The term hydrate includes hemihydrate, monohydrate, dihydrate, trihydrate. Hydrates of SARM compounds can be prepared by contacting a SARM compound with water under appropriate conditions to produce a selected hydrate. The term hemihydrate refers to a hydrate in which the molecular ratio of water molecules to the anhydrous compound is 1: 2.

The present invention further includes pharmaceutical products of the crystalline polymorph D form of the compound SARM (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2- methylpropanamide. The term pharmaceutical product means a composition suitable for pharmaceutical use (pharmaceutical composition) as defined herein.

Pharmaceutical compositions

The invention provides a composition comprising crystalline form D of compound (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide and a suitable carrier or diluent.

[0083] Crystalline Form D may be present in a composition comprising a mixture of any of the solid forms of the compound (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2- hydroxy-2-methylpropanamide according to the invention and a suitable carrier or diluent.

[0084] Thus, crystalline form D may be present in a composition comprising a mixture of crystalline and paracrystalline solid forms of the compound (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide and a suitable carrier or diluent.

Compositions containing different forms of the compound (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) 3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide may be in different ratios or in single embodiment, a composition that has properties useful in the treatment of conditions associated with the action of the androgen hormone described herein. Compositions containing the different isomers of the compound N- (4-cyano-3

PZ / 5402 / AG (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide may be in various ratios or as a single isomer per composition which has properties useful in treating androgen mediated conditions described herein.

[0086] Typically, the phrase pharmaceutical composition refers to a therapeutically effective amount of the active ingredient, ie the crystalline form D of a SARM compound, together with a pharmaceutically acceptable carrier or diluent. The term therapeutically effective amount refers to the amount which produces a therapeutic effect for a given condition and administration regimen.

Pharmaceutical compositions containing crystalline form D of the SARM agent may be suitable for administration to a patient by any method known to one of skill in the art, such as parenteral, intratumoral, transmucosal, transdermal, intramuscular, intravenous, intradermal, subcutaneous, intraperitoneal, intraventricular, intracranial or intracranial administration. tumor.

[0088] In another embodiment, the invention provides a crystalline form D composition according to the invention and a suitable carrier or diluent.

[0089] In one embodiment, the pharmaceutical compositions are to be administered orally and thus are formulated into a form suitable for oral administration, i.e., as a solid preparation. Suitable solid oral preparations include tablets, capsules, pills, granules, pellets. In one embodiment of the present invention, the SARM crystalline Form D compounds are formulated as capsules. According to this embodiment, the compositions of the invention contain a hard gelling capsule in addition to the crystalline form D of the active SARM compound and an inert carrier or diluent.

[0090] Oral preparations containing crystalline form D may contain any conventional oral forms including tablets, capsules, buccal forms, troches or lozenges. Capsules may contain mixtures of crystalline form A in the desired percentage together with any other SARM polymorph or SARM amorphous form. Capsules or tablets of the desired crystal form with the desired percentage composition can also be combined with mixtures of other active substances or inert fillers and / or diluents, such as pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweeteners, powdered celluloses such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc.

[0091] Tablet formulations may be made by conventional compression, wet granulation, or dry granulation methods and employ pharmaceutically acceptable diluents (fillers), binders, lubricants, disintegrants, suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, calcium carboxymethyl cellulose, polyvinylpyrrolidone, gelatin, alginic acid, acacia, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar . Oral formulations, in some embodiments, use standard retard or modified release formulations or spansules.

[0092] Examples of suitable excipient systems for the preparation of the formulations of the present invention include one or more fillers, disintegrants and lubricants.

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[0093] The filler ingredient can be any filler known in the art, including, but not limited to, lactose, microcrystalline cellulose, sucrose, mannitol, calcium phosphate, calcium carbonate, powdered cellulose, maltodextrin, sorbitol, starch, or xylitol.

[0094] Disintegrants suitable for use in the formulations of the invention can be selected from those known in the art, including pregelatinized starch and sodium starch glycolate. Other useful disintegrants include croscarmellose sodium, crospovidone, starch, alginic acid, sodium alginate, clays (e.g., Veegum or xanthan gum), cellulose flocs, ion exchange resins, or effervescent systems such as those using food acids (such as citric acid). , tartaric acid, malic acid, fumaric acid, lactic acid, adipic acid, ascorbic acid, aspartic acid, erythorbic acid, glutamic acid, succinic acid) and an alkali carbonate component (such as sodium bicarbonate, calcium carbonate, magnesium carbonate, potassium carbonate, ammonium carbonate, etc.). The disintegrant (s) useful in the present invention may range from 4% to 40% by weight of the composition, preferably from 15% to 35%, more preferably from 20% to 35%.

[0095] The pharmaceutical preparations can also contain an antioxidant or a mixture of antioxidants such as ascorbic acid. Other antioxidants that can be used include sodium ascorbate and ascorbyl palmitate, preferably in combination with an ascorbic acid content. An exemplary range of antioxidant (s) present is from 0.5% to 15% by weight, most preferably from 0.5% to 5% by weight.

[0096] In some embodiments of the present invention, the active pharmacological agent (s) comprises 0.5% to 20% by weight of the final composition, or in some embodiments 1% to 5% by weight, and the coating or capsule contains up to 8% by weight of the final composition. composition.

[0097] The formulations described herein may be used in uncoated or unencapsulated solid form. In some embodiments, the pharmacological compositions are optionally coated with, for example, 0.3% to 8% by weight of the total composition. The formulation coatings useful in the subject formulations are known in the art and generally consist of a polymer (typically of the cellulosic type), a dye, and a plasticizer. Additional ingredients such as wetting agents, sugars, flavors, oils, and glidants may be included in the shell formulations to impart specific properties to the shell. The compositions and preparations of the invention can also be combined and processed into a solid and then filled into a capsule such as a gelatin capsule.

[0098] In another embodiment, the active compound can be delivered in a vesicle, in particular a liposome (see Langer, Science 249: 1527-1533 (1990); Treat et al., In Liposomes in Therapy of Infectious Disease and Cancer, Lopez- Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989), Lopez-Berestein, at the same site, pp. 317-327; see generally therein).

[0099] The term pharmaceutically acceptable carriers or diluents as used herein is well known to those skilled in the art. The carrier or diluent can be a solid carrier or a diluent for solid preparations.

[0100] Solid carriers / diluents include, but are not limited to, gum, starch (e.g., corn starch, pregelatinized starch), sugar (e.g., lactose, mannitol, sucrose, dextrose), cellulosic material (e.g., microcrystalline cellulose), acrylate (e.g. polymethacrylate), calcium carbonate, magnesium oxide, talc or mixtures thereof.

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In addition, the compositions may additionally contain binders (e.g., acacia, corn starch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrants (e.g., corn starch, potato starch, potato starch). silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate), buffers (e.g. Tris-HCl, acetate, phosphate) with different pH and ionic strength, additives such as albumin or gelatin to prevent absorption on surfaces, detergents (e.g. Tween 20, Tween 80, Pluronik F68, bile salts), protease inhibitors, surfactants (e.g. sodium lauryl sulfate), absorption promoters, solubilizing agents (e.g. glycerol, polyethylene glycerol), antioxidants (e.g. ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g. hydroxypropyl cellulose, hydroxypropyl methylcellulose), viscosity increasing agents (e.g. carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweeteners (e.g. aspartame, citric acid), preservatives (e.g. thiomersal, benzyl alcohol, parabens), lubricants (lubricants) e.g. stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow aids (e.g. colloidal silicon dioxide), plasticizers (e.g. diethyl phthalate, triethyl citrate), emulsifiers (e.g. carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e.g. poloxamers or poloxamines), coating and film-forming agents (e.g. ethyl cellulose, acrylates, polymethacrylates) and / or adjuvants.

[0102] In one embodiment, the pharmaceutical compositions provided herein are controlled release compositions, ie, compositions in which the SARM compound is released for a period of time after administration. In another embodiment, the composition is an immediate release composition, ie, a composition in which all of the SARM compound is released immediately after administration.

[0103] In yet another embodiment, the pharmaceutical composition can be delivered in a controlled release system. For example, the agent can be administered using liposomes or other oral delivery means.

[0104] The compositions can also include incorporating the active ingredient into or onto particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, hydrogels and the like, or onto liposomes, microemulsions, micelles, monolayer or multilayer vesicles, erythrocyte shadows or spheroplasts. Such compositions will affect the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance.

[0105] The preparation of pharmaceutical compositions containing the active ingredient is well known in the art, for example, by mixing, granulating or forming tablets. The active drug ingredient is often mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient. For oral administration, SARMs or their physiologically tolerable derivatives, such as salts, esters, N-oxides, are mixed with conventional additives for this purpose, such as carriers, stabilizers or inert diluents, and converted into the appropriate administration forms by conventional means. such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oily solutions.

[0106] Crystalline Form D and / or the other active ingredient may be formulated into the composition as neutralized pharmaceutically acceptable salt forms. Pharmaceutically acceptable salts include acid addition salts (formed with free amino groups of the polypeptide or antibody molecule) that are formed with inorganic acids such as, for example, hydrochloric acid

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Or phosphoric acid, or with organic acids such as acetic, oxalic, tartaric, mandelic acid. Salts formed from free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium or iron hydroxides, and organic bases such as isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, procaine.

[0107] For use in medicine, the salts of the crystalline form D of the SARM compounds will be pharmaceutically acceptable salts. However, other salts may be useful in the preparation of the compounds of the invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of compounds of the present invention include acid addition salts, which can, for example, be prepared by mixing a solution of a compound of the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid.

Biological activity of compounds that are selective androgen receptor modulators

[0108] Compounds (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide with crystalline polymorphic form D may be selective receptor modulators androgenic steroids (SARMs) which are useful in oral testosterone replacement therapy, showing unexpected androgenic and anabolic activity in vivo. As envisaged in the present specification, appropriately substituted SARMs of crystalline form D of the present invention are useful in the preparation of medicaments for the treatment of various hormone-mediated conditions, for example, androgen deprivation conditions in aging male (ADAM) such as fatigue. , depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostatic hyperplasia, changes in mood and cognitive processes, and prostate cancer; in the treatment of ADIF-related conditions such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, changes in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine and ovarian cancer; in the treatment and / or prevention of chronic loss of muscle mass; as a medicament in oral androgen replacement therapy and / or other clinical therapeutic and / or diagnostic areas.

[0109] As used herein, receptors for extracellular signaling molecules are collectively referred to as cell signaling receptors. Many cell signaling receptors are transmembrane proteins on the cell surface; when they bind to an extracellular signaling molecule (ie, a ligand), they are activated to generate a cascade of intracellular signals that alter cell behavior. On the other hand, in some cases the receptors are inside the cell and the signaling ligand must enter the cell to activate them; such signaling molecules must therefore be sufficiently small and hydrophobic to diffuse across the plasma membrane of the cell. As used herein, these receptors are collectively referred to as intracellular cell signaling receptors.

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[0110] Steroid hormones are one example of small hydrophobic molecules that diffuse directly across the plasma membrane of target cells and bind to intracellular cell signaling receptors. These receptors are structurally related and constitute the superfamily of intracellular receptors (or the superfamily of steroid hormone receptors). Steroid hormone receptors include progesterone receptors, estrogen receptors, androgen receptors, glucocorticoid receptors, and mineralocorticoid receptors. The present invention specifically targets androgen receptors.

[0111] In addition to binding the ligand to its receptors, the receptors can be blocked to prevent ligand binding. When a substance binds to a receptor, the three-dimensional structure of the substance fits into the space formed by the three-dimensional structure of the receptor, like the head and cup.

[0112] The crystalline form D of the selective androgen receptor modulator can be an agonist. Thus, in one embodiment, the Crystalline D Forms of the SARMs of the present invention are useful for binding to and activating steroid hormone receptors. The agonist compound can be an agonist that binds to an androgen receptor. The compound may have high affinity for the androgen receptor. The agonist compound may also exhibit anabolic activity. Thus, crystalline form D may have the agonistic and anabolic activity of a non-steroidal compound for the androgen receptor.

[0113] The crystalline form D of the selective androgen receptor modulator compounds can be an antagonist. Thus, in one embodiment, Crystalline Form D may be useful for binding to and inactivating steroid hormone receptors. In another embodiment, the solid form D of the invention may have high affinity for the androgen receptor. In another embodiment, Solid Form D according to the subject invention may also exhibit anabolic activity. In another embodiment, the solid D form of the SARM compound may bind irreversibly to the androgen receptor. In another embodiment, the SARM solid form D is an alkylating agent.

The crystalline polymorphic form D of the compound (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide according to the present invention can be classified as being a partial agonist / antagonist of AR. The solid forms of SARMs act as AR agonists in some tissues and cause increased transcription of genes responsible for AR action (e.g. muscle anabolic effect). In other tissues, these compounds serve as AR inhibitors to prevent the agonistic effects of native androgens.

[0115] Assays to determine whether compounds are AR agonists or antagonists are well known to those skilled in the art. For example, AR agonist activity can be determined by monitoring the ability of the solid form D of the SARM compound to maintain and / or stimulate the growth of AR-containing tissue, such as prostate and seminal vesicle tissues, as measured by weight. The AR antagonist activity can be determined by monitoring the ability of a SARM compound having polymorphic form D to inhibit the growth of tissue containing AR.

[0116] In another embodiment, the solid D form of the SARM compound binds irreversibly to the androgen receptor of a mammal, for example a human. Thus, a compound of the present invention may contain a functional group (e.g., an affinity tag) that allows alkylation of the androgen receptor (i.e., formation of a covalent bond). Thus, in this case, the compounds are alkylating agents that bind irreversibly to the receptor and therefore cannot be replaced

By a steroid such as endogenous DHT ligands and testosterone. An alkylating agent is defined herein as an agent that alkylates (forms a covalent bond) of a cellular component, such as DNA, RNA, or a protein. It is a highly reactive chemical that introduces alkyl radicals into biologically active molecules and thus prevents them from working properly. An alkylating moiety is an electrophilic group that interacts with nucleophilic molecules in cellular components.

[0117] According to one embodiment, the crystalline form D of the SARM compound of the present invention can bind to an androgen receptor. The binding of the crystalline polymorph D to the androgen receptor enables its use in many hormone therapies.

[0118] In one embodiment, the crystalline polymorphic form D of the compound (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide can be the only active ingredient. However, it is also within the scope of the present invention to prepare a medicament for hormone therapy, which includes the use of the crystalline polymorphic form D in combination with one or more medicaments. Such agents include, but are not limited to: LHRH analogues, reversible antiandrogens, antiestrogens, anti-cancer drugs, 5-alpha reductase inhibitors, aromatase inhibitors, progestins, agents acting through other nuclear hormone receptors, selective estrogen receptor modulators (SERMs), progesterone, estrogen, inhibitors PDE5, apomorphine, bisphosphonate, and one or more solid SARMS forms, for example one with AR agonist activity.

[0119] Thus, in various embodiments, the present invention provides compositions and pharmaceutical compositions comprising the crystalline polymorph D of compound (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy). ) -2-hydroxy-2-methylpropanamide, in combination with an LHRH analog, reversible anti-androgen, anti-estrogen, anti-cancer drug, 5-alpha-reductase inhibitor, aromatase inhibitor, progestin, agents acting through other nuclear hormone receptors, selective estrogen receptor modulators (SERMs), progesterone, estrogen, PDE5 inhibitor, apomorphine, bisphosphonate, or in combination with one or more additional SARM compounds.

[0120] The following examples are provided to more fully illustrate the preferred embodiments of the invention.

DETAILS EXPERIMENTAL PART

EXAMPLE 1: SYNTHESIS OF COMPOUND S-1

[0121] (2R) -1-Methacryloylpyrrolidine-2-carboxylic acid. D-proline, (14.93 g, 0.13 mol) was dissolved in 71 mL of 2N NaOH and cooled in an ice bath; the resulting alkaline solution was diluted with acetone (71 ml). An acetone solution (71 ml) of methacryloyl chloride (13.56 g, 0.13 mol) and a 2N NaOH solution (71 ml) were simultaneously added over 40 minutes to the aqueous solution of D-proline in an ice bath. The pH of the mixture was kept at 10-11 ° C during the addition of methacryloyl chloride. After stirring (3 hours, room temperature), the mixture was evaporated in vacuo at 35-45 ° C to remove acetone. The resulting solution was washed with diethyl ether and acidified to pH 2 with concentrated HCl.

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The acidic mixture was saturated with NaCl and extracted with EtOAc (100 mL × 3). The combined extracts were dried over Na2SO4, filtered through celite and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexane afforded 16.2 (68%) of the desired compound as colorless crystals: mp 102-103 ° C (lithium). [214] mp 102.5-103.5 ° C); the NMR spectrum of this compound showed the existence of two conformational isomers of the title compound.¹H-NMR (300 MHz, DMSO-d6) δ 5.28 (s) and 5.15 (s) for the first conformational isomer, 5.15 (s) and 5.03 (s) for the second conformational isomer (sum of 2H , for both isomers, vinyl CH2), 4.48-4.44 for the first conformational isomer, 4.24-4.20 (m) for the second conformational isomer (sum of 1H, for both isomers, CH at the chiral center), 3 , 57-3.38 (m, 2H, CH2), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH2, CH Me); ¹³C-NMR (75 MHz, DMSO-d6) δ for the major conformational isomer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19, 5: for the minor conformational isomer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C = O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm^-1; [α] ο²⁶+ 80.8 ° (c = 1, MeOH); Elemental analysis calculated for C9H13Nr3: C 59.00, H 7.15, N 7.65. Found: C 59.13, H 7.19, N 7.61

<img file="PL2205552T3_D0029.tif" />

(3R, 8aR) -3-Bromomethyl-3-methyltetrahydropyrrolo [2,1-c] [1,4] oxazine-1,4-dione. A solution of NBS (23.5 g, 0.132 mol) in 100 ml of DMF was added dropwise under stirring to a solution of (methyl-acryloyl) pyrrolidine (16.1 g, 88 mmol) in 70 ml of DMF under argon at room temperature, and the mixture thus obtained stirred for 3 days. The solvent was removed in vacuo resulting in a yellow solid to precipitate. The solid was suspended in water, stirred overnight at room temperature, filtered and dried to give the title compound 18.6 (81%) (less weight on drying ~ 34%) as a yellow solid: mp 152-154 ° C (lithium). [214] mp 107-109 ° C for the S isomer); 1H-NMR (300 MHz, DMSO-d6) δ 4.69 (dd, J = 9.6 Hz, J = 6.7 Hz, 1H, CH at the chiral center), 4.02 (d, J = 11, 4 Hz, 1H, CHHa), 3.86 (d, J = 11.4 Hz, 1H, CHHb), 3.53-3.24 (m, 4H, CH2), 2.30-2.20 (m , 1H, CH), 2.04-1.72 (m, 3H, CH2 and CH), 1.56 (s, 2H, Me);¹³C-NMR (75 MHz, DMSO-d6) δ 167.3, 163.1, 83.9, 57.2, 45.4, 37.8, 29.0, 22.9, 21.6; IR (KBr) 3474, 1745 (C = O), 1687 (C = O), 1448, 1377, 1360, 1308, 1227, 1159, 1062 cm^-1; [α,] ϋ²⁶ + 124.5 ° (c = 1.3, chloroform); Elemental analysis calculated for C8H12BrNO3: C 41.24, H 4.61, N 5.34. Found: C 41.46, H 4.64, N 5.32.

<img file="PL2205552T3_D0030.tif" />

(R) -3-Bromo-2-hydroxy-2-methylpropanoic acid

[0123] (2R) -3-Bromo-2-hydroxy-2-methylpropanoic acid. A mixture of bromolactone (18.5 g, 71 mmol) in 300 mL of 24% HBr was refluxed for 1 hour. The resulting solution was diluted with brine (200 ml) and extracted with ethyl acetate (100 ml × 4). The combined extracts were washed with saturated NaHCOe solution (100 mL x 4). The aqueous solution was acidified with concentrated

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HCl to pH = 1 which was subsequently extracted with ethyl acetate (100 mL x 4). The combined organic solution was dried over Na2SO4, filtered through celite and evaporated in vacuo to dryness. Recrystallization from toluene provided 10.2 g (86%) of the desired compound as colorless crystals: mp. 107-109 ° C (m.p. 109-113 ° C for the S isomer); 1H-NMR (300 MHz, DMSO-d6) δ 3.63 (d, J = 10.1 Hz, 1H, CHHa), 3.52 (d, J = 10.1 Hz, 1H, CHHb), 1, 35 (s, 3H, Me); IR (KBr) 3434 (OH), 3300-2500 (COOH), 1730 (C = O), 1449, 1421, 1380, 1292, 1193, 1085 cm^-1; [a,] D²⁶+ 10.5 ° (c = 2.6, MeOH); Elemental analysis calculated for C4H7BrOs: C 26.25, H 3.86. Found: C 26.28, H 3.75.

<img file="PL2205552T3_D0031.tif" />

[0124] Synthesis of (2R) -3-bromo-N- [4-cyano-3- (trifluoromethyl) phenyl] -2-hydroxy-2-methylpropanamide. Thionyl chloride (46.02 g, 0.39 mol) was added dropwise to a cooled solution (below 4 ° C) of compound 6 (51.13 g, 0.28 mol) in 300 ml of THF under an argon atmosphere. The resulting mixture was stirred for 3 hours under the same conditions. Thereto was added Et3N (39.14 g, 0.39 mol) and stirred for 20 minutes under the same conditions. After 20 minutes, 5-amino-2-cyanobenzotrifluoride (40.0 g, 0.21 mol), 400 mL of THF was added and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure to give a solid which was treated with 300 mL of H 2 O, extracted with EtOAc (2 X 400 mL). The combined organic extracts were washed with saturated NaHCO3 solution (2 x 300 ml) and brine (300 ml). The organic layer was dried over MgSO4 and concentrated under reduced pressure to give a solid which was purified by column chromatography using CH2Cl2 / ethyl acetate (80:20) to give a solid. The solid thus obtained was recrystallized from CH2Cl2 / hexane to obtain 55.8 g (73.9%) of (2 R) -3-bromoN- [4-cyano-3- (trifluoromethyl) phenyl] -2-hydroxy-2-methylpropanamide in as a pale yellow solid.

[0125] ¹H NMR (CDCl3 / TMS), δ 1.66 (s, 3H, CH₃), 3.11 (s, 1H, OH), 3.63 (d, J = 10.8 Hz, 1H, C H2), 4.05 (d, J = 10.8 Hz, 1H, C H2) , 7.85 (d, J = 8.4 Hz, 1H, Ar H), 7.99 (dd, J = 2.1.8.4 Hz, 1H, Ar H), 8.12 (d, J = 2.1 Hz, 1H, Ar H), 9.04 (bs, 1H, NH). Calcd. Mass: 349.99, [MH]^-349.0. Mp: 124-126 ° C.

<img file="PL2205552T3_D0032.tif" />

(2R) -3-bromo-N- [4-cyano-3 (trifluoromethyl) phenyl] -2-hydroxy2-methylpropanamide

<img file="PL2205552T3_D0033.tif" />

(S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxymethylpropanamide

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Synthesis of (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide. A mixture of bromoamide ((2R) -3-bromo-N- [4-cyano-3- (trifluoromethyl) phenyl] -2-hydroxy-2-methylpropanamide, 50 g, 0.14 mol), anhydrous K2CO3 (59.04 g, 0 , 43 mol) and 4-cyanophenol (25.44 g, 0.21 mol) in 500 ml of 2-propanol was refluxed for 3 hours and then concentrated under reduced pressure to obtain a solid. The resulting residue was treated with 500 mL of H 2 O and then extracted with EtOAc (2 x 300 mL). The combined EtOAc extracts were washed with 10% NaOH (4 x 200 mL) and brine. The organic layer was dried over MgSO4 then concentrated in vacuo to give an oil that was treated with 300 mL of ethanol and activated charcoal. The reaction mixture was refluxed for 1 hour, then the hot mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to provide an oil. The oil was purified by column chromatography using CH2Cl2 / ethyl acetate (80:20) to give an oil which was crystallized from CH2Cl2 / hexane to yield 33.2 g (59.9%) of (S) -N- (4- cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide in the form of a colorless solid (wadded).¹H NMR (CDCl3 / TMS), δ 1.63 (s, 3H, CH3), 3.35 (s, 1H, OH), 4.07 (d, J = 9.04Hz, 1H, CH), 4 , 51 (d, J = 9.04 Hz, 1H, CH), 6.97-6.99 (m, 2H Ar H), 7.57-7.60 (m, 2H, Ar H), 7, 81 (d, J = 8.55 Hz, 1H, Ar H), 7.97 (dd, J = 1.95, 8.55 Hz, 1H, Ar H), 8.12 (d, J = 1, 95 Hz, 1H, Ar H), 9.13 (bs, 1H, NH). Calcd. Mass: 389.10, [MH]^-388.1. Mp: 92-94 ° C.

EXAMPLE 2: Crystallization of S-1 SARM

Materials and methods

Methods:

X-ray powder diffractometry (XRPD)

[0127] The XRPD method was used to determine the crystal structure or recognition of liquid crystals in partially crystalline mixtures. XRPD measurements were made using a PANalytical X-ray PW 1710 X-ray diffractometer in which the anode of the lamp was copper with K-alpha radiation. Image was acquired in step scan mode (step size 0.02 ° 2θ, pulse counting time 2.4 sec / step). The sample was measured without any special treatment except for applying light pressure to obtain a flat surface. Measurements were performed under ambient conditions.

Raman spectroscopy

[0128] FT-Raman spectra were recorded on a Bruker RFS 100 spectrophotometer using a Nd: YAG laser operating in the near infrared at 1064 nm and a liquid nitrogen cooled germanium detector. For each sample, 64 scans with a resolution of 2 cm¹. The laser power was 100 mW. Raman measurements were performed using aluminum sample holders or hermetically sealed glass tubes at room temperature.

Thermogravimetry coupled with Infrared Spectroscopy (TG-FTIR) and thermogravimetric analysis

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[0129] The TG-FTIR instrument consists of a Thermogravimetric Analyzer (TG) coupled to an Infrared Fourier Spectrometer (FTIR) for analyzing evolved gases such as H2O gases by measuring their mass loss in combination with the characteristics of the evolved components. Thermogravimetric measurements were carried out using the NETZSCH Thermo-Microbalance TG 209 device coupled with a Brukera Vector 22 FTIR spectrometer. The samples in the pans with holes were tested under a N2 atmosphere, with a heating rate of 10 K / min, in the temperature range from 25 to 250 ° C. Additional thermogravimetric analysis was performed with a TA Instruments Q500 TGA under various conditions.

Differential Scanning Calorimetry (DSC)

[0130] The thermal analysis was performed using a Perkin Elmer DSC7 calorimeter under the following experimental conditions: sample weight 3 to 6 mg, placed in closed gold crucibles, temperature range -50 ° C to 120 ° C, with a heating rate of 20 K / min. The samples were weighed in an atmosphere of air or dry N2. Additional thermal analysis was performed on a TA Instruments Q1000 DSC using airtight aluminum pans under various conditions.

Dynamic vapor sorption (DVS)

[0131] Quantification of vapor sorption isotherms under dynamic conditions is based on measuring the mass of water absorbed and then desorbed during the crystallization process. DVS measurements were performed to determine whether lot P1, P2 and P4 were hydrated polymorphs (Figure 9). The sample (13 to 14 mg) was placed in a Pt pan and the sample was allowed to equilibrate at 25 ° C / 50% RH before starting a predetermined humidity program (1.0 hour at 50%, 50% RH to 95% RH). : 5% a / h, 10 hours at 95% a / h, from 95% a / h to 0% ww: 5% a / h, 10 hours at 0% a / h, from 0% to 50% ww: 5% a / h , 1 hour at 50% above

Scanning electron spectroscopy (SEM)

[0132] Images of compound S-1 of the P1, P2 and P4 series (Fig. 8) were taken using a SEM CamScan CS24 apparatus.

Filtration

[0133] In the following experiments: slurry equilibration, precipitation, recrystallization, relative stability study and water solubility study, a filtration step was performed. Centrifuge filtering devices: Ultrafree-CL (0.22 µm), Millipore; The centrifuge or Eppendorf 5804R was used at 22 ° C, with a 2 minute centrifuge program at 3000 rpm.

High performance liquid chromatography (HPLC)

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[0134] HPLC was used to analyze the purity of the compound S-1. The HP 1090M HPLC instrument was used under the following conditions:

Column: Symmetry Shield RP18, 3.9 x 150 mm, 5 μm

Column temperature: 35 ° C

Injection volume: 10 μl

Solvent: acetonitrile + water 1: 1 v / v

Mobile phase A: 0.1% TFA - water

Mobile phase B: 0.1% TFA - acetonitrile

Flow rate: 1 ml / min.

Detection: UV at 271 nm

Working time: 21 min.

Retention time (S-1): 10.7 min.

Materials:

Solvents

[0135] Fluka or Merck grade solvents were used for all experiments. Water: deionized (Fluka # 95305)

Relationships

[0136] Compound S-1 was synthesized as described in Example 1.

Results:

[0137] Four series of compound S-1 were selected for characterization, respectively designated as (S-1-P1), (S-1P2), (S-1-P3) and (S-1-P4). Lots S-1-P1, S-1-P2 and S-1-P3 were single lots produced by the synthesis process described in Example 1. Lot S-1-P4 was a sample of lot S-1-P1 exposed to the conditions 40^aboutC / 75% relative humidity during storage. The following studies were performed to determine the stability, solubility, and characterization of the various solid forms of S-1.

[0138] The table below shows the X-ray diffraction results for form A of S-1 as shown in Fig. 4A:

<td>2Theta angle</td><td>Distance d value in Angstroms</td><td>The intensity of the reflexes in Cps</td><td>Reflection intensity in %%</td>

<td> 5,56</td><td> 15,9</td><td> 2250</td><td> 30</td>

<td> 7,47</td><td> 11,8</td><td> 470</td><td> 6</td>

<td> 8,61</td><td> 10,3</td><td> 1399</td><td> 19</td>

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<td> 9,93</td><td> 8,9</td><td> 3016</td><td> 40</td>

<td> 12,41</td><td> 7,1</td><td> 707</td><td> 9</td>

<td> 14,94</td><td> 5,93</td><td> 2647</td><td> 35</td>

<td> 16,66</td><td> 5,32</td><td> 6922</td><td> 92</td>

<td> 17,31</td><td> 5,12</td><td> 1049</td><td> 14</td>

<td> 18,03</td><td> 4,92</td><td> 397</td><td> 5</td>

<td> 18,52</td><td> 4,79</td><td> 930</td><td> 12</td>

<td> 19,25</td><td> 4,61</td><td> 830</td><td> 11</td>

<td> 19,83</td><td> 4,47</td><td> 823</td><td> 11</td>

<td> 20,63</td><td> 4,30</td><td> 740</td><td> 10</td>

<td> 21,80</td><td> 4,07</td><td> 988</td><td> 13</td>

<td> 22,33</td><td> 3,98</td><td> 7557</td><td> 100</td>

<td> 23,45</td><td> 3,79</td><td> 976</td><td> 13</td>

<td> 23,92</td><td> 3,72</td><td> 914</td><td> 12</td>

<td> 24,56</td><td> 3,62</td><td> 376</td><td> 5</td>

<td> 24,92</td><td> 3,57</td><td> 589</td><td> 8</td>

<td> 25,39</td><td> 3,51</td><td> 774</td><td> 10</td>

<td> 25,95</td><td> 3,43</td><td> 618</td><td> 8</td>

<td> 26,50</td><td> 3,36</td><td> 353</td><td> 5</td>

<td> 27,79</td><td> 3,21</td><td> 2123</td><td> 28</td>

<td> 28,80</td><td> 3,10</td><td> 734</td><td> 10</td>

<td> 29,68</td><td> 3,01</td><td> 410</td><td> 5</td>

<td> 30,07</td><td> 2,97</td><td> 656</td><td> 9</td>

<td> 30,49</td><td> 2,93</td><td> 423</td><td> 6</td>

<td> 31,42</td><td> 2,84</td><td> 391</td><td> 5</td>

<td> 32,49</td><td> 2,75</td><td> 330</td><td> 4</td>

<td> 33,66</td><td> 2,66</td><td> 431</td><td> 6</td>

<td> 34,78</td><td> 2,58</td><td> 444</td><td> 6</td>

[0139] The table below shows the X-ray diffraction results for form A + C of S-1 as shown in Fig. 12D, where the diffraction angles for form C were determined:

<td colspan="5">A mixture of Form A with Form C</td>

<td>Assigning non-diffractive reflections A</td><td>2Theta angle °</td><td>Distance d value in Angstroms</td><td>The intensity of the reflexes in Cps</td><td>Reflection intensity in%</td>

<td></td><td> 5,65</td><td> 15,6</td><td> 100</td><td> 41</td>

<td>sure</td><td> 6,89</td><td> 12,8</td><td> 7</td><td> 3</td>

<td></td><td> 7,43</td><td> 11,9</td><td> 8</td><td> 3</td>

<td></td><td> 8,68</td><td> 10,2</td><td> 42</td><td> 17</td>

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<td>likely</td><td> 9,46</td><td> 9,3</td><td> 25</td><td> 10</td>

<td></td><td> 9,94</td><td> 8,9</td><td> 111</td><td> 45</td>

<td></td><td> 11,20</td><td> 7,9</td><td> 7</td><td> 3</td>

<td></td><td> 12,60</td><td> 7,0</td><td> 12</td><td> 5</td>

<td>sure</td><td> 13,49</td><td> 6, 6</td><td> 9</td><td> 4</td>

<td></td><td> 14,89</td><td> 5,95</td><td> 82</td><td> 33</td>

<td></td><td> 15,17</td><td> 5,84</td><td> 22</td><td> 9</td>

<td>likely</td><td> 15,99</td><td> 5,54</td><td> 41</td><td> 17</td>

<td></td><td> 16,84</td><td> 5,26</td><td> 164</td><td> 67</td>

<td></td><td> 17,21</td><td> 5,15</td><td> 64</td><td> 26</td>

<td></td><td> 18,00</td><td> 4,92</td><td> 17</td><td> 7</td>

<td></td><td> 18,54</td><td> 4,78</td><td> 45</td><td> 18</td>

<td></td><td> 19,37</td><td> 4,58</td><td> 27</td><td> 11</td>

<td></td><td> 19,86</td><td> 4,47</td><td> 39</td><td> 16</td>

<td></td><td> 20,66</td><td> 4,29</td><td> 21</td><td> 9</td>

<td></td><td> 21,79</td><td> 4,08</td><td> 46</td><td> 19</td>

<td></td><td> 22,36</td><td> 3,97</td><td> 246</td><td> 100</td>

<td>sure</td><td> 22,84</td><td> 3,89</td><td> 52</td><td> 21</td>

<td></td><td> 23,53</td><td> 3,78</td><td> 46</td><td> 19</td>

<td></td><td> 23,91</td><td> 3,72</td><td> 38</td><td> 15</td>

<td></td><td> 24,84</td><td> 3,58</td><td> 16</td><td> 7</td>

<td></td><td> 25,41</td><td> 3,50</td><td> 37</td><td> 15</td>

<td></td><td> 26,15</td><td> 3,41</td><td> 14</td><td> 6</td>

<td></td><td> 26,60</td><td> 3,35</td><td> 12</td><td> 5</td>

<td></td><td> 27,89</td><td> 3,20</td><td> 60</td><td> 24</td>

<td></td><td> 28,86</td><td> 3,09</td><td> 31</td><td> 13</td>

<td></td><td> 30, 01</td><td> 2,98</td><td> 30</td><td> 12</td>

<td></td><td> 30,52</td><td> 2,93</td><td> 14</td><td> 6</td>

<td></td><td> 30,98</td><td> 2,88</td><td> 13</td><td> 5</td>

<td></td><td> 31,34</td><td> 2,85</td><td> 15</td><td> 6</td>

<td></td><td> 32,72</td><td> 2,73</td><td> 14</td><td> 6</td>

<td></td><td> 33,93</td><td> 2,64</td><td> 15</td><td> 6</td>

<td></td><td> 34,84</td><td> 2,57</td><td> 15</td><td> 6</td>

[0140] In one embodiment, form C has additional diffraction lines that coincide with the signals for form A.

[0141] Finding the positions of the reflexes and calculating the d-value were performed with EVA software version 10, 0, 0, 0, the software removed Cu Kalfa2 and only lines up to 35 ° 2theta are shown.

[0142] The PP148-P1 sample was measured in a 0.1mm sample holder on a PANalytical PW1710 diffractometer.

[0143] Sample PP148-P52 was measured in a 0.1 mm diameter holder on a Bruker D8 Advance diffractometer.

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[0144] The table below shows the X-ray diffraction results for form D of S-1 as shown in Fig. 18 (bottom):

<td>2-Theta angle</td><td>The value of the distance d In Angstroms</td><td>The intensity in Cps</td><td>I / Imax</td>

<td> 4,42</td><td> 19,99</td><td> 17733</td><td> 100,0</td>

<td> 8,48</td><td> 10,41</td><td> 3026</td><td> 17,1</td>

<td> 8,80</td><td> 10,04</td><td> 1755</td><td> 9,9</td>

<td> 11,35</td><td> 7,79</td><td> 4598</td><td> 25,9</td>

<td> 11,76</td><td> 7,52</td><td> 805</td><td> 4,5</td>

<td> 12,72</td><td> 6,96</td><td> 1462</td><td> 8,2</td>

<td> 13,84</td><td> 6,39</td><td> 8635</td><td> 48,7</td>

<td> 14,45</td><td> 6,13</td><td> 5597</td><td> 31,6</td>

<td> 14,64</td><td> 6,05</td><td> 9445</td><td> 53,3</td>

<td> 15,10</td><td> 5,86</td><td> 7013</td><td> 39,5</td>

<td> 16,14</td><td> 5,49</td><td> 1644</td><td> 9,3</td>

<td> 16,64</td><td> 5,32</td><td> 1678</td><td> 9,5</td>

<td> 16,95</td><td> 51,23</td><td> 2357</td><td> 13,3</td>

<td> 17,441</td><td> 5,09</td><td> 484</td><td> 2,7</td>

<td> 17,59</td><td> 5,04</td><td> 678</td><td> 3,8</td>

<td> 18,04</td><td> 4,91</td><td> 2308</td><td> 13,0</td>

<td> 18,71</td><td> 4,74</td><td> 3439</td><td> 19,4</td>

<td> 19,04</td><td> 4,66</td><td> 1824</td><td> 10,3</td>

<td> 19,46</td><td> 4,56</td><td> 4093</td><td> 23,1</td>

<td> 20,48</td><td> 4,33</td><td> 989</td><td> 5,6</td>

<td> 20,84</td><td> 4,26</td><td> 7616</td><td> 42,9</td>

<td> 22,15</td><td> 4,01</td><td> 5058</td><td> 28,5</td>

<td> 22,78</td><td> 3,90</td><td> 1933</td><td> 10,9</td>

<td> 23,15</td><td> 3,84</td><td> 3851</td><td> 21,7</td>

<td> 23,47</td><td> 3,79</td><td> 2352</td><td> 13,3</td>

<td> 23,88</td><td> 3,72</td><td> 5583</td><td> 31,5</td>

<td> 24,74</td><td> 3,60</td><td> 10043</td><td> 56,6</td>

<td> 24,94</td><td> 3,57</td><td> 5395</td><td> 30,4</td>

<td> 25,29</td><td> 3,52</td><td> 3149</td><td> 17,8</td>

<td> 25,67</td><td> 3,47</td><td> 1290</td><td> 7,3</td>

<td> 26,14</td><td> 3,41</td><td> 692</td><td> 3,9</td>

<td> 26,46</td><td> 3,37</td><td> 1095</td><td> 6,2</td>

<td> 27,80</td><td> 3,21</td><td> 2402</td><td> 13,5</td>

<td> 28,32</td><td> 3,15</td><td> 1565</td><td> 8,8</td>

<td> 28,64</td><td> 3,11</td><td> 998</td><td> 5,6</td>

<td> 28,90</td><td> 3,09</td><td> 1212</td><td> 6,8</td>

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<td> 29,38</td><td> 3,04</td><td> 3295</td><td> 18,6</td>

<td> 29,92</td><td> 2,98</td><td> 756</td><td> 4,3</td>

<td> 30,40</td><td> 2,94</td><td> 1278</td><td> 7,2</td>

<td> 31,19</td><td> 2,87</td><td> 851</td><td> 4,8</td>

<td> 31,86</td><td> 2,81</td><td> 1270</td><td> 7,2</td>

<td> 32,49</td><td> 2,75</td><td> 775</td><td> 4,4</td>

<td> 32,82</td><td> 2,73</td><td> 920</td><td> 5,2</td>

<td> 33,66</td><td> 2,66</td><td> 842</td><td> 4,7</td>

<td> 34,50</td><td> 2,60</td><td> 977</td><td> 5,5</td>

<td> 35,80</td><td> 2,51</td><td> 638</td><td> 3,6</td>

<td> 36,06</td><td> 2,49</td><td> 700</td><td> 3,9</td>

<td> 36,83</td><td> 2,44</td><td> 777</td><td> 4,4</td>

<td> 37,16</td><td> 2,42</td><td> 698</td><td> 3,9</td>

<td> 38,02</td><td> 2,36</td><td> 733</td><td> 4,1</td>

<td> 38,44</td><td> 2,34</td><td> 859</td><td> 4,8</td>

<td> 38,97</td><td> 2,31</td><td> 844</td><td> 4,8</td>

<td> 39,99</td><td> 2,52</td><td> 791</td><td> 4,5</td>

<td> 40,89</td><td> 2,21</td><td> 641</td><td> 3,6</td>

<td> 41,30</td><td> 2,18</td><td> 515</td><td> 2,9</td>

Water vapor sorption (humidity chamber)

[0145] The compound was stored in a glass tube at 96% r.h. in a humidity chamber at room temperature. After different storage times, Raman measurements were made using hermetically sealed glass test tubes. The results are shown in Table 1:

Table 1:

<td>The starting figure</td><td>Solvent</td><td>Concentration mg / ml</td><td>Conditions</td><td>Created character</td>

<td rowspan="4">AND</td><td rowspan="4"></td><td rowspan="4"></td><td>was stored in a moist chamber at 96% w / 23 ° C</td><td>(Powder)</td>

<td>4 weeks</td><td>A + a small amount of B 'characters</td>

<td>9 weeks</td><td>A + character B '</td>

<td>11 weeks</td><td>A + approx. 20% of B 'form (see Fig. 17A)</td>

<td rowspan="2">AND</td><td rowspan="2">water</td><td rowspan="2"> 111/5,0</td><td>23 ° C</td><td>(suspension)</td>

<td>sonicated 5 min.</td><td>(suspension)</td>

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<td></td><td></td><td></td><td>stirred 19 h / 37 ° C, filtered and air dried</td><td>B '(see Fig. 17B)</td>

<td rowspan="3">AND</td><td rowspan="3">water + 5% ethanol v / v</td><td rowspan="3"> 123/2,1</td><td>23 ° C</td><td>(suspension)</td>

<td>stirred for 3h / 83 ° C</td><td>sticky glutinous mass</td>

<td>cooled to 47 ° C for 1.5 hours, filtered and air dried</td><td>B '</td>

<td rowspan="2">AND</td><td rowspan="2">acetic acid / water 1: 2 v / v</td><td rowspan="2"> 138/2,0</td><td>23 ° C</td><td>(suspension)</td>

<td>stirred at 20h / 23 ° C, filtered and air dried</td><td>A (see Fig. 17C)</td>

<td rowspan="4">AND</td><td rowspan="4">water + 5% acetic acid v / v</td><td rowspan="4"> 105/2,0</td><td>23 ° C</td><td>(suspension)</td>

<td>stirred for 12 min / 40 ° C</td><td>(suspension)</td>

<td>sonicated for 2 min.</td><td>(suspension)</td>

<td>stirred 17h / 40 ° C cooled to room temperature and the solution was removed</td><td>sticky glutinous mass B '</td>

Approximate solubility measurement

[0146] To determine the approximate solubility at room temperature, solvent was gradually added to the solid material. The sample was mixed well after each addition. The solvent addition was continued until complete dissolution or until 15 ml of solvent was added. The solubilities of solid forms A and B 'at 23 ° C are shown in Table 2.

Table 2:

<td>Solvent</td><td>Permanent figure</td><td>Solubility (mg / ml)</td>

<td>ethanol</td><td>AND</td><td> &gt; 200</td>

<td>acetone</td><td>AND</td><td> &gt; 200</td>

<td>TBME</td><td>AND</td><td> &gt; 200</td>

<td>ethyl acetate</td><td>AND</td><td> &gt; 200</td>

<td>THF</td><td>AND</td><td> &gt; 200</td>

<td>acetonitrile</td><td>AND</td><td> &gt; 200</td>

<td>dichloromethane</td><td>AND</td><td> &gt; 200</td>

<td>1,4-dioxane</td><td>AND</td><td> &gt; 200</td>

<td>acetic acid</td><td>AND</td><td> &gt; 200</td>

<td>toluene</td><td>AND</td><td>&lt;6 cloudy solution</td>

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<td>ethanol / water 3: 1 v / v</td><td>AND</td><td> &gt; 200</td>

<td>ethanol / water 1: 1 v / v</td><td>AND</td><td> 50</td>

<td>ethanol / water 1: 3 v / v</td><td>AND</td><td> &lt; 5</td>

<td>ethanol / n-heptane 1: 1 v / v</td><td>AND</td><td> 180</td>

<td>ethanol / n-heptane 1: 3 v / v</td><td>AND</td><td> 50</td>

<td>acetone / n-heptane 1: 1 v / v</td><td>AND</td><td> &gt; 200</td>

<td>acetone / n-heptane 1: 3 v / v</td><td>AND</td><td> 90</td>

<td>THF / n-heptane 1: 1 v / v</td><td>AND</td><td> &gt; 200</td>

<td>THF / n-heptane 1: 3 v / v</td><td>AND</td><td> 65</td>

<td>acetonitrile / toluene 1: 1 v / v</td><td>AND</td><td> &gt; 200</td>

<td>acetonitrile / toluene 1: 3 v / v</td><td>AND</td><td> 170</td>

<td>ethyl acetate / n-heptane 1: 1 v / v</td><td>AND</td><td> 65</td>

<td>ethyl acetate / n-heptane 1: 2 v / v</td><td>AND</td><td> 9</td>

<td>ethyl acetate / n-heptane 1: 2 v / v</td><td>B '</td><td>&gt; 9 convert from solid to solid A</td>

<td>ethyl acetate / n-pentane 1: 2 v / v</td><td>AND</td><td> 13</td>

<td>ethyl formate / n-pentane 1: 2 v / v</td><td>AND</td><td> 12</td>

<td>methyl acetate / n-pentane 1: 2 v / v</td><td>AND</td><td> 8</td>

<td>ethyl acetate / n-heptane 1: 3 v / v</td><td>AND</td><td>&lt;5 cloudy solution</td>

Suspension equilibration tests

[0147] Suspension equilibration studies were performed using 81-128 mg of the compound. The suspensions were mixed with a magnetic stirrer. The samples obtained after filtration were dried in air at ambient temperature for a short time only to prevent possible desolvation of labile hydrates or solvates. The results of the suspension equilibration tests for solid forms A and B 'are presented in Table 3.

Table 3:

<td>The starting figure</td><td>Solvent</td><td>Concentration mg / ml</td><td>Conditions</td><td>Created character</td>

<td rowspan="2">AND</td><td rowspan="2">n-heptane</td><td rowspan="2"> 108/2,0</td><td>23 ° C</td><td>(suspension)</td>

<td>sonicated 5 min.</td><td>(suspension)</td>

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<td></td><td></td><td></td><td>stirred 17h / 37 ° C, filtered and air dried</td><td>A (see Fig. 10a)</td>

<td rowspan="3">AND</td><td rowspan="3">n-heptane + 5% ethanol v / v</td><td rowspan="3"> 117/2,1</td><td>23 ° C</td><td>(suspension)</td>

<td>sonicated 5 min.</td><td>(suspension)</td>

<td>stirred 18h ​​/ 37 ° C, filtered and air dried</td><td>AND</td>

<td rowspan="2">B '</td><td rowspan="2">ethyl acetate + n-heptane 1: 2 v / v</td><td rowspan="2"> 81/1,7</td><td>23 ° C</td><td>(suspension)</td>

<td>stirred for 2h / 23 ° C, filtered and air dried</td><td>A (see Fig. 10b)</td>

<td rowspan="2">AND</td><td rowspan="2">ethyl acetate + n-heptane 1: 2 v / v</td><td rowspan="2"> 124/2,0</td><td>23 ° C</td><td>(suspension)</td>

<td>stirred for 3 days / 23 ° C, filtered and air dried</td><td>AND</td>

<td rowspan="2">AND</td><td rowspan="2">ethyl acetate + n-heptane 1: 2 v / v</td><td rowspan="2"> 126/2,0</td><td>+ 2 ° C</td><td>(suspension)</td>

<td>stirred for 3 days / 2 ° C, filtered and air dried</td><td>AND</td>

<td rowspan="2">B '</td><td rowspan="2">ethyl acetate + npentane 1: 2 v / v</td><td rowspan="2"> 101/1,0</td><td>23 ° C</td><td>(suspension)</td>

<td>stirred 22h / 23 ° C, filtered and air dried</td><td>A (see Fig. 13c)</td>

<td rowspan="2">AND</td><td rowspan="2">ethyl acetate + npentane 1: 2 v / v</td><td rowspan="2"> 128/2,0</td><td>23 ° C</td><td>(suspension)</td>

<td>stirred 20 h / 23 ° C, filtered and air dried</td><td>A (see Fig. 10d)</td>

<td rowspan="2">AND</td><td rowspan="2">ethyl formate + npentane 1: 2 v / v</td><td rowspan="2"> 112/2,0</td><td>23 ° C</td><td>(suspension)</td>

<td>stirred at 20h / 23 ° C, filtered and air dried</td><td>A (see Fig. 10e)</td>

<td rowspan="2">AND</td><td rowspan="2">methyl acetate + npentane 1: 2 v / v</td><td rowspan="2"> 126/2,0</td><td>23 ° C</td><td>(suspension)</td>

<td>stirred at 20h / 23 ° C, filtered and air dried</td><td>A (see Fig. 10f)</td>

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[0148] Vapor diffusion studies were performed with a solution of the compound in various solvents. The solutions were placed in small, open containers which were stored in larger vessels containing miscible, volatile anti-solvents. Larger vessels were then sealed.

The anti-solvents diffused through the vapor phases into the solutions and saturation or supersaturation was achieved. The results of the vapor diffusion study for solid forms A and B 'are shown in Table 4.

Water vapor diffusion studies

Table 4:

<td>Solvent</td><td>Anti-solvent</td><td>Concentration mg / ml</td><td>Conditions</td><td>Created character</td>

<td>ethanol</td><td>n-hexane</td><td>204 mg P1 0.4 ml solvent</td><td>vapor diffusion, 23 ° C, 7 days, solution was removed</td><td>sticky glutinous mass</td>

<td>acetone</td><td>n-hexane</td><td>210 mg P1 0.5 ml solvent</td><td>vapor diffusion, 23 ° C, 7 days, solution was removed</td><td>sticky glutinous mass</td>

<td>TBME</td><td>n-hexane</td><td>205 mg P 1 0.6 ml solvent</td><td>vapor diffusion, 23 ° C, 7 days, solution was removed</td><td>sticky glutinous mass</td>

<td>ethyl acetate</td><td>n-hexane</td><td>206 mg P 1 0.6 ml solvent</td><td>vapor diffusion, 23 ° C, 2 days, filtered and air dried</td><td>very similar to the character A</td>

<td>THF</td><td>n-hexane</td><td>212 mg P1 0.6 ml solvent</td><td>vapor diffusion, 23 ° C, 7 days, solution was removed</td><td>sticky glutinous mass</td>

<td>toluene</td><td>n-hexane</td><td>44 mg P1 2.0 ml solvent</td><td>vapor diffusion, 23 ° C, 2 days, solution was removed</td><td>very similar to form A (see Fig. 11A)</td>

<td>dichloromethane</td><td>n-hexane</td><td>204 mg P1 1.6 ml solvent</td><td>vapor diffusion, 23 ° C, 2 days, solution was removed</td><td>very similar to the character A</td>

<td>1,4-dioxane</td><td>n-hexane</td><td>215 mg P1 0.5 ml solvent</td><td>vapor diffusion, 23 ° C, 7 days, solution was removed</td><td>sticky glutinous mass</td>

<td>acetic acid</td><td>water</td><td>219 mg P1 0.3 ml solvent</td><td>vapor diffusion, 23 ° C, 7 days, solution was removed</td><td>very similar to</td>

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<td></td><td></td><td></td><td></td><td>Form A (see Figure 11B)</td>

<td>acetonitrile</td><td>water</td><td>212 mg P1 0.4 ml solvent</td><td>vapor diffusion, 23 ° C, 6 days, the solution was removed</td><td>sticky glutinous mass</td>

Evaporation Study

[0149] The compound solutions were dried at room temperature (under a stream of dry nitrogen) without stirring. The results of the evaporation test for solid form A are shown in Table 5.

Table 5:

<td>The starting figure</td><td>Solvent</td><td>Concentration mg / ml</td><td>Conditions</td><td>Created character</td>

<td rowspan="2">AND</td><td rowspan="2">ethanol</td><td rowspan="2"> 100/2,0</td><td>23 ° C</td><td>(solution)</td>

<td>evaporated (under dry N2) for 2 days / 23 ° C</td><td>B</td>

<td rowspan="2">AND</td><td rowspan="2">ethyl acetate</td><td rowspan="2"> 109/2,0</td><td>23 ° C</td><td>(solution)</td>

<td>evaporated (under dry N2) for 1 day / 23 ° C</td><td>very similar to form A (see Fig. 12A)</td>

<td rowspan="2">AND</td><td rowspan="2">THF</td><td rowspan="2"> 183/2,0</td><td>23 ° C</td><td>(solution)</td>

<td>evaporated (under dry N2) for 5 days / 23 ° C</td><td>A + C (see Fig. 12B)</td>

Precipitation study

[0150] Precipitation studies were performed using 42-79 mg of the compound. A non-dissolving solvent was added to the solution. Samples obtained after filtration (glass funnel with a P4 frit) were air dried at ambient temperature and only for a short time to prevent possible desolvation of labile hydrates or solvates. The results from the solid form A precipitation studies are shown in Table 6.

Table 6:

<td>The starting figure</td><td>Solvent</td><td>Concentration mg / ml</td><td>Conditions</td><td>Created character</td>

<td rowspan="2">AND</td><td rowspan="2">ethanol</td><td> 79/0,2</td><td>23 ° C</td><td>(solution)</td>

<td> 79/1,2</td><td>1.0 ml of n-heptane was added</td><td>(with phase division)</td>

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<td></td><td></td><td></td><td>stored 11 weeks / - 20 ° C; the solution was removed and the solid residue was dried (N2 43 ml / min) for 50 min at RT.</td><td>very similar to the character A</td>

<td rowspan="3">AND</td><td rowspan="3">ethyl acetate</td><td> 42/0,2</td><td>23 ° C</td><td>(solution)</td>

<td rowspan="2"> 42/1.2</td><td>1.0 ml of n-heptane was added</td><td>(sticky sticky mass)</td>

<td>stirred 14h / 40 ° C, filtered and air dried</td><td>AND</td>

<td rowspan="3">AND</td><td rowspan="3">THF</td><td> 62/0,2</td><td>23 ° C</td><td>(solution)</td>

<td rowspan="2"> 62/1,2</td><td>1.0 ml of n-heptane was added</td><td>(sticky sticky mass)</td>

<td>stirred 14h / 40 ° C, filtered and air dried</td><td>AND</td>

<td rowspan="3">AND</td><td rowspan="3">dichloromethane</td><td> 75/0,3</td><td>23 ° C</td><td>(solution)</td>

<td rowspan="2"> 75/1,2</td><td>1.0 ml of n-heptane was added</td><td>(sticky sticky mass)</td>

<td>stirred all the time at 13h / 40 ° C, filtered and air dried</td><td>AND</td>

Recrystallization from solution

[0151] The compound was dissolved in various solvent systems at room temperature and cooled to + 5 ° C or to -20 ° C. Samples obtained after filtration (glass funnel with a P4 frit) were air dried at ambient temperature for a short time to prevent possible desolvation of labile hydrates or solvates.

[0152] The results of the solid form A recrystallization experiments are shown in Table 7.

Table 7:

<td>The starting figure</td><td>Solvent</td><td>Concentration mg / ml</td><td>Conditions</td><td>Created character</td>

<td>AND</td><td>ethanol + n-heptane 1: 1 v / v</td><td> 72/0,4</td><td>23 ° C</td><td>(solution)</td>

<td></td><td></td><td></td><td>Stored for 4 weeks / + 5 ° C; filtered, washed</td><td>AND</td>

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<td></td><td></td><td></td><td>(n-heptane) and air dried</td><td></td>

<td rowspan="2">AND</td><td rowspan="2">ethyl acetate + n-heptane 1: 1 v / v</td><td rowspan="2"> 80/1,2</td><td>23 ° C</td><td>(solution)</td>

<td>Stored for 4 weeks / - 20 ° C; filtered and air dried</td><td>very similar to form A (see Fig. 13A)</td>

<td rowspan="2">AND</td><td rowspan="2">acetonitrile + toluene 1: 1 v / v</td><td rowspan="2"> 91/0,2</td><td>23 ° C</td><td>(solution)</td>

<td>stored for 4 weeks / -20 ° C; the solution was removed and the solid residue was dried (N2 43 ml / min) for 212 min at RT.</td><td>very similar to the character A</td>

<td rowspan="2">AND</td><td rowspan="2">ethanol + n-heptane 1: 3 v / v</td><td rowspan="2"> 52/0,4</td><td>23 ° C</td><td>(solution)</td>

<td>Stored for 1 day / + 5 ° C; filtered, washed (n-heptane) and air dried</td><td>AND</td>

<td rowspan="2">AND</td><td rowspan="2">acetonitrile + toluene 1: 3 v / v</td><td rowspan="2"> 65/0,4</td><td>23 ° C</td><td>(solution)</td>

<td>Stored for 4 weeks / - 20 ° C; filtered and air dried</td><td>very similar to form A (see Fig. 16B)</td>

Lyophilization test

[0153] The compound was dissolved in 1,4-dioxane and the solution was cooled to -50 ° C. During solvent sublimation, the solids temperature was &lt;0 ° C as shown in Table 8:

Table 8:

<td>The starting figure</td><td>Solvent</td><td>Concentration mg / ml</td><td>Conditions</td><td>Created character</td>

<td rowspan="3">A PP148-P1</td><td rowspan="3">1,4-dioxane</td><td rowspan="3"> 102/2,0</td><td>23 ° C</td><td>(solution)</td>

<td>lyophilized &lt;0 ° C</td><td>sticky glutinous mass</td>

<td>stored for 12 days / room temperature</td><td>very similar to form A (see Fig. 14)</td>

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[0154] The sample was dried overnight under an atmosphere of dry N2 at room temperature, after which the sample cup for DSC was closed.

[0155] The results are included in Table 9:

Drying test

Table 9:

<td>The starting figure</td><td>mg</td><td>Conditions</td><td>DSC</td>

<td>B '</td><td>3.6 mg</td><td>dried overnight at 23 ° C (weight loss 1.0%)</td><td>Fig. 15</td>

Cooling and reheating studies in the melting study

[0156] After heating in the DSC assay to 120 ° C, the samples were cooled to -50 ° C and reheated to 120 ° C. The results are summarized in Table 10:

Table 10:

<td>The starting figure</td><td>mg</td><td>Conditions</td><td>DSC</td>

<td>AND</td><td>3.4 mg</td><td>quickly cooled to -50 ° C, heated: from -50 ° C to 120 ° C / 20 K / min, quickly cooled to -50 ° C reheated: from - 50 ° C to 120 ° C / 20 K / min</td><td>Fig. 7A</td>

<td>PP148-P2</td><td>4.4 mg</td><td>quickly cooled to -50 ° C, heated: from -50 ° C to 120 ° C / 20 K / min, quickly cooled to -50 ° C reheated: from - 50 ° C to 120 ° C / 20 K / min</td><td>Fig. 7B</td>

<td>AND</td><td>3.4 mg</td><td>quickly cooled to -50 ° C, heated: from -50 ° C to 120 ° C / 20 K / min, quickly cooled to -50 ° C reheated: from - 50 ° C to 120 ° C / 20 K / min</td><td>Fig. 7C</td>

<td>B '</td><td>2.9 mg</td><td>quickly cooled to -50 ° C, heated: from -50 ° C to 120 ° C / 20 K / min, quickly cooled to -50 ° C reheated: from - 50 ° C to 120 ° C / 20 K / min</td><td>Fig. 7D</td>

Relative stability studies

[0157] Suspension studies were performed using 130-145 mg of the compound. The suspensions were stirred with a magnetic stirrer and filtered after a specified time. Samples obtained after filtration (glass funnel with a P4 frit) were dried in air at ambient temperature. The results are shown in Table 11:

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Table 11:

<td>The starting figure</td><td>Solvent</td><td>Concentration mg / ml</td><td>Conditions</td><td>Created character</td>

<td rowspan="2">AND</td><td rowspan="2">ethyl acetate / n-heptane 1: 2 (v / v)</td><td rowspan="2">about. 130 / 2.0</td><td>23 ° C</td><td>(suspension)</td>

<td>stirred for 3 days / 23 ° C; filtered and air dried</td><td>A (see Fig. 16A)</td>

<td rowspan="2">AND</td><td rowspan="2">ethyl acetate / n-heptane 1: 2 (v / v)</td><td rowspan="2"> (81 + 64)/2,0</td><td>23 ° C</td><td>(suspension)</td>

<td>stirred for 1 day / 23 ° C; filtered and air dried</td><td>A (see Fig. 16B)</td>

Water solubility of solid forms A and B '

[0158] The solid form suspensions (25 or 50 mg in 3.5 or 7.0 ml double-distilled water) were shaken (800 rpm) and filtered after 0.5 hour, 1.5 hours, 4 hours and 20 hours. After filtration, the solid residue was checked by Raman spectroscopy and the concentration in the clear solution was determined by HPLC.

[0159] The solubility of solid form A of compound S-1 in water at 22 ° C is shown in Table 12:

Table 12:

<td>Suspension equilibration time [h]</td><td>Solubility ^and)[mg / 1000ml]</td><td>Permanent residue ^b)</td>

<td> 0,5</td><td> 21,0 ± 3,9</td><td>A + B '(about 95% + 5%)^c)</td>

<td> 1,5</td><td> 24,0 ± 1,4</td><td>A + B ' (about 90% + 10%)^c&gt;</td>

<td> 4,0</td><td> 27,6 ± 1,5</td><td>A + B ' (around 85% + 15%)^c)</td>

<td> 20</td><td> 24,5 ± 1,7^d)</td><td>A + B ' (around 75% + 25%)^c&gt;</td>

<td colspan="3">a) Mean value of two measurements (± standard deviation) b) Raman spectra measurements c) Estimated data d) pH value of the solution: 8.7</td>

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[0160] The water solubility of form B 'of compound S-1 at 22 ° C is shown in Table 13:

Table 13:

<td>Suspension equilibration time [h]</td><td>Solubility ^and&gt; [mg / 1000ml]</td><td>Permanent residue ^b)</td>

<td> 0,5</td><td> 27,4 ± 0,9</td><td>B '</td>

<td> 1,5</td><td> 27,3 ± 0,8</td><td>B '</td>

<td> 4,0</td><td> 25,6 ± 0,1</td><td>B '</td>

<td> 20</td><td> 26,7 ± 0,3^c)</td><td>B '</td>

<td colspan="3">a) Mean value of two measurements (± standard deviation) b) Raman spectra measurements c) Estimated data d) pH value of the solution: 8.7</td>

Characterization of Form A of S-1 -P1

[0161] The starting material for the polymorphism study, lot No. S-1 -P1, is crystalline and in crystalline form A. TG-FTIR analysis shows that the weight loss up to 200 ° C is very low (&lt;0.2%) and therefore series S -1 - P1 is not a hydrate or a solvate. Lot No. S -1 - P1 melts at 82 ° C (DSC peak temperature, heating rate 20 K / min). After melting and quenching to -50 ° C in DSC, an anhydrous liquid crystal form is produced. The sample showed a phase-conversion temperature of about 52 ° C and did not recrystallize on heating in DSC. The S -1 - P1 series may contain a small amount (about 5%) of the B 'or B form.

[0162] Measurement of the DVS of Form A at 25 ° C shows no evidence of classical hydrate formation under the experimental conditions used. The maximum water content at 93% relative humidity is 1.5%. The very slight hysteresis is most likely due to a sticky layer (possibly consisting of solid form B ') on the surface of the particles which affects the rate of water exchange. In fact, after storage of Form A at a relative humidity of 96% at room temperature for 11 weeks, Raman spectroscopy and DSC showed formation of approximately 20% of Form B '.

Characteristics of the solid form B '

[0163] Studies by DSC and XRPD indicate that the solid form produced when the solid form A was stored at 40 ° C and 75% relative humidity. (lot S-1-P4; 40 ° C / 75% r.h.) is a paracrystalline form with a limited order in the lower range. This limited ordering most likely corresponds to the endothermic peak in the DSC at about 55 ° C and the broad shoulder at about 17 ° in the diffraction pattern. A solid embodiment of batch S-1-P4 at 40 ° C / 75% relative humidity is Form B '.

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[0164] The behavior in the DVS study of solid form B 'at 25 ° C is not typical hydrate sorption behavior. The maximum water content at 94% relative humidity is approximately 2.4%. Although some hysteresis is observed, there is no clear threshold on the sorption curve that would clearly indicate the existence of a classical hydrate.

Formation of the solid form B '

[0165] In addition to the observed high relative humidity conversion, solid form B 'can be prepared by stirring a slurry of solid form A in water at 37 ° C overnight.

Formation of the solid form B

[0166] The routes to produce solid form B are melting and cooling the molten material and slowly evaporating the solutions in solvents such as ethanol. Polymorph B can be prepared from polymorphs A and D by heating above their respective melting points of 80 ° C and 130 ° C. Forms B 'and B cannot be distinguished by any of the analytical methods used so far, but can be distinguished based on their paths of formation. Form B 'is assigned a lyotropic liquid crystal form due to the solvent mediated formation, while Form B is assigned a thermotropic liquid crystal form due to the thermal preparation process. Evaporation of drug from solvents such as ethanol without anti-solvent also produces form B.

Formation of the solid form C.

[0167] Polymorph C can only be obtained as a mixture with polymorph A by dissolving and then evaporating the drug with THF at ambient temperature.

Formation of the solid form D

[0168] Polymorph D was initially prepared by crystallization from a solvent / anti-solvent mixture at 50 ° C, using ethyl acetate and cyclohexane as solvent and anti-solvent, respectively. Form D can also be made from other polymorphs by inoculating a sample with a small amount of Form D and storing at 110 ° C / 0% rt for 7 days or at 50 ° C in water for 24 hours and drying.

Formation of a solid solvate with toluene

[0169] The toluene solvate was prepared by any method of crystallization using a solvent / anti-solvent in which toluene was used as an anti-solvent.

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Water solubility of solid forms A and B '

[0170] The solubility of Form A and B 'of Compound S-1 in water at 22 ° C is 24.0 ± 1.4 mg / 1000 ml and 27.3 ± 0.8 mg / 1000 ml, the values ​​were obtained for 1.5 at the time of equilibration of the suspension. The solubilities are very similar due to the rapid conversion of form A to form B 'on the particle surface during the dissolution experiments.

Characteristics of the different series of the solid form A

[0171] Samples of lots S-1-P1, S-1-P2 and S-1-P3 show the same diffraction pattern. DSC measurements show that they most likely contain a few% of B 'or B' solids as indicated by a change in heat capacity at about 50 ° C. Sample S-1-P2 shows the highest level of solid form B 'or B (approx. 20%). To better understand the DSC results, electron micrographs (SEM) were performed for samples S-1-P1 and S-1-P2. While the images of sample S-1-P1 show quite well formed particles, the images of sample S-1-P2 show a partial conversion, possibly caused by too high a drying temperature or partial contact with water. Partial formation of solid B 'or B may also be due to rapid precipitation and a relatively high anti-solvent / solvent ratio after precipitation.

Solvent systems for crystallization of solid form A

[0172] Crystalline form A is highly soluble in many solvents commonly used for crystallization. Due to the high solubility, solvent / anti-solvent mixtures are required for crystallization.

The room temperature equilibration experiments showed that the solid form B '(lot S-1-P4; 40 ° C / 75% relative humidity) could be converted to the solid form A by stirring the ethyl acetate / heptane suspensions in ratio 1: 2 v / v or ethyl acetate / pentane in a ratio of 1: 2. In addition, slurry equilibration experiments using solid form A in a ratio of 1: 2 v / v ethyl formate / pentane. and methyl acetate / pentane 1: 2 v / v. they did not show solid form A conversion. Accordingly, such class 3 solvent / anti-solvent mixtures can be used for the crystallization of Form A. The advantageous features of such solvent systems are significantly lower boiling points and hence lower drying temperatures as possible.

[0174] The S-1-P1 characterization details for Solid Form A are shown in Table 14:

Table 14:

<td>Relationship</td><td colspan="2">S-1</td>

<td>Series number</td><td colspan="2">S-1-P1</td>

<td>XRPD</td><td>• constant form A</td><td>Figures XRPD-1a and XRPD-1b (see Fig. 4A)</td>

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<td>Raman</td><td>• solid form A · sample may contain a small amount of form B 'or B</td><td>Fig. Raman-1 (see Fig. 5A)</td>

<td>TG-FTIR</td><td>• weight loss from 25 ° C to 245 ° C: &lt;0.2%</td><td>Figure TG-FTIR-1 (see Fig. 6A)</td>

<td>DSC</td><td>Melting point: 82.4 ° C (peak temperature, sample hermetically sealed in a gold crucible, heating rate 20 K / min) • AH: -42 J / g • the sample may contain a small amount (about 5%) of B 'or B form</td><td>Figures DSC-1a and DSC-1b (see Fig. 7A)</td>

<td>SEM</td><td>• fairly well formed particles</td><td>Figures SEM-1 (see Fig. 8A</td>

<td>DVS</td><td>• water content at 50% relative humidity: 0.4% • maximum water content at 93% relative humidity: 1.5%</td><td>Figures DVS-1a and DVS-1b Fig. 9A</td>

[0175] The characteristics of S-1-P2 for solid form A are detailed in Table 15:

Table 15:

<td>Relationship</td><td colspan="2">S-1</td>

<td>Series number</td><td colspan="2">S-1-P2</td>

<td>XRPD</td><td>• constant form A</td><td>Figures XRPD-2a and XRPD-2b (see Fig. 4B)</td>

<td>Raman</td><td>• constant form A + B 'or B</td><td>Figure Raman-2 (see Fig. 5B)</td>

<td>TG-FTIR</td><td>• weight loss from 25 ° C to 245 ° C: &lt;0.2%</td><td>Figure TG-FTIR-2 (see Fig. 6B)</td>

<td>DSC</td><td>Melting point: 85.4 ° C (peak temperature, sample hermetically sealed in a gold crucible, heating rate 20 K / min) • AH: -43 J / g • sample contains approx. 20% of B 'or B form</td><td>Figures DSC-2a and DSC-2b (see Fig. 7B)</td>

<td>SEM</td><td>• partial images show transformation</td><td>Figures SEM-2 (see Fig. 8B)</td>

<td>DVS</td><td>• water content at 50% relative humidity: 0.3% • maximum</td><td>Figures DVS-2a ​​and DVS-2b (see Fig. 9B)</td>

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<td></td><td>water content at 95% relative humidity: 0.6%</td><td></td>

[0176] The S-1-P3 characteristics details for Solid Form A are shown in Table 16:

Table 16:

<td>Relationship</td><td colspan="2">S-1</td>

<td>Lot no</td><td colspan="2">S-1-P3</td>

<td>XRPD</td><td>• constant form A</td><td>Figures XRPD-3a and XRPD-3b (see Fig. 4C)</td>

<td>Raman</td><td>• constant form A • the sample may contain a small amount of form B 'or B</td><td>Figure Raman-3 (see Fig. 5C)</td>

<td>TG-FTIR</td><td>• weight loss from 25 ° C to 245 ° C: &lt;0.2%</td><td>Figure TG-FTIR-3 (see Figure 6C</td>

<td>DSC</td><td>Melting point: 84.4 ° C (peak temperature, sample hermetically sealed in a gold crucible, heating rate 20 K / min) • AH: -42 J / g • the sample may contain a small amount (about 5%) of B 'or B form</td><td>Figures DSC-3a and DSC-3b (see Figure 7C</td>

<td>SEM</td><td>- not analyzed</td><td> -</td>

<td>DVS</td><td>- not analyzed</td><td> -</td>

[0177] The S-1-P4 characteristics details for Solid Form B 'are shown in Table 17:

Table 17:

<td>Relationship</td><td colspan="2">S-1</td>

<td>Lot no</td><td colspan="2">S-1-P4 40 ° C / 75% relative humidity</td>

<td>XRPD</td><td>• constant form B ' • the sample may contain a small amount of form A</td><td>Figures XRPD-4a and XRPD-4b (see Fig. 4D)</td>

<td>Raman</td><td>• constant form B '</td><td>Figure Raman-4 (see Fig. 5D)</td>

<td>TG-FTIR</td><td>• weight loss from 25 ° C to 245 ° C: 1.0% (water)</td><td>Figure TG-FTIR-4 (see Fig. 6D)</td>

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<td>DSC</td><td>• endothermic peak: ~ 55 ° C (peak temperature, hermetically sealed sample closed in a gold crucible, heating rate 20 K / min) • AH: ~ 10 J / g</td><td>Figures DSC-4a and DSC-4b (see Fig. 7D)</td>

<td>SEM</td><td>• significant change in morphology</td><td>Figures SEM-3 (see Fig. 8C)</td>

<td>DVS</td><td>• water content at 50% relative humidity: ~ 0.8% • maximum water content at 94% relative humidity: ~ 2.4%</td><td>Figures DVS-3a and DVS-3b (see Fig. 9C)</td>

[0178] The different series P1, P2 and P3 of the compound S-1 revealed crystalline Form A with similar performance characteristics of XRPD, Raman spectra, TG FTIR, DVS and DSC. The P4 series revealed the presence of a paracrystalline solid form, well characterized by the results from XRPD, Raman spectra, TG FTIR, DVS and DSC as described above.

Relative stability of polymorphic forms under dry conditions

[0179] The DSC thermograms of Forms A and D shown in Fig. 19 show Form A melts near 80 ° C, while Form D has a melting point close to 130 ° C. The enthalpy of fusion for Form A is 40 ± 5 J / g and the enthalpy of melting for D is 75 ± 5 J / g. The melting point and enthalpy lead to the conclusion that form D has greater stability compared to form A.

[0180] Figure 17D shows that the melting of polymorph A or D leads to liquid crystal polymorph B instead of a precisely isotropic liquid phase. No formation of a fine liquid phase was observed even after heating the sample to 200 ° C. Cooling polymorph B to ambient temperature does not lead to recrystallization back to form A or D. This is confirmed by the absence of a melting endotherm in the DSC curve (Fig. 17D) a sample reheated after it has melted and then cooled to ambient temperature. The DSC curve also shows that Form B undergoes a phase change around 55 ° C. A similar glass transition is observed for form B ', which together with the broad shoulder at about 17 ° shown in Fig. 4D are the basis for their designation as liquid crystalline phases.

[0181] Figure 17e shows that heating polymorphs A and B to 110 ° C in the presence of form D causes forms A and B to convert to form D. This confirms that forms A and B are in metastable phases below 130 ° C. C so that it can be converted to form D. However, possibly due to the high energy barrier to conversion, the conversion rates of form A or B to D are very slow without the presence of form D initially present for seed crystallization. Thus, forms A and B can be considered to be practically stable at ambient temperature. Above 130 ° C, form D melts and transforms into B, which is now the most stable form. Micronization of polymorphic form A molecules under dry conditions also showed ~ 25% conversion to form B.

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Relative stability of polymorphs under humid conditions

[0182] Polymorph A is stable in its Form A for at least 7 days when stored at ambient / 75% RH, ambient / 100% RH, 30 ° C / 75% RH and 50 ° C / 0% WW. But it transforms into polymorph B 'when stored at 50 ° C / 75% RH. Some results are shown in Figure 17F. In fact, polymorph A stored at 25 ° C / 60% RH and 30 ° C / 65% RH was stable for 36 months and 9 months, respectively, while a sample stored at 40 ° C / 75% RH was converted to Form B 'within one month. These results indicate that polymorph A converts to form B 'in the presence of moisture.

[0183] On the other hand, polymorph D remains stable at 50 ° C / 75% RH as well as other conditions at ambient temperature / 75% RH, ambient temperature / 100% RH, 30 ° C / 75% RH and 50 ° C. C / 0% RH. In fact, polymorph D in the presence of moisture acts as a seed for the crystallization process and drives the transition of polymorphs A and B 'to form D, as does its effect in seeding crystallization for form A in D under dry conditions. Figure 17G (a) shows the change over time of polymorph A seeded with a small amount of form D at 50 ° C / 75% RH. The amount of polymorph D initially added to the sample is very small so that it is not detectable by DSC measurement under a heating rate of 10 ° C / min. After 24 hours, most of the polymorphic form A was converted to form B 'but a small amount of the sample was also converted to form D and the amount of the sample of form D increased with time. The transformation process is accelerated, as shown in Figure 17G (b), when the sample is kept in water at 50 ° C. Form A converts to both Form B 'and D after 6 hours, but the sample is predominantly Form D after 24 hours. This is in contradiction with the transformation of polymorph A into polymorph B 'which does not further convert to form D. It is not yet clear whether form A can convert to form D directly with seeding in water, or whether it only transforms to form B '(which then transforms to form D, in water). Further work showed that forms A and B 'transform to form D in the presence of moisture at lower temperatures, also at lower speeds.

Relative stability of the toluene solvate in toluene

[0184] Recrystallization of S-1 from a solvent / anti-solvent system that uses toluene as an anti-solvent produces a toluene solvate. The toluene solvate has a melting point close to 100 ° C with a heat of fusion of 70 ± 5 J / g. The TGA plot for the toluene solvate shown in Figure 20 shows that the solvate has a toluene content of ~ 7%, which is one toluene molecule for every three S-1 molecules. The solvent / drug weight ratio remained the same for each series of samples prepared and indicates that the toluene molecules are inside the unit cell structure rather than in channels or layers outside the lattice. Due to the low solubility of S-1 in toluene (&lt;2 mg / ml), after suspending (50 mg / ml) in toluene for 4 days, both at ambient temperature and at 50 ° C, no noticeable conversion was observed from form D to the toluene solvate. Sonifification of the slurry for 10 minutes resulted in a partial conversion to the toluene solvate.

[0185] As will be appreciated by those skilled in the art, the present invention is not limited to what has been mainly shown and described above. Rather, the scope of the invention is defined in the following claims.

PZ / 5402 / AG

EP 2 205 552 B1