MX360801B

Solid forms of selective androgen receptor modulators.

Abstract

The present invention relates to solid forms of (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)- 3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide and process for producing the same.

MX360801B, drawing sheet 1 — Sheet 1 of 250

Term

2 yearsleft in the term

Expires 11 September 2028.

3 claims: 1 independent, 2 dependent

1
117 'V;117 'V;· INSTITUTO MEXICANO ? MEXICAN INSTITUTE? DE LA PROPIEDAD ¡NDUSim V-· ·*ί-' OF THE PROPERTY ¡NDUSim V- · · * ί- ' 1. Use of crystalline form D of (R) or (S) - / V- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide, in preparation of a medicament to treat a hormone-related condition selected from adult male androgen depletion (ADAM), androgen depletion in women (ADIF), chronic muscle wasting, and prostate cancer. 1. Uso de la forma cristalina D de (R) o (S)-/V-(4-ciano-3(trifluorometil)fen¡l)-3-(4-cianofenoxi)-2-hidroxi-2-metilpropanamida, en la preparación de un medicamento para tratar una condición relacionada con hormonas seleccionada de la disminución de andrógenos en el hombre adulto (ADAM), disminución de andrógenos en las mujeres (ADIF), desgaste muscular crónico y cáncer de próstata.

1,139 paragraphs in 60 sections, as filed

PATENT TITLE No. 360801

Owner (s): GTx, INC.

Address:

175 Toyota Plaza, 7 *hFloor, Memphis, Tennessee, 38103, USA

<td>Denomination:</td><td>SOLID FORMS OF SELECTIVE ANDROGEN RECEIVER MODULATORS.</td>

<td>Classification:</td><td>CIP: C07C255 / 60; C07C233 / 00 CPC: C07C255 / 607C07B2200 / 13 to> - s = -.: r</td>

<td>Inventor (s):</td><td>TAI AHN; JAMES T. DALTON; DAVE DICKASON: SEOUNG- SOO HONG; THOMAS G BIRD REQUEST</td>

<td>Number:</td><td>Dated <lé PreaeNfación International:</td>

<td>MX / a / 2017/007289</td><td>September 11, 2008</td>

Diviatonal de la Patenté Udmaroc 351841

Country:

US

PRIORITY

Date:

September 2007

Validity: Twenty years

Expiration date:

Issue Date: November 16, 2018

The reference patent is granted based on the articles 1 ° 2 ° f'acciófFV,i6th failed * leaves the Industrial Property Law.

In accordance with article 23 of the ImMnLJa ImMnLJa Property Law, it is valid for a period of twenty years, non-extendable, counted from the date of filing the MefhagioM application and will be subject to all rights.

Who subscribes to the present title lo hasew »funáaBiemosnlodi ^) uestop« f <»article ^ se * traw« lW III y? · W2 island Industrial Property Law (Official Gazette of the Federation (0.0 F.) 08/27/1991 , rafcrmája on ΜΜ994, ¿/ 10Í19Í6, 12/26 / 1YES7, 05/17/1999, 01/26/2004, 06/16/2005, 01/25/2006, 05/06/2009. 01/06/2010 , 06/18 / 3010,28 / DS / 2OT (V27 / qH / 2012.X> 9fep * 2012. '· Ρΐ / β · «<1 · and 13 / Ό3 / 20181 prtimilos 1», 3' fraction V subsection a). 4or and 12th sections I and III of the Regulation tMkuÜgb Wétino dé fc ^ apiedád Mpsthal (D.QJ 14? | 2 / 199pt «Formed on 07/01/2002, 07/15/2004, 07/28/2004 and 09/07/2007); Articles 1 ', 3, 4% *> 5' ftoB ^ iL.'AoMp a), it betrayals I and ttl and JJt of the Organic Statute of the Mexican Institute of Industrial Property (DOF 12/27/1999 reform # i) |. w / 1®20 <® JM) 7 / Ü) O ^ DWM4 y'tíw 07} R “, 3or and 5or subsection a) of the Agreement that delegates powers to the Deputy General Directors. CoosM ^ (^ | ^^ oeÉ ^ [Svi®onstós. 'íTh ^ K »í of ^ Regional Offices, Divisional Deputy Directors, Departmental Coordinators and other subordinates of the Thstiftrto MféwnD ^ e ^ PiOpiedeÉJueCfstnal. (DOF 12/15/1999, amended on 02/04/2000, 07/29/2004, 08/04/2004 and 09/13/2007).

September 2028

This official letter is signed with an advanced electronic signature (FIEL), based on articles 7 BIS 2 of the Industrial Property Law; 3 of its Regulations and 1 section III, 2 section V, 26 BIS and 26 TER of the Agreement establishing the guidelines for the use of the Payment and Electronic Services Portal (PASE) of the Mexican Institute of Industrial Property, in the procedures indicated.

THE DIVISIONAL DIRECTOR OF PATENTS

NAHANNY CANAL REYES

Original string:

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Tribularia | 1695 || MX / 2018/98907 | MX / a / 2017/007289 | Normal patent title with divisional PCT | 1220 | RRGO | Page (s) 1 | sRx9Ox6jQlvwv58zGhGmmfFqKyo =

Digital stamp:

M / pTQKIjFBcAaPELW4FQfX7 / KNGF / jTzksl9b5IYXY9Vs2ICSf4RZgqcz35HagUIVattFTRCg0Uw0oPSeo / 7cRuQNP e7MQCgCZfgJFBYexE9C05qmQPA / fl77AX25FLtkuaTMJVwFgyMRax7V / KKyHnfhBFKZf3jgXwiCLGGaHL4VLw4ZAR Kgh1 / VDOJbXFeJbkFOdg5Lm3PxT7pOcZXhHAkyFi3fBgx43fKTu 9ExGhLWXCfdrOf4 + + + nudALCWYYwHPSCfoO OJ6gAaq4ID719IGo4X9v99IKUUDCdDYnoEncy4fUvJMuLD5q8v7laxwidOtw61xh1aqLmBBA == qKhL you Sania Maria Tepepan, XocNmüco, 16020.

..tódttó from Mexico.

40700 w.yw qob.inx / impi

MX / 2018/98907

3 & 38O1

, FNSTITÍ'TO MEXICAN

SOLID SHAPES OF SELECT1 MODULATORS «Μϊ

ANDROGEN RECEIVER ___________

Field of Invention

The present invention describes solid forms of (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide and processes for the preparation of the same.

Background of the Invention

The androgen receptor ("AR") is a ligand-activated transcriptional regulatory protein that mediates the induction of male sexual development and its function through its activity with endogenous androgens. Androgens are generally known as the male sex hormones. Androgen hormones are steroids that are produced in the body by the testes and cortex of the adrenal gland or can be synthesized in the 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 pattern (Matsumoto, Endocrinol. Met. Clin. N Am. 23: 857-75 (1994)). Endogenous spheroidal androgens include testosterone and dihydrotestosterone C'DHT ”). Testosterone is the main

INSTITUTO MEXICANO I heard LA PROPERTY INDUSTRIAL spheroid secreted by the testes and it is the main androgen that circulates found in the plasma of men. Testosterone is converted to DHT by the 5 alpha-reductase enzyme in many peripheral tissues. DHT is conceived to serve as the intracellular mediator for most androgen actions (Zhou, et al., Molec. Endocrinol. 9: 208-18 (1995)). Other spheroidal androgens include testosterone esters, such as cypionate, propionate, phenylpropynate, cypinoate, isocarporate, enanthate, and decanoate esters, and other synthetic androgens such as 7-Methyl-Nortestosterone ("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 ") . Because RA is understood for male sexual development and its function, RA is a common target for male contraception or other forms of hormone replacement therapy.

New novel approaches are urgently needed at both basic science and clinical levels to develop compounds, which are useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decay in a

Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction,

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hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition, and prostate cancer; c) treatment of conditions associated with ADIF, such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognitions and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and / or prevention of acute and / or chronic muscle wasting conditions;

e) prevention and / or treatment of dry eye conditions;

f) oral androgen replacement therapy; and / or g) decrease in incidence or provocation of a regression of prostate cancer.

Polymorphs, solvents, and drugs have been described in the literature as novel properties that they impart to drugs. Small ones have a tendency to self-assemble into various polymorphic forms that depend on the environment conducting self-assembly. Heat and solvent mediated effects can also lead to changes that transform one polymorphic form to another.

Identifying which polymorphic form is the most stable under each condition of interest, and the processes that lead to changes in the polymorphic form is crucial for the design of the

INSTITUTO MEXICANO Di LA PROPERTY 4 INDUSTRIAL

drug manufacturing process, in order to ensure that the final product is in its preferred polymorphic form. Different polymorphic forms of a pharmaceutical active ingredient (API) can lead to changes in drug solubility, dissolution rate, pharmacokinetics, and ultimately its bioavailability and efficiency in patients.

Brief Description of the Invention

In one embodiment, the present invention describes solid forms of (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide and processes of preparation of the same. In some embodiments, such compounds are useful for their androgenic and anabolic activity. (R) or (S) - N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4cyanophenoxy) -2-hydroxy-2-methylpropanamide are selective androgen receptor modulators (SARMS) useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decay in Aging Man (ADAM); c) treatment of conditions associated with Androgen Decay in a Woman (ADIF); d) treatment and / or prevention of chronic muscle wasting; and / or) decline in the incidence of, interruption or provocation of a regression to prostate cancer; f) oral androgen replacement and / or other clinical therapeutic areas and / or areas of diagnosis.

In one embodiment, the present invention provides, a

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ΠΕ LAfWPItOM 'industrial crystalline form of a compound (R) or (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide.

In one embodiment, the present invention provides an anhydrous crystalline form of a compound (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy- 2m ethyl pro p anamide.

In another embodiment, the present invention provides, a composition comprising a therapeutic amount of a crystalline form of an anhydrous crystalline form of a (R) or (S) -N- (4-cyan or-3- (trifluoromethyl) phenyl ) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide and a suitable carrier or diluent.

In one embodiment, the present invention provides a process for the preparation of a crystalline form of (R) or (S) -N- (4-cia non-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) - 2-hydroxy-2-methylpropanamide, said process that comprises dissolving (R) or (S) - N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide in at least one of the organic solvents at temperatures between approximately -20 ° C to + 5 ° C under permissive conditions for crystallization, therefore obtaining said crystalline form.

In one embodiment, the present invention provides, a paracrystalline compound (R) or (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-26

INSTITUTO MEXICANO DE Ι.Λ INDUSTRIAL PROPERTY methylpropanamide.

In another embodiment, the present invention provides a composition comprising a paracrystalline form of (R) or (S) - N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy -2-methylpropanamide and a suitable carrier or diluent.

In one embodiment, the present invention provides, a process for the preparation of a paracrystalline compound (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) - 2-hydroxy-2-methylpropanamide comprising a suspension of a crystalline form of a compound (R) or (S) - N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy- 2-methylpropanamide in water at room temperature of about 20 to 30 ° C for at least 5 hours, to obtain a paracrystalline compound.

In one embodiment the present invention provides, a composition comprising a mixture of solid crystalline and paracrystalline forms of a compound (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy ) -2-hydroxy-2-methylpropanamide and a suitable carrier or diluent.

Brief Description of Drawings

The subject recognized as the present invention is particularly noted and distinctively claimed in the concluding part of the specification. The present invention, however, both the organization and the method of operation,

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together with the objects, characteristics and advantages that can be better understood by reference to the following detailed description, when read with the accompanying drawings where:

Figure 1 schematically illustrates the synthesis of racemic mixtures of compound 1.

Figure 2 schematically illustrates the (S) enantiomer of compound S-1.

Figure 3 schematically illustrates the synthesis of the (R) -enantiomer of compound R-1

Figures 4A to 4D illustrate the XRPD patterns for solid forms of compound S-1. Solid form 4A forms A-P1 batch of compound S-1; solid form 4B forms A-lot P2 of compound S-1; the solid form 4C forms an ote-A P3 of compound S-1, the solid form 4D forms a batch-B 'P4 of compound S-1.

Figures 5A to 5D are a Raman spectrum of sample batches P1 to P4 of compound S-1, respectively. The laser power setting was 100 mW, at a resolution of 2 cm-1.

Figures 6A to 6D are a TG-FTIR spectrum of sample batches P1 to P4 of compound S-1, respectively. The conditions included in the operation of the temperature range in the dynamic mode of 25 ° C / 10.0 / 250 ° C, in an atmosphere of N2.

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Figures 7A to 7D are an acpprtrn-ngC * i »c Iau» sample from P1 to P4 of compound S-1, respectively. The asterisk indicates an adjustment effect, an artifact of the machinery used.

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

Figures 9A, 9B and 9C are Dynamic Vapor Absorption (DVS) spectra of sample batches, P1, P2, and P4 of compound S-1, respectively. 9A is a DVS of form A.

9B is a DVS of form A. 9C is a DVS of form B '.

Figures 10A-10F demonstrate that the XRPD spectrum of the compound obtained after varying the S-1 concentration in presented solvents, the solvents or a combination thereof vary.

Figure 10A shows that the XRPD spectrum after compound S-1, Form A, suspended in n-heptane, 108 mg / 2.0 mL.

Figure 10B shows that the XRPD spectrum after compound S-1, Form b ', suspended in ethyl acetate 20 + n-heptane 1: 2 (v / v), 81 mg / 1.7mL.

Figure 10C shows the XRPD spectrum after compound S-1, Form B 'suspended in ethyl acetate + npentane 1: 2 (v / v /), 101 mg / 1.0 mL.

Figure 10D shows the XRPD spectrum after compound S-1 Form A, suspended in ethyl acetate

+ npentane 1: 2 (v / v), 128 mg / 2.0 mL.

Figure 10 E- shows the XRPD spectrum after compound S-1 Form A, suspended in ethyl acetate + npentane 1: 2 (v / v), 112 mg / 2.0 mL.

Figure 10 F shows the XRPD spectrum after compound S-1 Form A, suspended in methyl acetate + npentane 1: 2 (v / v), 126 mg / 2.0 mL.

Figures 11A-11D show the XRPD pattern representing the results of vapor diffusion experiments carried out with compound S-1.

Figure 11A shows the XRPD spectrum of compound S-1 in toluene and n-hexane at 23 ° C for 2 hours.

Figure 11B shows a superimposed spectrum of XRPD from batch P1 (Form A) and the XRPD obtained in Figure 11A.

Figure 11C shows the XRPD spectrum obtained for compound S-1 in acetic acid and water at 23 ° C for 7 days.

Figure 11D shows an XRPD spectrum of batch P1 (Form A) and the XRPD obtained in Figure 11B.

Figures 12A-12D show the XRPD pattern that represents the results of the evaporation experiment where the solutions of the compounds were dried at room temperature (N flow2 dry) without agitation. Figure 12A demonstrates the XRPD pattern obtained from compound S-1 (batch P1) in a

-jl: J »

ethyl acetate solution. Figure 12B demonstrates a superimposed spectrum of XRPD from batch P1 (Form A) and the XRPD obtained in Figure 12A. Figure 12C demonstrates the XRPD pattern obtained from compound S-1 (batch P1) from THF, to provide form C. Figure 12D demonstrates the XRPD patterns of a mixture of form A (red, top) and form C (blue, bottom), as presented in figure 12C.

Figures 13A-13D show the XRPD spectrum that represents the recrystallization results of the solution experiment where compound S-1 was dissolved in a different solvent system at room temperature, and cooled to + 5 ° C or -20 ° C.

Figure 13A shows the XRPD spectrum obtained from compound S-1 (batch P1) in ethyl acetate + n-heptane1: 1 (v / v).

Figure 13B shows a superimposed spectrum of XRPD from batch P1 (Form A) and the XRPD obtained in Figure 13A.

Figure 13C shows an XRPD spectrum obtained from compound S-1 (batch P1) in acetonitrile + toluene 1.3 v / v. Figure 13D shows a superimposed spectrum of XRPD from batch P1 (Form A) and e XRPD obtained in Figure 13B.

Figures 14A and 14B show the XRPD spectrum representing the results of the cooling drying experiment.

Figure 14A shows the XRPD spectrum obtained from compound S-1 (batch P1) in 1-4dioxane and cooled to -50 ° C.

Figure 14B shows a superimposed spectrum of XRPD from batch P1 (Form A) and the XRPD obtained in the figure.

4Α.

Figure 15 demonstrates a DSC thermogram representing the results of a drying experiment when compound S-1 (batch P4) was dried overnight in a N atmosphere.2 dry. The asterisk indicates a configuration effect, an artifact of the machinery used.

Figures 16A-16D demonstrate the XRPD spectrum representing the results of a relative stability of the experiments, where the suspension experiments were carried out with batch mixtures of S-1.

Figure 16 A shows the XRPD spectrum obtained from a mixture of batches of compound S-1 (P1, P18, P24, P30, P37 and P38, all batches have an XRPD characteristic of Form A) in ethyl acetate + n-heptane 1 : 2 (v / v) 130 mg / 2.0 mL.

Figure 16 B shows a superimposed spectrum of batch P1 (Form A) and XRPD obtained in Figure 16 A.

Figure 16C shows the XRPD spectra obtained from a mixture of batches of compound S-1 (P1 and P52 where batch 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.

Figure 16D shows a superimposed spectrum of the XRPD from batch P1 (Form A) and the XRPD obtained in Figure 16B.

Figures 17A-17G (b) provide a DSC thermogram and an XRPD pattern, representing the results of vapor absorption.

IMPI.

INSTITUTO MIXICANCnt LA ITOTOAC INDUSTRIAL

of water where S-1 (batch P1) was stored in a glass tube under 96% rh (relative humidity) at room temperature.

Figure 17A- shows the DSC results obtained for compound S-1 batch P1 with no solvent after 11 weeks.

Figure 17B- demonstrates XRPD of compound S-1 from batch P1 (form A) in water after 19 hours at 37ORC, which results in the formation of the B 'form.

Figure 17C- demonstrates XRPD of compound S-1 lot P1 (form A) in acetic acid + water 1: 2 (v / v) after 20 hours at 23 ° C.

Figure 17D- shows a DSC thermogram of heating a sample of Form A (black), cooling the sample after melting (gray) and reheating the sample (white). The heating rates were 10 ° C / min while the cooling rate was 1 ° C / min. Heating form A beyond melt temperature produces B that does not revert to A even when the sample is cooled back to room temperature.

Figure 17 E illustrates ° C / min DSC which is carried out in the form A (gray), B "(black) mixture of A and D (white) and mixture of B" and D (dark gray). A and B can carry out a crystallization to D, but only in the presence of D for

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OF THE PROPERTY

INDUSTRIAL act as seeds for crystallization.

Figure 17 F presents the DSC plots for Form A stored at room temperature / 100% RH for 7 days (light gray), 50 ° C / 0% RH for 7 days (dark gray) and 50 ° C / 75% RH for 6 hours (white) along with the DSC plot of the original sample (black).

Figure 17 G (a) presents DSC plots of polymorph A planted with form D and stored at 50 ° C / 75% RH.

Figure 17 G (b) presents DSC plots of Form A planted with Form D and stored at 50 ° C in water.

Figure 18 demonstrates the XRPD patterns of an XRPD superimposed spectrum of form A (top) and form D (bottom) of compound S-1.

Figure 19 demonstrates a DSC thermogram of forms A and D.

Figure 20 of the thermogravimetric analysis (TGA) graph of the toluene solvent (red) and form D (black).

Detailed description of the invention

In some embodiments, the present invention provides solid forms of (R) or (S) -N (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide and processes for the preparation of the same. The present invention also provides pharmaceutical compositions comprising the solid forms of (R) or (S) N (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy -two-

methylpropanamide, and uses thereof.

(R) or (S) - N (4-cyano-3- (trifluoromethyl) phenyl) -3- (4cyanophenoxy) -2-hydroxy-2-methylpropanamide is an androgen receptor targeting agent (ARTA), demonstrating androgenic and anabolic activity. In some embodiments, methyl propionamides, as described herein, are selective androgen receptor modulators (SARMs), which in some embodiments are useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decay in Aging Man (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 conditions associated with ADIF, such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognitions and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and / or prevention of acute and / or chronic muscle wasting conditions; e) decrease the incidence of, interruption or provocation of a regression of prostate cancer; f) androgen replacement

oral and / or other clinical therapeutic areas and / or areas of diagnosis.

In some embodiments, the present invention provides solid polymorphic forms of compounds of (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2- methylpropanamide of the present invention. In one embodiment, the term "polymorph" refers to a specific form of the SARM compounds of the present invention, for example, polymorphs may represent crystalline forms that can vary in pharmaceutically relevant physical properties from one form to another; for example under different crystallization conditions, environmental conditions, hygroscopic activity of the compounds, etc.

In one embodiment, the present invention provides, a crystalline form of the compound (R) or (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy- 2methylpropanamide.

In one embodiment, the present invention provides a crystalline form of the anhydrous compound of (R) or (S) -N- (4-cyano-3- (trifluorom ethyl) f en i I) -3- (4-cyanophenoxy) -2- hydroxy-2-methylpropanamide.

In one embodiment, the present invention provides, a crystalline form of the anhydrous compound (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide.

In another embodiment, the crystalline form of (S) -N- (4-cyano-3 (frifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide (compound S-1), is characterized by:

to. an X-ray powder diffraction pattern comprising peaks at angles of ° 2 (d A 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); Y

b. a melting point of about 80 ° C.

According to this aspect and another embodiment, said crystalline form of compound S-1, having all or part of the characteristics listed in (a) and (b) is referred to in the present invention as crystalline form A.

In another embodiment, the solubility of Form A in water is between 20 to 30 mg / L at 22 ° C. In another embodiment, the solubility of Form A in water is between 23 to 27 mg / L at 22 ° C.

In one embodiment, the present invention provides a crystalline form of a (R) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3 (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide (compound R-1), where said crystalline form is obtained by methods similar to those of the S isomer, as described in the present invention. In some modalities, this form

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OF THE INDUSTRIAL MOTHERY 17 crystalline compound R-1, is structurally related and / or has characteristics similar to that of compound S-1.

In one embodiment, the present invention provides a paracrystalline compound of (R) or (S) -N- (4-cyano-3 (trifluoro methyl) phenyl) -3- (4-cy to nphenoxy) -2-hyd roxy-2-methylpropanamide

In one embodiment, the paracrystalline form of (S) -N- (4cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide (compound S-1) is characterized by:

to. an X-ray powder diffraction pattern showing a wide halo with two harmonic peaks between 15-25 ° 2θ and

b. a glass transition point of about 55 ° C.

According to this aspect and in another embodiment, said paracrystalline form of compound S-1, having all or part of the characteristics listed in (a) and (b) is referred to in the present invention as paracrystalline form B '.

In one embodiment, the term "paracrystalline" refers to the state of the material that exhibits a short-range order without a long-range order, such as liquid crystals or other lamellar structures. In one embodiment, the paracrystalline form is a liquid crystal. In another embodiment, the B 'form of compound S-1 is a paracrystalline. In another mode,

Form A of S-1 can convert form B in whole or in part to S-1.

In another embodiment, the solubility of form B 'in water is between 20 to 30 mg / L at 22 ° C. In another embodiment, the solubility of form B 'in water is between 23 to 27 mg / L at 22 ° C.

In one embodiment, the present invention provides a paracrystalline B "form of (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide, characterized by :

to. an X-ray powder diffraction pattern showing a broad halo with two harmonic peaks between 15-25 ° 2Θ and

b. a glass transition point of about 55 ° C.

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

to. an X-ray powder diffraction pattern comprising single peaks at ° 2θ (dA value) angles of approximately 6.9 (12.8), 9.5 (9.3), 13.5 (6.6), 16.0 (5.6), 22.8 (3.9).

In another embodiment, the crystalline form C of compound S-1 is obtained as a mixture of form A and form C, by evaporating A out of THF.

INJTITUTO MEXICANC?

πε industrial property

In one embodiment, the present invention provides a crystalline D form of (S) -N- (4-cia non-3- (trifl or orom eti I) f in i I) -3- (4-cyanophenoxy) -2-h ¡Drox¡-2-methylpropanamide characterized by:

to. an X-ray powder diffraction pattern comprising single peaks atOR26 (d value A) angles of approximately 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), 1.6.6 (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), 29.3 (3.0); Y,

b. a melting point of about 130 ° C.

In another embodiment, the crystalline D form of compound S-1 is stable at 50 ° C / 75% RH (Relative Humidity) as well as the other conditions of ambient / 75% RH, ambient / 100% RH, 30 ° C / 75 % RH and 50 ° C / 0% RH.

In another embodiment, the characteristics of the solid forms different from S-1 are presented in Example 2 and in Figures 4 to 20.

The solid forms of the present invention may be analyzed by any method known in the art as an example, and in one embodiment, X-ray powder diffraction. In another embodiment, the analysis of the solid forms of the present invention may comprise TG -FTIR (Fourier infrared transformation thermogravimetric). In other

tNSTtTtTO MEXICAN Dt LA INDUSTRIAL CURRENCY

In embodiment, the analysis of the solid forms of the present invention may comprise FT-Raman (Fourier Ramantransformation). In another embodiment, the analysis of the solid forms of the present invention may comprise DSC (Differential Calorimetry Scanning). In another embodiment, the analysis of the solid forms of the present invention may comprise DVS (dynamic vapor absorption). In another embodiment, the analysis of the solid forms of the present invention may comprise SM (scanning electron microscopy).

In one embodiment, the present invention provides a polymorphic mixture comprising crystalline forms A and B ', in a ratio of about 95: 5 to 85:15, respectively. In another embodiment, the ratio is between about 85:15 to 72:25, respectively. In another embodiment, the ratio is between about 75:25 to 65:35, respectively. In another embodiment, the ratio is between about 95: 5 to 90:10, respectively. In another embodiment, the ratio is between about 97: 3 to 93: 7, respectively. In another embodiment, the ratio is between approximately 85:15 to 80:20. In another embodiment, the ratio is between about 70:20 to 60:20. In another embodiment, the ratio is between about 50:50, respectively.

In one embodiment, the present invention provides a

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OF PROPERTY C '«j INDUSTRIAL' W.

polymorphic mixture comprising crystalline forms A, B 'and C in a ratio of between about 90: 5: 5 to 80:10:10, respectively. In another embodiment, the ratio is between about 80:10:10 to about 75:15:10, respectively. In another embodiment, the ratio is between about 95: 3: 2 to 90: 7: 3, respectively. In another embodiment, the ratio is between approximately 75:15:10 to 65: 20: 15. In another embodiment, the ratio is between approximately 70:20:10 to 60:20:20.

In one embodiment, the present invention provides a polymorphic mixture comprising crystalline forms A, B ', and D in a ratio of between about 5: 5: 90 to 10:10:80, respectively. In another embodiment, the ratio is between approximately 10:10:80 to 10:15:75, respectively. In another embodiment, the ratio is between about 2: 3: 95 to 3: 7: 90, respectively. In another mode, the ratio is between approximately 10:15:75 to 15:20:65. In another embodiment, the ratio is between approximately 10:20:70 to 20:20:60.

In one embodiment, the present invention provides a polymorphic mixture comprising crystalline forms A and C in a ratio of between about 98: 2 to 95: 5, respectively. In one embodiment, the present invention provides a polymorphic mixture comprising crystalline forms A and C in a ratio of between about .'iNJ * »» ·. ·· ** '

95: 5 to 90:10, respectively. In one embodiment, the present invention provides a polymorphic mixture comprising crystalline forms A and C in a ratio of between about 90:10 to 85:15, respectively. In one embodiment, the present invention provides a polymorphic mixture comprising crystalline forms A and C in a ratio of between about 85:15 to 80:20, respectively. In one embodiment, the present invention provides a polymorphic mixture comprising crystalline forms A and C in a ratio of between about 50:50, respectively.

In one embodiment, the present invention provides a polymorphic mixture comprising crystalline forms A and D in a ratio of between about 2:98 to 5:95, respectively. In one embodiment, the present invention provides a polymorphic mixture comprising crystalline forms A and D in a ratio of between about 5:95 to 10:90, respectively. In one embodiment, the present invention provides a polymorphic mixture comprising crystalline forms A and D in a ratio of between about 10:90 and 15:85, respectively. In one embodiment, the present invention provides a polymorphic mixture comprising crystalline forms A and D in a ratio of between about 15:85 to 20:80, respectively. In one embodiment, the present invention

I

- «X Λ MEXICAN INSTITUTE

OF THE industrial PROPERTY

provides a polymorphic mixture comprising crystalline forms A and D in a ratio of between about 50:50, respectively.

In one embodiment, the present invention provides a polymorphic mixture comprising crystalline forms B 'and D in a ratio of between about 2:98 and 5:95, respectively. In one embodiment, the present invention provides a polymorphic mixture comprising crystalline forms B 'and D in a ratio of between about 5:95 to 10:90, respectively. In one embodiment, the present invention provides a polymorphic mixture comprising crystalline forms B 'and D in a ratio of between about 10:90 to 15:85, respectively. In one embodiment, the present invention provides a polymorphic mixture comprising crystalline forms B 'and D, in a ratio of between about 15:85, 20:80, respectively. In one embodiment, the present invention provides a polymorphic mixture comprising crystalline forms B 'and D, in a ratio of between about 50:50, respectively.

In one embodiment, the present invention provides a polymorphic mixture comprising crystalline forms B 'and C in a ratio of between about 98: 2 to 95: 5, respectively. In one embodiment, the present invention provides a polymorphic mixture comprising the forms

INSTITUTO MEXICANO DE LA PROPIEDAD INDUSTRIAL crystalline B 'and C in a ratio of approximately 95: 5 to 90:10, respectively. In one embodiment, the present invention provides a polymorphic mixture comprising crystalline forms B 'and C in a ratio of between about 90:10 to 85:15, respectively. In one embodiment, the present invention provides a polymorphic mixture comprising crystalline forms B 'and C in a ratio of between about 85:15 to 80:20, respectively. In one embodiment, the present invention provides a polymorphic mixture comprising crystalline forms B 'and C in a ratio of between about 50:50, respectively.

In one embodiment, the ratio of crystalline form A to crystalline form B 'is between about 95: 5 to 85: 1 5. In another embodiment, the ratio of crystalline form

A and crystal form B 'is between about 98: 2 to 95: 5. In another embodiment, the ratio of crystalline form A to crystalline form B is between about 85:15 to 75:25. In another embodiment, the ratio of crystalline form 20 A to crystalline form B 'is between about 75:25 to 65:35, respectively.

In one embodiment, a 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. In another modality, the percentage of

various solid forms in a sample (for example, the percentage of solid form A and solid form B in a sample) can be determined by carrying out Modulated DSC (Differential Scanning Calorimetry) at a heating rate of 3 ° C / min from 10 ° C to 130 ° C, followed by a linear integration of solid form A and / or solid form B to obtain the enthalpy of each.

In one embodiment, the solid form of a SARM compound can influence its bioavailability, stability, processing, and ease of manufacture, and uses thereof should be considered part of the present invention.

In one embodiment, the present invention provides a process for the preparation of a crystalline form of (R) or (S) -N- (4-cyan o-3- (trifluorom ethyl) phen i 1) -3- (4- cyanophenoxy) -2-hydroxy-2-methylpropanamide which comprises dissolving the (R) amorphous or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2- methylpropanamide in at least one organic solvent at a temperature between approximately -20 ° C to + 30 ° C under conditions permissive for crystallization, therefore obtaining the crystalline form.

In one embodiment, the present invention provides a process for the preparation of a crystalline form of A of (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy -2-methylpropanamide which comprises dissolving a (S) -N (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-225

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Amorphous methylpropanamide in at least one organic solvent at a temperature of between about -20 ° C to + 30 ° C under conditions permissive for crystallization, therefore obtaining the crystalline form.

In another embodiment, the crystallization temperature of (S) N- (4-c¡ a no-3- (trifluoromethyl) f in i 1) -3- (4-ci a nophenoxy) -2-h id rox¡ -2methylpropanamide, is about 5 ° C. In another embodiment, the temperature is about -20 ° C. In another embodiment, the temperature is about 20 ° C.

In another embodiment, the temperature is between about 20 to 50 ° C. In another embodiment, the temperature is about -10 0 ° C. In another embodiment, the temperature is about 0 to 5 ° C. In another embodiment, the temperature is about -10 ° C to 15-20 ° C.

In another embodiment, Form A of (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide (compound S-1) is prepared by crystallization of an organic solvent comprising a mixture of solvents. In another embodiment the mixture comprises two solvents in a ratio of 1: 2 v / v, respectively. In another embodiment, the mixture comprises two solvents in a ratio of 1: 3 v / v, respectively. In another embodiment, the mixture comprises at least two solvents in a proportion of

1: 4 v / v, respectively. In another modality, the mixture

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OF THE PROPERTY

INDUSTRIAL comprises ethyl and pentane formate in a 1: 2 v / v ratio, respectively. In another embodiment , the mixture comprises methyl acetate and pentane in a ratio of 1: 2 v / v, respectively. In another embodiment, the mixture comprises ethyl acetate and n-hexane. In another embodiment, the mixture comprises toluene and n-hexane. In another embodiment, the mixture comprises acetic acid and water in a ratio of 1: 2 v / v. In another embodiment, Form A is prepared by crystallizing a solvent / antisolvent mixture at room temperature. In another embodiment, ethyl acetate, ethanol. Dichloromethane or acetonitrile are the solvents and n-hexane, n-pentane, n-heptane and cyclohexane, etc., are used as antisolvents. In another embodiment, the solvent / antisolvent ratios are between about 1: 2 and 1: 3.

In another embodiment, the crystalline form A of the compound S-1 is prepared by forming a suspension of a paracrystalline form of the compound of the formula S-1 in a solvent / antisolvent mixture. In another embodiment, solid form A is prepared by forming a suspension of a 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. In another embodiment, solid form A is prepared by forming a suspension of a paracrystalline form of the compound of formula S-1 in a mixture of ethyl acetate and pentane in a ratio of 1: 2 v / v, respectively. In other

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

In the embodiment, the crystalline form A of compound S-1 is prepared by forming a suspension of the form B 'in a mixture of solvent / antisolvent at above concentrations being the saturation limit at 23 ° C for several hours, followed by the dried to form A.

In another embodiment, the D-form of (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide (compound S-1) is prepared by crystallizing the solvent / antisolvent mixture at 50 ° C, using ethyl acetate and cyclohexane as the solvent and antisolvent, respectively. In another embodiment, form D is prepared from other polymorphic forms by "planting" the sample with a small amount of D and storing it at 110 ° C / 0% RH for 7 days or at 50 ° C in water for 24 hours, followed by drying. In another embodiment, heating forms A and / or B "to 110 ° C in the presence of D causes forms A and B" to readjust to their D form. In another embodiment, form D in the presence of moisture acts acts as the seed for the crystallization process and leads the transformation of forms A and B "to form D.

In another embodiment, Figure 17G shows the time evolution of polymorph A planted with a small amount of D at 50 ° C / 75% RH. The amount of polymorph D initially added to the sample is very small so that it cannot be detected by the DSC with the heating rate of

IMPI

10orC / min. After 24 hours, most of the polymorph A has been converted to B ', but a small amount of the sample has also been converted to D and the amount of the sample in D increases with time. The transformation process is accelerated in Figure 17G by storing the sample in water at 50 ° C. Form A has been converted to both B 'and D after 6 hours, but the sample is predominantly in form D for 24 hours.

In one embodiment, the present invention provides a process for the preparation of paracrystalline (R) or (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy -2methylpropanamide which comprises stirring a suspension of a crystalline form of (R) or (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2m ethylpropanamide in water at room temperature at about 20 to 30 ° C for at least 0.5 hours, to obtain a compound for crystallization.

WICKED

MEXICAN INSTITUTE

OF THE IWDUSTXIAL PROPERTY 'SUb. * - obtain a paracrystalline compound.

In one embodiment, the present invention provides a process for the preparation of a paracrystalline form B 'of (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2 -methylpropanamide comprising when stirring a suspension of a crystalline form A of (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide in water at room temperature from about 20 to 30 ° C for at least 0.5 hours, to obtain a paracrystalline compound. In another embodiment, paracrystalline form B 'is prepared by stirring a suspension of crystalline form A at 50 ° C in water for 24 hours. In another embodiment, the paracrystalline form B 'is prepared by stirring a suspension of a crystalline form A at 37 ° C overnight to obtain the paracrystalline form B'.

In one embodiment, the solid form B 'of (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide is prepared by storage of the solid form A at 40 ° C and 75% relative humidity (rh) for 1 to 2 hours. In another embodiment, solid form A is stored at 40 ° C and 75% rh for 2 to 4 hours. In another embodiment, solid form A is stored at 40 ° C and 75% rh for 4 to 10 hours. In another embodiment, solid form A is stored at 40 ° C and 75% rh for 10 to 15 hours. In another embodiment, solid form A is stored at 40 ° C and 75%

INSTITUTO MEXICANO PE LA PROPERTY INDUSTRIAL of rh for 15 to 24 hours. Otherwise, solid form A is stored at 40 ° C and 75% rh for 24 hours. In another embodiment, solid form A is stored at 40 ° C and 75% rh for 30 days.

In one embodiment, the solid form B 'of (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide is prepared by storage of the form Solid A at 40 ° C and 75% relative humidity (rh). In other

<td>modality,</td><td>solid form A is</td><td colspan="2">stored</td><td>to</td><td>a</td><td>rank</td><td>of</td>

<td>temperature</td><td>approximately</td><td>30 to</td><td>40 ° C</td><td>Y</td><td>a</td><td>rank</td><td>of</td>

<td colspan="3">relative humidity of approximately</td><td>50 to</td><td colspan="2"> 75%.</td><td colspan="2">In other</td>

<td>modality,</td><td>solid form A is</td><td colspan="2">stored</td><td>to</td><td>a</td><td>rank</td><td>of</td>

<td>temperature</td><td>approximately</td><td>40 to</td><td>50 ° C</td><td>Y</td><td>a</td><td colspan="2">humidity</td>

<td>relative of</td><td>about 60 to</td><td> 8 0%.</td><td colspan="2">In other</td><td colspan="2">modality,</td><td>the</td>

Solid form A is stored at a temperature range of approximately 40 to 50 ° C and a relative humidity of approximately 60 to 80%.

In one embodiment, form B 'is assigned as a lyotropic liquid crystalline form due to its solvent-mediated formation.

In one embodiment, the liquid crystalline form B "of (S) -N (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide is prepared by melting or heating solid form A of (S) -N- (4-cyano-325 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2 MEXICAN INSTITUTE

Of the property

INDUSTRIAL methylpropanamide at 80 ° C, followed by cooling.

In one embodiment, the B "form of (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide is prepared by melting or heating to 130 ° C the solid form D of (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4cyanophenoxy) -2-hydroxy-2-methylpropanamide followed by cooling.

In one embodiment, evaporation of (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide from solvents, such as ethanol without an antisolvent, yields form B ".

In one embodiment, form B "is assigned as a thermotropic liquid crystalline form from its thermal method of preparation.

In one embodiment, the present invention provides a process for the preparation of a solid form C of (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide which comprises dissolving crystalline form A of (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide in THF, followed by evaporation to obtain the solid form C.

In another embodiment, form C is obtained as a mixture with form A.

In one embodiment, the present invention provides a process for the preparation of a solid solvent form of

(S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide toluene comprising using any solvent / antisolvent crystallization method using toluene as the antisolvent.

In another embodiment, the solid form of the toluene solvent has a melting point of approximately 100 ° C with the enthalpy of fusion of 70 ± 5 J / g.

In another embodiment, the graph of the thermogravimetric analysis (TGA) of the toluene solvent in Figure 20 shows that the toluene content in the solvent is approximately 7%, which corresponds to one APRA molecule of toluene for every three molecules of S- 1. In another embodiment, the toluene molecules reside within the structure of the cell unit, rather than in the channels or layers outside the grid. In another embodiment, the solid form of the toluene solvent is the most stable form of toluene.

In some embodiments, the crystalline forms of SARMs of the present invention comprise the alteration of a given crystal form to one similar in structure, but not identical to the original form. In one embodiment, such changes in the crystal forms can produce one that is structurally more stable than the original form. In some embodiments, the crystal forms of the present invention comprise altered crystal forms, as well as parent forms, in a single preparation. In some embodiments, these crystalline forms

they may comprise a small percentage of the total SARM compound preparation, for example, close to 1% or in another embodiment close to 5%, or close to 10% or close to 15%, or close to 25% of the preparation. In another embodiment, said altered forms may comprise the majority of the SARM compound preparation and may comprise 55%, or in another embodiment 65%, or in another embodiment 75% or 80% or 85% or 90% or 95% or close to 100% of the SARM compound preparation. In one embodiment, the favorable crystalline form is thermodynamically favorable. In another embodiment, the favorable crystalline form is a result of a change in humidity. In another embodiment, the favorable crystalline form is a result of a change in temperature. In another embodiment, the favorable crystalline form is a result of a change in solvents.

In some embodiments, the process for preparing the polymorph of compounds (R) or (S) -N- (4-c¡ to no-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy -2-methylpropanamide yield various crystalline forms. In one embodiment, the process yields a mixture of crystalline / paracrystalline forms A, B ', C and D. In one embodiment, the process yields a mixture of crystalline / paracrystalline forms A, B', B ", C and D. In In another embodiment, the process yields a mixture of crystalline forms A and C. In another embodiment, the process yields a mixture of crystalline / paracrystalline forms A and B '. In other

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL modality, the process yields a mixture of crystalline forms A and O. In another modality, the process yields a mixture of crystalline / paracrystalline forms B 'and D. In another modality, the process yields a mixture of crystalline forms / paracrystalline B ”and D. In another embodiment, the process yields a mixture of crystalline forms C and D. In another embodiment, the process yields a mixture of crystalline / paracrystalline forms B 'and C. In another embodiment, the process yields a mixture of crystalline / paracrystalline forms A and B ". In another embodiment, the process yields a mixture of paracrystalline forms B 'and B ". In another embodiment, the process yields a mixture of crystalline / paracrystalline forms C and B ". In another embodiment, the process yields a mixture of crystalline / paracrystalline forms A, D, and

B ". In another embodiment, the process yields a mixture of crystalline / paracrystalline forms.

B ',

B ”and C.

In another embodiment, the process yields a mixture of crystalline / paracrystalline forms

TO,

B 'and B ”.

In another modality, the process yields a mixture of crystalline / paracristaline forms.

D, B 'and B "

In one embodiment, the solid form compounds of the present invention are dried from solution under vacuum and at room temperature, followed by a gradual increase in temperature. In another embodiment, the solid form compounds of the present invention are filtered from solution.

In one embodiment, the term "room temperature" is

refers to room temperature. In another embodiment, the term "room temperature" refers to 20 to 25 ° C. In another embodiment, "room temperature" refers to 25 to 30 ° C.

In another embodiment, form D is the most thermodynamically stable polymorph under both dry conditions and in the presence of water at room temperature close to its melting point of 130 ° C. In another embodiment, Figure 19 illustrates a Differential Scanning Calorimeter (DSC) thermographic of Form A and Form D, where Form A melts at approximately 80 ° C and Form D melts at approximately 130 ° C. In another embodiment, the enthalpy of fusion for form A is 40 ± 5 J / g, while the enthalpy of fusion for form D is 75 ± 5 J / g.

In another embodiment, form A is stable in its form A for at least 7 days under storage conditions at room temperature / 75% RH (Relative Humidity), ambient temperature / 100% RH, 30 ° C / 75% RH and 50 ° C / 0% RH. In another embodiment, form A is converted to B 'when stored at 50 ° C / 75% RH. In another embodiment, form A is converted to B 'when stored at 40 ° C / 75% RH within a month. In another embodiment, Form A stored at 25 ° C / 60% RH and 30 ° C / 65% RH is stable for 36 months and 9 months, respectively.

In one embodiment, (R) or (S) -N- (4-cyano-3 (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-237

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

methylpropanamide are prepared by chiral synthesis.

In one embodiment, the (S) -N- (4-cyano-3 (trifluoroethyl) f in ¡I) -3- (4-cyanophenoxy) -2-h id rox¡-2 methylpropanamide can be prepared by a process according to the following synthetic scheme:

In one embodiment, the process described in the above scheme comprises reacting it with acylanilide in step 5 with the cyanophenol, and said reaction can be conducted in the presence of potassium carbonate, sodium carbonate or cesium carbonate. In one embodiment, the reaction in the presence of potassium carbonate unexpectedly results in a product with fewer impurities when compared to the reaction conducted in the presence of cesium carbonate. This represents an improvement and a more efficient synthetic process to produce a final product, minimizing the need for steps

additional purification processes. This finding is also advantageous to the production of other compounds, such as 6, 9, 12 and 14 below.

In one embodiment, the present invention provides a process for preparing (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3 (4-cyanophenoxy) -2-hydroxy-2-methiipropanamide, said process comprising the Steps of:

a) preparing a carboxylic acid of the formula I by opening in the ring of a cyclic compound of the formula

2, in the presence of HBr

free

react an amine of formula 3:

with the carboxylic acid of formula 2 in the presence of a coupling reagent, to produce an amine of the

formula 4

IMPI

INSTITUTO MEXICANO j

OF THE rWOl'l AGE Q ^ aaggr «yj / z INDUSTRIAL ----—

c) reacting the compound amide of formula 5:

formula 4 with

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

In one embodiment, the present invention provides a process for preparing a compound of formula 6:

This process includes the steps of:

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

HBr

b) reacting an amine of formula 7:

NC

with the carboxylic acid of formula 2 in the presence of a coupling reagent, to produce an amide of formula 8:

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

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

In one embodiment, the present invention provides a process for preparing a compound of formula 9:

This process includes the steps of:

a) prepare a carboxylic acid of formula 1 by a / -> and opening of the ring presence of HBr

INSTITUTO MEXICANO Dt LA PRONHMD INDUSTRIAL of a cyclic compound of formula 2 in the un

with

IIBr

react an amine of the

formula

the carboxylic acid of formula 2 coupling reagent to produce in formula 4

C) amide presence of

react

Form ula amide with a compound of formula 10:

11O

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

In one embodiment, the present invention provides a process for the preparation of a compound of formula 12;

This process includes the steps of:

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

free

b) reacting an amine of formula 3:

Τ Μ DI

11η i 1

MEXICAN INSTITUTE ί ·. '' Λ

Df. THE PKOI-IEOAD Ρ> «®ΪΛ4 /

INOUSTXIAL Xy with the carboxylic acid of formula 2 in the presence of a coupling reagent, to produce an amide of formula 4

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

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

In one embodiment, the present invention provides a process for preparing a compound of formula 14:

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

T is OH, OR, NHCOCHs, or NHCOR;

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

And it's CF3, F, I, Br, Cl, CN, CR3 or SnR3;

Q is alkyl, halogen, CF3, CN, CR3, MR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCHs, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OR, COR, OCOR, BEAR2R, SO2R, SR; or Q together with the benzene ring to which they are attached, is a fused ring system represented by the structure A, B or C:

R is alkyl, haloalkyl, d, haloalkyl, tri haloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl, or OH; Y

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

This process includes the steps of:

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

16 , x HIV where L, Ri and T are as defined above, and Ti is O or NH;

IMPI

b) reacting an amine of formula 17:

NII2

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

NI I,

R <'T; Y

II

c) coupling the amide of formula II with a compound of formula 1 9;

IIX

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

In one embodiment, the crystalline and paracrystalline forms of the present invention are prepared by any process *: «·, · ^ ·> & · β-

that can perform the same, such as, but not limited to, those exemplified in the present invention, as will be appreciated by one of ordinary skill in the art. In one embodiment, said process will use a starting material for the preparation of crystalline or paracritaline forms of the present invention, which instead, in some embodiments, is prepared according to the method, schematically illustrated above in the present invention. In some embodiments, the preparation of the starting material comprises a specific reaction of the amide of formula 4 with a compound of formula 5, in the presence of potassium carbonate and a polar solvent, such as for example and in some embodiments, Tetrahydrofuran results in the production of a highly pure preparation, which in turn can improve the rate of crystallization. In some embodiments, the use of the pure preparation as described in the present invention, depending on the crystallization conditions used, can result in a varied proportion of the crystalline forms obtained. In some embodiments, the use of a pure preparation as described in the present invention, which depends on the crystallization conditions used, can result in a varied proportion of crystalline forms, and the rate at which these forms are produced.

In one embodiment, the process further comprises the step of converting the modulator compound

selective androgen receptor (SARM) (R) or (S) -N- (4cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide to its analog, isomer, polymorph , polymorphic form A, paracrystalline form B ', solvent, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, N-oxide, hydrate, hemi-hydrate or any combination thereof.

In one embodiment, the present invention provides a process for preparing an analog of a selective androgen modulator compound of the present invention. In another embodiment, the present invention provides a process for preparing an isomer of a selective androgen modulator compound of the present invention. In another embodiment, the present invention provides a process for preparing a metabolite of a selective compound of the androgen modulator of the present invention. In another embodiment, the present invention provides a process for preparing a derivative of a selective androgen modulator compound of the present invention. In another embodiment, the present invention provides a process for preparing a pharmaceutically acceptable salt of a selective androgen modulator compound of the present invention. In another embodiment, the present invention provides a process for preparing a pharmaceutical of a selective androgen modulator compound of the present invention. In other

In embodiment, the present invention provides a process for preparing an N-oxide of a selective androgen modulator compound of the present invention. In another embodiment, the present invention provides a process for preparing a hydrate of a selective androgen modulator compound of the present invention. In another embodiment, the present invention provides a process for preparing a polymorph of a selective androgen modulator compound of the present invention. In another embodiment, the present invention provides a process for preparing a polymorph A form, as described in the present invention, of a selective androgen modulator compound of the present invention. In another embodiment, the present invention provides a process for preparing a paracrystalline form B ', as described, of a selective androgen modulator compound of the present invention. In another embodiment, the present invention provides a process for preparing a polymorph X form, as described, of a selective compound of the androgen modulator of the present invention. In another embodiment, the present invention provides a process for preparing a polymorph D form, as described, of a selective androgen modulator compound of the present invention. In another embodiment, the present invention provides a process for preparing a paracrystalline form of a selective compound modulator of

INSTITUTO MEXICANO PF LA PROPERTY INDUSTRIAL androgen of the present invention. In another embodiment, the present invention provides a process for preparing a solvent of a selective androgen modulator compound of the present invention. In another embodiment, the present invention provides a process for preparing a combination of any analog, isomer, metabolite, derivative, polymorph, polymorph form A, paracrystalline form B ', paracrystalline, solvent, pharmaceutically acceptable salt, N-oxide and / or hydrates of a selective androgen modulator compound of the present invention. In one embodiment, the present invention comprises any prepared compound.

In one embodiment, the term "isomer" includes, but is not limited to, optical isomers and analogs, structural isomers and analogs, conformational isomers and analogs, and the like.

In one embodiment, the SARMs are the pure (R) -enantiomers. In another embodiment, the SARMs are the pure (S) -enantiomers. In another embodiment, the SARMs are a mixture of (R) and (S) enantiomers. In another embodiment, the SARMs are a racemic mixture comprising an equal amount of (R) and (S) enantiomers. In one embodiment, the process of the present invention further provides a step to convert the SARM compound to its optically active isomer.

In one embodiment, the separation of the (R) enantiomer or (S) enantiomer, from the racemic SARM compounds of the ti

ITEM

INSTITUTO M «! C« o O £ LA PROPERTY INDUSTRIAL

The present invention encompasses crystallization techniques. In another embodiment, the crystallization techniques include differential crystallization of enantiomers. In another embodiment, the crystallization techniques include differential crystallization of diastereomeric salts (tartaric salts or quinine salts). In another embodiment, the crystallization techniques include a differential crystallization of chiral auxiliary derivatives (menthol esters, etc.). In another embodiment, the separation of the optically active enantiomer (R) or enantiomer (S), of the racemic SARM compounds of the present invention comprises reacting the racemate mixture with another chiral group, forming a diastereomeric mixture followed by the separation of the diastereomers. and removing the additional chiral group to obtain the pure enantiomers. In another embodiment, the separation of the optically active (R) enantiomer or (S) enantiomer, from the racemic SARM compounds of the present invention comprises chiral synthesis. In another embodiment, the separation of the optically active (R) enantiomer or (S) enantiomer from the racemic SARM compounds of the present invention comprises biological resolution. In another embodiment, the separation of the optically active (R) enantiomer or (S) enantiomer from the racemic SARM compounds of the present invention comprises enzymatic resolution. In another embodiment, the separation of the optically active (R) enantiomer or (S) enantiomer from the

! NS r 1

TITt.'TOMIZICANE of the proprietary and industrial racemic SARM compounds of the present invention comprise a chromatographic separation using a stationary chiral phase. In another embodiment, the separation of the optically active (R) enantiomer and (S) enantiomer of the racemic SARM compounds of the present invention comprises affinity chromatography. In another embodiment, the separation of the optically active (R) or (S) enantiomer from the racemic SARM compounds of the present invention comprises capillary electrophoresis. In another embodiment, the separation of the optically active (R) or (S) enantiomer of the racemic SARM compounds of the present invention comprises the formation of an ester group of the hydroxyl group of the chiral carbon with an optically active acid, for example (- ) -champanic acid, separating the diastereomeric esters, additionally obtained, by a fractional crystallization or preferably, by a flash chromatography, and then by hydrolyzing each separated ester to the alcohol.

In another embodiment, the S-enantiomer of the SARM compound of the present invention can be converted to the R-enantiomer or its racemate. In another embodiment, the R-enantiomer of the SARM compound of the present invention can be converted to the S-enantiomer or its racemate. In one embodiment, one enantiomer can be converted to the other enantiomer or to its racemate using a chiral reagent, a solvent, a biocatalyst, a chiral catalyst, a hydrogenation

INSTITUTO MEXICANO OE LA moniDM! INDUSTRIAL asymmetric, an enzyme or a combination thereof

In some embodiments, the solid compounds of the present invention comprise solvents. In one embodiment, the term "solvent" refers to solvents in combination with the SARM compounds, for example, an ethyl acetate solvent, which is part of a polymorphic structure of the SARM compound. Such solvents include ethanol, acetone, ethyl acetate, THF, acetonitrile, dichloromethane, 1,4-dioxane, acetic acid, toluene, water, n-heptane, toluene, n-pentane TBME, or any combination thereof.

In another embodiment, the process of the present invention additionally provides a conversion step of the SARM compound to its pharmaceutically acceptable salt. In one embodiment, the pharmaceutically acceptable salts include salts of the substituted amino compounds with organic and inorganic acids, eg, citric acid and hydrochloric acid. The present invention also includes N-oxides of the amino substituents of the compounds described in the present invention. Pharmaceutically acceptable salts can also be prepared from phenolic compounds by treatment with inorganic bases, for example sodium hydroxide. Also, the esters of the phenolic compounds can be made with aliphatic or aromatic carboxylic acids, for example, acetic acid and benzoic acid esters.

The present invention includes "pharmaceutically acceptable salts" of the compounds of the present invention, which can be produced by reacting a compound of the present invention with an acid or a base.

The pharmaceutically acceptable salts of amines of formula I can be prepared from an inorganic acid or from an organic acid. In one embodiment, examples of inorganic salts of amines are bisulfates, bromides, chlorides, hemisulfates, hydrobromides, hydrochlorides, 2-hydroxyethylsulfonates (hydroxyethanesulfonates), iodates, iodides, isothionates, nitrates, persulfates, phosphates, sulfates, sulfamates, sulfanilates (alkyl sulphonates, arylsulphonates, halogen substituted alkyl su Ifo natos, halogen substituted arylsulphonates), sulphonates or thiocyanates.

In one embodiment, examples of organic salts of amines include aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acids and organic acid limes, examples of which are acetates, arginines, aspartates, ascobates, adipates, anthranilate, alginate, alkane carboxylates, substituted alkane carboxylates, alginates, benzenesulfonates, benzoates, bisulfates, butyrates, bicarbonates, bicarbonates, carboxylates, citrates, camphorates, Camphorsulfonates, cyclohexylsulphamates, cyclopentanepropionates, calcium edetates, camsylates, carbonates, clavulanates, cinnamates, dicarboxylates, digluconates, dodecyl sulfonates, dihydrochlorides, decanoates,

enantuates, ethanesulfonates, edetates, edisylates, estolates, esylates, fumarates, formats, fluorinated, galacturonates, gluconates, glutamates, glycolates, glucorate, glucoheptanoate, glycerophosphates, gluceptates, glutamates, glycolates, glycolatosheprosylates, glutamate, glutamate, glumate glutamate, heptanoates, hexanoates, hydroximale.ates, hydrocarboxylic acids, hexylresorcinates, hydroxybenzoates, hydroxynaphthoate, hydrofluorate, lactates, lactobiontes, laurates, malates, maleates, methylene bis (beta-oxinaphthoate), malonates, mandel atos, me si latos, su Ifon atos of methane, methyl bromides, methyl nitrates, methylsulfonates, monopotassium maleates, mucate, monocarboxylates, 2 mittensulftalenosulphrates, naphthalenosulphrates Nats, N-methylglucamines, N-methylglucamines, oxalates, octanoates, oleates, pamates, phenylacetates, picrates, phenyl benzoates, pivalates, propionates, phthalates, phenylacetate, pectinates, phenyl propionates, palmitates, pantothenates, polygalacturates, pyruvates, quinates, ici latos salt, succi natos, stea rats, sulfanilate, subacetate, rat tart, theophyllineacetates, p-toluenesulfonate (tosy latos), trifluoroacetates, terephthalates, tricarboxylates, tannates, tereboxylates , undecanoates or valerates.

In one embodiment, examples of inorganic salts of carboxylic acids or phenols include ammonium, alkali metals which

includes lithium, sodium, potassium, cesium, alkali earth metals including calcium, magnesium, aluminum; zinc, barium, hills, or quaternary ammoniums.

In another embodiment, 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-glucamines, N, N'.dibenzylethylenediamines, nicotinamides, organic amines, ornithines, pyridines, picolinates, piperazines, procaine, tris (hydroxymethyl) methylamines, triethylamines, triethanolamines, triimethylamines, tromethamines or ureas.

In one embodiment, the salts may be formed by conventional means, such as reacting the free base or the free acid form of the product with one or more equivalents of the appropriate acid or base in a solvent or medium where the salt is insoluble or in a solvent such as water, which is removed in vacuo or by freeze drying, or by exchanging the ions of an exiting salt for another ion or a suitable ion exchange resin.

In one embodiment, the present invention also includes

N-oxides of the amino substituents of the compounds λ,. * ·. ^ .xy "S5M-WfiWeeem"

described in the present invention. Also, the phenolic compounds can be made with aliphatic or aromatic carboxylic acids, for example, acetic acid or benzoic acid esters.

The present invention further includes a process for preparing derivatives of the SARM compounds. In some embodiments, the term "derivative" includes, but is not limited to, ether derivatives, acid derivatives, amide derivatives, ester derivatives, and the like. Methods for preparing derivatives are known to a person skilled in the art. For example, ether derivatives are prepared by a coupling of the corresponding alcohols. The amide and ester derivatives are prepared by the corresponding carboxylic acid by reaction with amines and alcohols, respectively.

In some embodiments, the present invention comprises a process for preparing hydrates of the SARM compounds. In one embodiment, the term "hydrate" includes, but is not limited to, hemihydrate, monohydrate, dihydrate, and the like. Hydrates of SARM compounds can be prepared by contacting the SARM compounds with water under conditions suitable to produce the hydrate of choice. The term "hemihydrate" refers to a hydrate where the molecular ratio of the water molecules to the anhydrous compound is 1: 2.

The present invention further includes a

process for preparing pharmaceuticals from SARM compounds. The term "pharmaceutical product" means a composition suitable for pharmaceutical use (pharmaceutical composition), as defined in the present invention.

In some embodiments, the present invention comprises a process for preparing analogs of the SARM compounds. In one embodiment, the term "analog" refers to a compound with a structure, which is similar, but not identical to that of the reference compound. In another embodiment, the term "analog" refers to an isomer or derivative of the SARM compound. In another embodiment, the term "analog of a SARM compound" of the present invention refers to a compound having different substituents on each or both of the phenyl rings in the compound. In another embodiment, the term "analog" refers to the incorporation of the different aromatic rings, eg pyridyl rings, in place of one or both benzene rings. In another embodiment, the term "analog" refers to the incorporation of a sulfur atom in place of each or both of the ether or keto groups.

In some embodiments, the present invention comprises a metabolite of the SARM compounds. The term "metabolite" refers, in some embodiments, to any substance produced by another substance by mimicking or by a metabolic process. In some embodiments, these metabolites can be synthetically prepared and are active in situ,

INSTITUTE MFX1CAN · Di INDUSTRIAL PROPERTY as they are comparable to naturally produced metabolites.

Pharmaceutical Compositions

In one embodiment, the present invention provides a composition containing a crystalline form of (R) or (S) -N (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy. -2-methylpropanamide anhydrous and a suitable carrier or diluent.

In another embodiment, the present invention provides a composition comprising a crystalline form A of (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide anhydrous and a suitable carrier or diluent.

In one embodiment, the present invention provides a composition comprising a paracrystalline form of (R) or (S) -N- (4-cyano-3- (trifluoromethyl) pheno 1) -3- (4-cyanophenoxy) ) -2-hydroxy-2-methylpropanamide and a suitable carrier or diluent.

In one embodiment, the present invention provides a composition comprising a paracrystalline form B 'of (S) N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide and a suitable carrier or diluent.

In one embodiment, the present invention provides a composition comprising a mixture of any solid form of compound (R) or (S) -N- (4-cyano-3-

(trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide of the present invention and a suitable carrier or diluent.

In another embodiment, the present invention provides a composition comprising a mixture of solid crystalline and paracrystalline forms of the compound (R) or (S) -N- (4-cyan o3- (trifluoromethyl) phenyl) -3- (4 -cyanophenoxy) -2-hydroxy-2-methylpropanamide and a suitable carrier or diluent.

In another embodiment, the present invention provides a composition comprising a mixture of the crystalline form A and the para-crystalline solid form B 'of the compound (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4 -cyanophenoxy) -2-hydroxy-2-methylpropanamide and a suitable carrier or diluent.

In one embodiment, the present invention comprises compositions comprising the different forms of (R) or of (S) -N- (4-cyano-3- (trifluoromethyl) phen i 1) -3- (4-cyanophenox i) - 2-hydroxy-2-methylpropanamide, and can be different in proportion or a single form per composition, which possesses useful properties in the treatment of androgen-related conditions described in the present invention. In another embodiment, the present invention comprises compositions comprising different isomers of N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-h-hydroxy-2-methylpropanamide, these may be different in the proportions or a single isomer per composition, which has

Useful properties in the treatment of androgen-related conditions described in the present invention.

In some embodiments, the "pharmaceutical composition" phase refers to a "therapeutically effective amount" of the active ingredient, eg, the SARM compound, together with a pharmaceutically acceptable carrier or diluent. In some embodiments, the phase "therapeutically effective amount" refers to an amount which provides a therapeutic effect for a given condition and a regimen of administration.

Pharmaceutical compositions containing the MRSA agent can be administered to a subject by any method known to one skilled in the art, such as parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitoneally, intraventricularly, intracranial or intratumoral.

In another embodiment, the present invention provides a composition of the solid forms of the present invention, and an acceptable carrier or diluent.

In one embodiment, the pharmaceutical compositions are administered orally, and are further formulated in a suitable form for oral administration, for example, as a solid preparation. Suitable solid oral formations include tablets, capsules, pills, granules, pellets, and the like. In one embodiment of the present invention,

I Ν'ΓΠΤνΤΟ Μ «OCA NO

OF THE PROPERTY

INDUSTRIAL SARM compounds are formulated in a capsule. According to this modality, the SARM compounds are formulated in a capsule. According to this embodiment, the compositions of the present invention comprise, in addition to the SARM active compound and the inert carrier or diluent, a hard gelatin capsule.

Oral formulations containing the present polymorph can comprise any conventionally used oral form, including tablets, capsules, buccal forms, troches, or lozenges. The capsules can contain mixtures of crystalline form A in the desired percentage together with any other polymorphs of SARM or of the amorphous SARM. Capsules and tablets of the desired crystalline form of the percentage of composition can also be combined with mixtures of other active compounds or fillers and / or inert diluents such as pharmaceutically acceptable starches (for example, cornstarch, potato or tapioca), sugars , artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, fluorines, gelatins, gums, and so on.

Tablet formulations can be made by conventional compression, wet granulation, or dry granulation methods and can use pharmaceutically acceptable diluents (fillers), binding agents, lubricants, disintegrants, suspending agents, or

stabilization including but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, calcium carboxymethylcellulose, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex of silicates, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar. Oral formulations, in some embodiments, use standard delay or time-release formulations.

Exemplary excipient systems suitable for preparing formulations of the present polymorph include one or more fillers, disintegrants, and lubricants.

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

Suitable disintegrants for use in the present formulations 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 (eg, veegum or xanthan gum), cellulose floc, ion exchange resins, or effervescent systems, such as those that use acids.

IMPI in food (such as citric acid, tartaric acid, methyl acid, fumaric acid, lactic acid, adipic acid, ascorbic acid, aspartic acid, erythorbic acid, glutamic acid, and succinic acid) and an alkaline carbonate component ( such as sodium bicarbonate, calcium carbonate, magnesium carbonate, potassium carbonate, ammonium carbonate, and so on). The disintegrants useful in the present invention may comprise from about 4% to about 40% of the composition by weight, preferably from about 15% to about 35%, more preferably from 20% to about 35%.

Pharmaceutical formulations can also contain an antioxidant or mixture of antioxidants, such as ascorbic acid. Other antioxidants which can be used include sodium ascorbate and sodium palmitate, preferably in conjunction with an amount of ascorbic acid. An exemplary range for antioxidants is from about 0.5% to about 15% by weight, more preferably from 0.5% to about 5% by weight.

In some embodiments of the present invention, the active pharmacological agents comprise from about 0.5% to about 20% by weight, to the final composition, or in some embodiments, from about 1% to about 5%, and the coating or capsule comprises 8% by weight, of the composition

final.

The formulations described in the present invention can be used in an uncoated or unencapsulated solid form. In some embodiments, the drug compositions are optionally coated with a layer coating, for example, comprising from about 0.3% to about 8% of the weight of the total composition. Suitable layer coatings with the present formulations are known in the art and generally consist of a polymer (usually a cellulosic type of polymer), a colorant, and a plasticizer. Additional ingredients such as wetting agents, sugars, flavors, oils, and lubricants can be included in topcoat formulations to impart certain characteristics to the topcoat. The compositions and formulations of the present invention can also be combined and processed as a solid, then placed in a capsule form, such as a gelatin capsule.

In another embodiment, the active compound can be delivered in a vesicle, in a particular liposome (see Langer, Science 249.1527-1533 (1990); Treat et al., In Liposomes in Infectious Disease and Cancer Therapy, López-Berestein and Fidler (editorials), Liss, New York, pp 353-365 (1989); López - Berestein, ibid, pp- 317 to 327, see

generally ib id).

As used in the present invention "pharmaceutically acceptable carriers or diluents" are well known to those skilled in the art. The carrier or diluent can be a solid carrier or diluent for solid formulations.

Solid carriers / diluents include, but are not limited to, a gum, a starch (eg, cornstarch, stained pregel starch), a sugar (eg, lactose, mannitol, sucrose, dextrose), a cellulosic material (eg, microcrystalline cellulose), an acrylate (eg, polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.

Additionally, the compositions may further comprise bonding agents (e.g. acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), agents disintegration agents (e.g. cornstarch, potato starch, alginic acid, silicone dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate), buffers (e.g. Tris-HCi, acetate, phosphate) or various pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), inhibitors

INSTITUTO MEXICANO DE LA FROHEDAD INDUSTRIAL protease, surfactants (for example, sodium lauryl sulfate), permeation enhancers, solubilizing agents (for example, glycerol, polyethylene, glycerol), anti-oxidants (for example, ascorbic acid, Hate metabisulfite, butylated hydroxyanisole), stabilizers (eg, hydroxypropyl cellulose, hydroxypropylmethyl cellulose), viscosity increasing agents (eg, carbomer, colloidal silicone dioxide, ethyl cellulose, guar gum), sweeteners (eg, aspartame, citric acid), preservatives (eg, Thimerosal, benzyl alcohol, parabens), lubricants (eg, stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow aids (eg, colloidal silicone dioxide), pastifiers (eg, diethyl phthalate, triethyl citrate), emulsifiers (eg, carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (eg poloxa mers or pol oxa min as), coating and layer-forming agents (eg ethyl cellulose, acrylates, polymethylacrylates) and / or adjuvants.

In one embodiment, the pharmaceutical compositions provided in the present invention are controlled by release compositions, eg, compositions wherein the SARM compound is released over time after administration. In another embodiment, the composition is an immediate release composition, for

example a composition where all SARM compounds are released immediately after administration.

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 modes of oral administration.

The compositions can also include the incorporation of the active material in or on the particular preparations of polymeric compounds, such as polylactic acid, polyglycolic acid, hydrogels, etc., or on liposomes, microemulsions, electrically charged particles, unilamellar or multilamellar vesicles, phantoms erythrocyte, or spheroplasts. Such compositions will influence the physical state, solubility, stability, rate of release in vivo, and rate of clearance in vivo.

The preparation of pharmaceutical compositions which contain an active component is well understood in the art, for example by tabletting, granulating or mixing processes. The therapeutically active ingredient is often mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient. For oral administration, MRSA agents or their physiologically tolerated derivatives such as salts, esters, N-oxides, and the like are mixed with frequent additives for this purpose, such as carriers,

stabilizers, or diluent inerts, and converted by common drugs into forms suitable for administration, such as tablets, coated tablets, soft or hard gelatin capsules, oily, alcoholic or aqueous solutions.

An active component can be formulated into the composition as pharmaceutically acceptable neutralized salt forms. Pharmaceutically acceptable salts include acid addition salts (formed with free amino groups of the antibody or polypeptide molecule), which are formed with inorganic salts such as, for example, hydrochloric or phosphoric acids, or such organic acids such as acetic. , oxalic, tartaric, m and he ico, and the like. The salts formed from the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonia, calcium, or ferric hydroxides, and such organic bases as isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.

For use in medicine, the salts of the SARM will be pharmaceutically acceptable salts. However, other salts may be useful in the preparation of compounds according to the present invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts which, for example, can be formed by mixing a solution of the VS'ñTJ5'u'es'fo ^J3'e according to the present 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,

INSTITUTO MEXICANO DE LA RROPIEDAD INDUSTRIAL citric acid, tartaric acid, carbonic acid or phosphoric acid.

The Biological Activity of Modulator Compounds

Selective Androgen

The solid forms and processes to produce the same provided in the present invention, in some embodiments, are directed at selective androgen receptor modulators (SARMs), which are useful for oral testosterone replacement therapy, having anabolic and anabolic activity. androgenic in vivo not expected. In some embodiments, appropriately substituted compounds are effective for treating prostate cancer and useful for prostate cancer imaging.

As contemplated in the present invention, the appropriately substituted SARM compounds of the present invention are useful for

a) a male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Declension of

Androgen in Male

Aging (ADAM), such as for fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism,

osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with ADIF, such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, cancer uterine and ovarian cancer; d) treatment and / or prevention of chronic muscle wasting; e) decrease the incidence of, interrupt or cause a regression of prostate cancer; f) oral androgen replacement and / or other diagnostic and / or therapeutically clinical areas.

As used in the present invention, receptors for extracellular signaling molecules are collectively referred to as "cell signaling receptors."

Many cell signaling receptors are transmembrane proteins on a cell surface; When they unite an extracellular signaling molecule (eg, a ligand), they are activated to generate a cascade of intracellular signals that alter cell behavior. In contrast, in some cases, the receptors are inside the cell and the signaling ligand has to enter the cell to activate them;

these signaling molecules therefore must be sufficiently

small and hydrophobic to diffuse through the plasma membrane of the cell. As used in the present invention, these receptors are collectively referred to as "intracellular cell signaling receptors."

Steroid hormones are an example of small hydrophobic molecules to diffuse directly across the plasma membrane of target cells and bind to intracellular cell signaling receptors. These receptors are structurally related and constitute the intracellular receptor superfamily (or steroid hormone-estrogen receptor superfamily). Spheroid hormone receptors include progesterone receptors, estrogen receptors, androgen receptors, glucocorticoid receptors, and corticosteroid receptors. The present invention is particularly directed to androgen receptors.

In addition to the ligand that binds to the receptors, the receptors can be blocked to prevent ligand binding. When a substance is attached to a receptor, the substance's three-dimensional structure fits into a space created by a receptor's three-dimensional structure in a plug or ball configuration.

In one embodiment, the present invention is directed to the process for preparing solid forms and compounds of

selective androgen receptor modulator which are agonist compounds. Therefore, in one embodiment, the SARM compounds of the present invention are useful in binding and activating spheroidal hormone receptors. In one embodiment, the agonist compound of the present invention is an agonist which binds the androgen receptor. In another embodiment, the compound has a high affinity for the androgen receptor. In another embodiment, the present invention provides androgen modulator compounds which have anabolic and agonistic activity of a non-spheroidal compound for the androgen receptor. In one embodiment, the present invention is directed to the process for preparing solid forms of selective androgen receptor modulator compounds which with antagonist compounds. Therefore, in one embodiment, the solid forms of the SARM compounds of the present invention are useful for binding and inactivating spheroidal hormone receptors. In another embodiment, the solid forms of the present invention have a high affinity for the androgen receptor. In another embodiment, the solid forms of the present invention also have anabolic activity. In another embodiment, the solid forms of the SARM compounds irreversibly bind to the androgen receptor. In another embodiment, the solid forms of the SARM compounds are alkylating agents.

In yet another embodiment, the solid forms of the SARM compounds of the present invention can be classified as partial AR antagonists / agonists. Solid forms of SARMs are AR agonists in some tissues, and cause increased transcription of AR-responsive genes (eg, anabolic effect of muscle). In other tissues, these compounds serve as inhibitors in RA to avoid agonistic effects of native androgens.

Assays to determine whether the compounds of the present invention are AR agonists or antagonists are well known to one of skill in the art. For example, agonistic AR activity can be determined by monitoring the ability of solid forms of SARM compounds to maintain and / or stimulate the growth of AR containing tissue such as prostate and seminal vesicles, as measured by weight. AR antagonistic activity can be determined by monitoring the ability of SARM compounds to inhibit the growth of AR-containing tissue.

In another embodiment, the solid forms of the MRSA compounds irreversibly bind to the androgen receptor of a mammal, for example a human, Therefore, in one embodiment, the compounds of the present invention may contain a functional group (e.g. eg, affinity tag) that allows alkylation of the androgen receptor (eg, covalent bond formation). For the

IMPI therefore, in this case, the compounds are alkylating agents which bind irreversibly to the receptor and, consequently, cannot be dislodged by a steroid, such as endogenous DHT ligands and testosterone. An "alkylating agent" is defined in the present invention as an agent which is alkylated (forms a covalent bond) with a cellular component, such DNA, RNA, or protein. It is a highly reactive chemical that introduces alkyl radicals into biologically active molecules and therefore prevents their proper function. The alkylation moiety is an electrophilic group that interacts with nucleophilic moieties in cellular components.

In accordance with one embodiment of the present invention, a method is provided for binding the solid forms of the SARM compounds of the present invention to an androgen receptor by contacting the receptor with the solid forms.

<td>of the compound</td><td>MRSA,</td><td>such as</td><td>a</td><td>form</td><td colspan="2">polyform A, shape</td>

<td>polymorphic C,</td><td>form</td><td>polymorphic</td><td>D,</td><td>form</td><td>paracrystalline</td><td>B ',</td>

<td>paracrystalline</td><td>B ", a</td><td>solvent</td><td>of</td><td>same,</td><td>a polymorph</td><td>of</td>

itself, a metabolite thereof, etc., or any combination thereof, under conditions effective to cause the selective androgen receptor modulator compound to bind the androgen receptor. Unification of the solid forms of the selective androgen receptor modulator compounds to the androgen receptor enables the τ and

11¾

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compounds of the present invention to be useful as a male contraceptive in a number of hormone therapies. Agonist compounds unify and activate the androgen receptor. The antagonist compounds unify and activate the androgen receptor. The binding of the antagonist or agonist compounds is reversible or irreversible.

In one embodiment, the solid forms of the SARM compounds of the present invention are administered as the sole active ingredient. However, also within the scope of the present invention are methods for hormone therapy, for treating prostate cancer, for delaying the progression of prostate cancer, and for preventing and / or treating recurrence of prostate cancer, which comprises administering the solid forms of the SARM compounds in combination with one or more therapeutic agents. These agents include, but are not limited to: LHRH analogs, reversible antiandrogens, antiestrogens, anticancer drugs, 5-alpha reductase inhibitors, aromatase inhibitors, progestins, agents that act through other nuclear hormone receptors, receptor modulators selective estrogen (SERM), progesterone, estrogen, PDE5 inhibitors, apomorphine, bisphosphonate, and one or more solid forms of the SARMS, eg, one with AR agonistic activity.

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Therefore, in one embodiment, the present invention provides compositions and pharmaceutical compositions comprising solid forms of the selective androgen receptor modulator compound, in combination with LHRH analog. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising the solid forms of a selective androgen receptor modulator compound, in combination with a reversible antiandrogen. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising the solid forms of the selective androgen receptor modulator compound, in combination with an antiestrogen. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising the solid forms of the selective androgen receptor modulator compound, in combination with an anticancer drug. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising the solid forms of the selective androgen receptor modulator compound, in combination with a 5-alpha reductase inhibitor. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising the solid forms of the selective androgen receptor modulator compound, in combination with an aromatase inhibitor. In other

INSTITUTO MEXICANO DE LA PROPII-DAO INDUSTRIAL modality, the present invention provides compositions and pharmaceutical compositions comprising the solid forms of the selective androgen receptor modulator compound, in combination with a progestin. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising solid forms of the selective androgen receptor modulator compound, in combination with an agent that acts through other nuclear hormone receptors. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising the solid forms of the selective androgen receptor modulator compound, in combination with selective estrogen receptor modulators (SERMs). In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising the solid forms of the selective androgen receptor modulator compound, in combination with progesterone. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising solid forms of the selective androgen receptor modulator compound, in combination with estrogen. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising solid forms of the selective androgen receptor modulator compound, in combination with

PDE5 inhibitors. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising solid forms of the selective androgen receptor modulator compound, in combination with apomorphine. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising solid forms of the selective androgen receptor modulator compound, in combination with a bisphosphonate. In another embodiment, the present invention provides compositions and pharmaceutical compositions comprising solid forms of the selective androgen receptor modulator compound, in combination with one or more additional SARMs.

The following examples are presented to more fully illustrate the embodiments of the present invention. However, they should not be presented as limiting the scope of the present invention for any reason.

EXPERIMENTAL DETAILS SECTION EXAMPLE 1: COMPOUND SYNTHESIS S-1

(2R) -1 -Metacryloylpyrrolidine-2-carboxylic acid-D-Proline, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath; the resulting alkaline solution was diluted with acetone (71 mL). A solution of acetone (71 mL) of methacryolyl chloride (13.56 g, 0.13 mol) and a solution of 2N NaOH (71 mL) were added simultaneously · »· ** '

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FROM LA? ¡> \> PUOAU INÜUÓTÜA1 about 40 minutes to the aqueous solution of D-proiin in an ice bath. The pH of the mixture was maintained at 10 to 11 ° C during the addition of methacryolyl chloride. After stirring (3 h, at room temperature), the mixture was evaporated in vacuo at a temperature of 35 to 45 ° C to remove the acetone. The resulting solution was washed with ethyl ether and acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 mL x 3). The combined extracts were dried over Na2SW4 and filtered through Celite, and evaporated in vacuo to provide the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes yielded 16.2 (68%) of the desired compound as colorless crystals: mp 102-103 ° C (lit. [214] mp 102.5-103.5 ° C); the NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound.1H NMR (300 MHz, DMSO-d6) δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5-03 (s) for the second rotamer (2H totally for both rotamers, vinyl CH2). 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (1H totally for both rotamers, CH in 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 a major rotamer 173.3, 169.1, 140.9, 1 16.4, 58.3, 48.7, 28.9, 24.7, 19.5: for a minor rotamer 174.0, 170.0, 141.6, 1 15.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737

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INDUSTRIAL (CO), 1647 (CO, COOH), 1584, 1508, 1495, 1369, 1348, 1 178 cm '1; [a] D26 + 80.8 ° (c = 1, MeOH); Anal. Caled, for CgHuNO3:

C 59.00, H 7.15, n 7.65. Found: C 59.13, H 7.19, N.761.

Br (3R, 8Ar) -3-Bromomethyl-3-methyl-tetrahydro-pyrrolo [2.1cni, 4] oxazine-1,4-dione.

A solution of NBS (23.5 g, 0.132 mol) in 100 mL of DMF h was added dropwise to a stirred solution of (methyl-acryloyl) -pyrrolidine (16.1g, 88 mmol) in 70 mL of DMF under argon at temperature room, and the resulting mixture was stirred 3 days. The solvent was removed in vacuo, and a yellow solid was precipitated. The solid was suspended in water, stirred overnight at room temperature, filtered, and dried to provide 18.6 (81%) (smallest weight when dried ~ 34%) of the title compound as a yellow solid; mp 152-154 ° C (lit [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, chyralic center), 4.02 (d, J = 11.4 Hz, 1H, CHHto), 3.86 (d, J - 11.4 Hz, 1H, CHHb), 3.533.24 (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, 1645 (C = O), 1687 (C = O), 1448, 1377, 1360, 1308, 1227,

159, 1062cm '1; [to]D26 +1 24.5 ° (c = 1.3, chloroform); Anal.

Caled. For C9H12BrNO3: C 41.24, H 4.61 N.34. Found: C

<td>,.or</td><td>Reflux</td><td>HO 'Br</td>

<td>H3C</td><td></td><td>(R) -3-bromo-2-hydroxy-2- acid</td>

methylpropanoic

(2R) -3-Bromo-2-hydroxy-2-methylpropanoic acid. A mixture of bromolactone (18.5 g, 71 mmol) in 300 mL of 24% HBr was heated under reflux for 1 hour. The resulting solution was diluted with brine (200 mL), and was extracted with ethyl acetate (100 mL x 4). The combined extracts were washed with NaCHO3 (100 mL x 4). The aqueous solution was acidified with concentrated HCl to pH = 1, which in return was extracted with ethyl acetate (100 mL x 4). The combined organic solution was dried over Na2SW4, filtered through Celite, and evaporated in vacuo until dry. Recrystallization from toluene produced 10.2 g (86%) of the desired compound as colorless crystals: mp 107-109 ° C (lit. [214] mp 109-113 ° C for the S-isomer);1H NMR (300 MHz, DMSO-d6) δ 3.63 (d, J =

10.1 Hz, 1H, CHHto=, 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; [to]D26 + 10.5 ° (c = 2.6,

MeOH); Anal. Caled. For C4H7BrO3: C 26.25, H 3.86.

Found: C 26.28, H 3.75.

HO X Br H3C 'oh

cr Br

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

NC.

Synthesis of (2R) -3-Bromo-N- [4-cyano-3- (trifluoromethyl) phenyl] -2-h id roxy-2-methiIpropanamide. Thionyl chloride (46.02 g, 0.39 mol) was added dropwise to a cooled solution (less than 4 ° C) of 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 condition. After 20 minutes, 5-amino-2-cyanobenzotrifluoride (40.0 g, 0.21 mol), 400 mL of THF was added and subsequently the mixture was allowed to stir overnight at room temperature. The solvent was removed under reduced pressure to provide a solid which was treated with 300 mL of H2Or, extracted with EtOAc (2 x 300 mL) and brine (300 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure to provide a solid which was purified from column chromatography using CH2CI2/ EtOAc (80:20) to provide

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INDUSTRIAL ”* ¿1. *** a solid. This solid was recrystallized from CH2CL2/ hexane to provide 5.8 g (73.9%) of (2R) -3-Bromo-N- [4-cyano-3 (trifluoromethyl) phenyl] -2-hydroxy-2-methylpropanamide as a yellow solid.

1H NMR (CDCI3 / TMS) δ 1.66 (s, 3H, CHj), 3.11 (s, 1H, OH), 3.63 (d, J = 10.8 Hz, 1H, CH2), 4.05 (d, J = 10.8 Hz, 1H, CH2), 7.85 (d, J = 8.4 Hz, 1H, ArH), 7.99 (dd, J = 2.1, 8.4 Hz, 1H, ArH), 8.12 (d, J = 2.1 Hz, 1H, ArH), 9.04 (bs, 1H, NH). Calculated mass: 349.99, [MH] '349.0. Mp: 124-126 ° C.

(2R) -3-bromo-N- [4-cyano-3 (tnfluoromethyl) phenyl] -2-hydroxy-2-methylpropanamide

K2CO3 NC

2-propanol

F3C h3<_;

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

Synthesis of (S) -N- (4-cyano-3 ~ (trifluoromethyl) phenyl) -3- (4cyanophenoxy) -2-hydroxy-2-methylpropanamide. A mixture of bromoamide ((2R) -3-bromo-N- [4-cyano-3- (trifluoromethyl) phenyl] -2hydroxy-2-methylpropanamide, 50 g, 0.14 mol), K2CO3 anhydrous (59.04 g, 0.43 mol), and 4-cyanophenol (25.44 g, 0.21 mol) in 500 mL of 2-propanol was heated under reflux for 3 hours and subsequently concentrated under reduced pressure to provide a solid. The resulting residue was treated with 500 mL of H2O and subsequently 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

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INDUSTRIAL ^ a. »8 * was dried over MgSO4 and subsequently concentrated under reduced pressure to provide an oil which was treated with 300 mL of ethanol and an activated carbon. The reaction mixture was heated under reflux for 1 hour and subsequently the hot mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to provide an oil. This oil was purified by column chromatography using CH2CL2/ EtOAc (80:20) to provide an oil which was crystallized from CH2CL2/ hexane to provide 33.2 g (59.9%) of (S) -N- (4-cyano-3- (trifluorom ethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide as a colorless solid ( a type of cotton).

1H NMR (CDCI3/ TMS) δ 1.63 (s, 3H, CH3), 3.35 (S, 1H.OH), 4.07 (d, J - 9.04 Hz, 1H, CH), 4.51 (d, J = 9.04 Hz, 1H, CH),

6.97 - 6.99 (m, 2H, ArH), 7.57-7.60 (m, 2H, ArH), 7.81 (d, J =

8.55 Hz, 1H, ArH), 7.97 (dd, J = 1.95, 8.55 Hz, 1H, ArH), 8.12 (d, J - 1.95 Hz, 1H, ArH), 9.13 (bs, 1H, NH). Calculated mass: 389.10, [M-HJ- 388.1. Mp: 92-94 ° C.

EXAMPLE 2: CRYSTALLIZATION OF SARM S-1 COMPOUND

Materials and methods

Methods:

X-ray powder diffraction (XRPD)

XRPD was used for crystal structure determination or material recognition of liquid crystals in partially crystalline mixtures. XRPD was executed with a • V

INSTITUTO MEZICANO DE LA PROPERTY INDUSTRIAL PANalytic X-ray diffractometer PW 1710, where the tube anode was Cu with Ka radiation. The standard was collected in the scan mode step (step size 0.02 ° 20, counting time 2.4 s / step. The sample was measured without any special treatment other than the application of light pressure to have a flat surface. The measurements were carried out in an atmosphere of ambient air Raman spectroscopy

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

Fourier Transformation Infrared - Thermo Gavimetric (TG-FTIR) and Thermo Gavimetric Analysis.

The TG-FTIR instrument consists of a thermogravimetric (TG) analyzer coupled with a Fourier Transformation Infrared (FTIR) spectrometer for the analysis of evolved gases such as H gases.2Or, due to its loss of mass combined with the characterization of the evolved components. Thermo-gavimetric measurements were carried out with a Netzsch Termo-Microbalance TG 209

coupled to a Bruker 22 FTIR Spectrometer Vector. The sample pans with a bolt hole were used under an atmosphere of N2, in a heating range of 10 K / min, with a temperature range of 25 to 250 ° C. Additional Thermogravimetric Analyzes were conducted using TA Q500 TGA Instruments under various conditions.

Differential Scanning Calorimetry (DSC)

Thermal analysis was carried out with an Elmer Perkin DSC7 with the following experimental conditions; 3-6mg sample mass, closed gold sample pan, temperature range -50 ° C to 120 ^ 0, heating range 20K / min. The samples were weighed in air or atmosphere for N2 dry. Additional thermal analysis was conducted using TA Q1000 DSC Instruments using airtight aluminum pans under various conditions.

Dynamic Vapor Absorption (DVS)

Dynamic vapor absorption quantification is related to the mass of water absorbed and subsequently desorbed during the crystallization process. In order to define if batches P1, P2 and P4 are hydrated polymorphs, DVS measurements were conducted (Figure 9). A sample (13 to 14 mg) was placed in a Pt pan, and the sample was equilibrated at a temperature of 25 ° C / 50% rh before starting a pre-defined humidity program (1.0 hours 50%, 50% Rh at 95% rh: 5% rh / hour, 10 hours at 95% rh, from

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INDUSTRIAL NSl_kí - 95% rh to 0% rh: 5% rh / hour, 10 hours at 0% rh, from 0% rh to 50% rh: 5% rh / hour, 1 hour at 50% rh

Scanning Electron Spectroscopy (SEM)

Images of batch S-1 P1, P2 and P4 (Figure 8) were taken with a SEM CamScan CS24 system.

Filtration

During the following experiments: suspension equilibrium, precipitation experiment, recrystallization, relative stability experiments, and water solubility experiments, a filtration step was conducted. Centrifugal filter devices: Ultrafree-CL (0.22 / a, m),

Millipore; centrifugal type or Eppendorf 5804R were used at a temperature of 22 ° C and a centrifugation program of 2 minutes at 3000 rpm.

High Performance Liquid Chromatography (HPLC)

HPLC was used to analyze the purity of the S-1 machine. The HP 1090, HPLC machine was used with the following conditions:

Column: RP18 Symmetry Shield, 3.9 X 150 mm, 5 micram

Column temperature: 35 ° C

Injection volume: 10 micraL

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 A 271 NM

Running time: 21 minutes

Retention time (S-1): 10.7 minutes.

Materials:

Solvents

For all experiments, Fluka or Merck grade solvents were used. Water: de-ionized (Fluka no. 05305)

Chemicals

Compound S-1 was synthesized as described in Example 1.

Results:

Four consistently designated S-1 compound lots, (S-1-P1), (S-1-P2), (S-1-P3), and (S-1-P4) were selected for characterization. . S-1-P1, S-1-P2, and S-1-P3 were individual batches prepared by the synthetic process described in Example 1. Lot S-1-P4 was a sample of batch S-1-P1 exposed at 40 ° C / 75% rh during storage. The following experiments were conducted to determine the stability, solubility, and characteristics of different solid forms of compound S-1.

The following table presents the X-ray diffraction results of form A of S-1 as shown in Figure

4A:

<td>Angle 2-Theta °</td><td>Angstrom value</td><td>Intensity Cps</td><td>intensity% %</td>

The following table presents the X-ray diffraction results of the A + C form of S-1 as shown in Figure 12D, where the diffraction angles of the C form were identified:

Mixture

Form A with Form C

<td>Peak assignment without shape A line</td><td>Angle 2-Theta °</td><td>of value Anqstrom</td><td>Intensity Cps</td><td>Intensity%</td>

:> F. ·

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<td>probable</td><td> 9.46</td><td> 9.3</td><td> 25</td><td> 10</td><td rowspan="23"></td>

<td>Probable</td><td> 15.99</td><td> 5.54</td><td> 41</td><td> 17</td>

In one embodiment, Form C has additional lines which are overlapped by signals of Form A.

Peak search and d-value calculation were performed with a software version EVA 10, 0, 0, 0, Cu Kalfa2 was removed by software, and only lines up to 35 ° 2tet were listed.

Sample PP148-P1 was measured in a 0.1 mm sample holder on a PW1710 PANalytic diffractometer.

Sample PP148-P52 was measured in a 0.1 mm sample holder on a Bruker D8 Advance diffractometer.

The following table presents diffraction results of

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X-ray of the D form of S-1 as shown in Figure (below):

| Angle T give value | Intensity [I / Itnax]

<td>2-Theta 0</td><td>Angstrom</td><td>Cps</td><td></td>

Water vapor absorption (humidity chamber)

The compound was stored in a glass tube under 96% rh (relative humidity) in a humidity chamber at room temperature. After the different storage time, the Raman measurements were conducted using hermetically sealed glass tubes. The results are summarized in Table 1:

Table 1:

<td>Start form</td><td>Solvent</td><td>Concentration mg / ml</td><td>Terms</td><td>Produced form</td>

<td rowspan="4">TO</td><td rowspan="4"></td><td></td><td>stored in a 96% rh / 23 ° C humidity chamber</td><td>(dust)</td>

<td rowspan="3"></td><td>4 weeks</td><td>A + a small amount of form B '</td>

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

<td>11 weeks</td><td>A + approximately 20% of form B '(see figure 17A)</td>

<td rowspan="3">TO</td><td rowspan="3">Water</td><td rowspan="3"> 111/5.0</td><td>23 ° C</td><td>(suspension)</td>

<td>sonication 5 minutes</td><td>(suspension)</td>

<td>stirred 19h / 37 ° C filtered & air dried</td><td>B '(see figure 17B)</td>

<td rowspan="3">TO</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 3 h / 83 ° C</td><td>viscous sticky dough</td>

<td>cooled to 47 ° C in 1.5 h filtered & air dried</td><td>B '</td>

<td rowspan="2">TO</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 20 h / 23 ° C filtered & air dried</td><td>A (see figure 17C)</td>

<td rowspan="4">TO</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 12 min / 40 ° C</td><td>(suspension)</td>

<td>sonicated 2 minutes</td><td>(suspension)</td>

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

Approximate solubility measurement

To determine the approximate solubility at room temperature, the solvent was added in steps to the solid material. After each addition, the sample was shaken. The addition of

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Table 2

<td>Solvent</td><td>Solid shape</td><td>Solubility (mg / ml)</td>

<td>ethanol</td><td>TO</td><td> >200</td>

<td>acetone</td><td>TO</td><td> >200</td>

<td>ethyl acetate</td><td>TO</td><td> >200</td>

<td>acetonitrile</td><td>TO</td><td> >200</td>

<td>dichloromethane</td><td>TO</td><td> >200</td>

<td>1,4-dioxane</td><td>TO</td><td> >200</td>

<td>acetic acid</td><td>TO</td><td> >200</td>

<td>toluene</td><td>TO</td><td>> 6 cloudy solution</td>

<td>ethanol / water 3: 1 v / v</td><td>TO</td><td> >200</td>

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

<td>ethanol / water 1: 3 v / v</td><td>TO</td><td> <5</td>

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

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

<td>acetone / n-heptane 1: 1 v / v</td><td>TO</td><td> >200</td>

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

<td>THF / n-heptane 1: 1 v / v</td><td>TO</td><td> >200</td>

<td>THF / n hcptan 1: 3 v / v</td><td>TO</td><td> 65</td>

<td>acetonitrile / toluene 1: 1 v / v</td><td>TO</td><td> >200</td>

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

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

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

<td>ethyl acetate / n-heptane 1: 2 v / v</td><td>B</td><td>> 9 transformation from solid form to solid form A</td>

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

<td>ethyl / n-pentane 1: 2 v / v format</td><td>TO</td><td> 12</td>

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

<td>ethyl acetate / n-heptane 1: 3 v / v</td><td>TO</td><td><5 cloudy solution</td>

Suspension equilibrium experiments

Suspension equilibrium experiments were carried out with 81 to 128 mg of the compound. The

suspensions were stirred with a magnetic stirrer.

Samples the air to prevent possible solvents or labile hydrates. Results of Solid Form Suspension Equilibrium Experiments

Table 3:

<td>Start Form</td><td>Solvent</td><td>Concentration mg / ml</td><td>Terms</td><td>Produced Form</td>

<td rowspan="3">TO</td><td rowspan="3">n-heptane</td><td rowspan="3"> 108/2.0</td><td>23 ° C</td><td>(suspension)</td>

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

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

<td rowspan="3">TO</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 18 h / 37 ° C filtered & air dried</td><td>TO</td>

<td rowspan="2"> 8’</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 2 h / 23 ° C filtered & air dried</td><td>A (see Fig 10b)</td>

<td rowspan="2">TO</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 3 days / 23 ° C filtered & air dried</td><td>TO</td>

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

<td> 126/2.0</td><td>stirred 3 days / + 2 ° C filtered & air dried</td><td>TO</td>

<td rowspan="2">B '</td><td rowspan="2">ethyl acetate + n-pentane 1: 2 v / v</td><td rowspan="2"> 101/1.0</td><td>23 ° C</td><td>(suspension)</td>

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

<td rowspan="2">TO</td><td rowspan="2">ethyl acetate + n-pentane 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 & air dried</td><td>A (see Fig 10d)</td>

<td rowspan="2">TO</td><td rowspan="2">ethyl + n-pentane 1: 2 v / v format</td><td rowspan="2"> 112/2.0</td><td>23 ° C</td><td>(suspension)</td>

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

<td rowspan="2">TO</td><td rowspan="2">methyl acetate + n-pentane 1: 2 v / v</td><td rowspan="2"> 126/2.0</td><td>23 ° C</td><td>(suspension)</td>

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

Vapor diffusion experiments

Vapor diffusion experiments were carried out with the solution of the compound in different solvents. The solutions were placed in small open containers that were stored in larger vials containing miscible volatile antisolvents. The larger jars were later tightly closed. The antisolvents diffused through the vapor phases in the solutions, and saturation or supersaturation were reached.

The results of diffusion experiments

solid form A and B 'are presented in Table 4.

Table 4:

<td>Solvent</td><td>Antisolvent</td><td>Concentration mg / ml</td><td>Terms</td><td>Produced form</td>

<td>ethanol</td><td>n-hexane</td><td>204 mg P1 0.4 mi solvent</td><td>vapor diffusion, 23 ° C, 7 days, solution stirred</td><td>viscous sticky dough</td>

<td>acetone</td><td>n-hexane</td><td>210 mg P1 0.5 my solvent</td><td>vapor diffusion, 23 ° C, 7 days, solution stirred</td><td>viscous sticky dough</td>

<td>TBME</td><td>n-hexane</td><td>205 mg P1 0.6 my solvent</td><td>vapor diffusion, 23 ° C, 7 days, solution stirred</td><td>viscous sticky dough</td>

<td>ethyl acetate</td><td>n-hexane</td><td>206 mg P1 0.6 mi solvent</td><td>vapor diffusion, 23 ° C, 2 filtered and air dried</td><td>very similar to A</td>

<td>THF</td><td>n-hexane</td><td>212 mg P1 0.6 mi solvent</td><td>vapor diffusion, 23 ° C, 7 days, solution stirred</td><td>viscous sticky dough</td>

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

<td>dichloromethane</td><td>n-hexane</td><td>204 mg P11.6 my solvent</td><td>vapor diffusion, 23 ° C, 2 days, solution stirred</td><td>very similar to A</td>

<td>1,4-dioxane</td><td>n-hexane</td><td>215 mg P1 0.5 my solvent</td><td>vapor diffusion, 23 ° C, 7 days, solution stirred</td><td>viscous sticky dough</td>

<td>acetic acid</td><td>Water</td><td>219 mg P1 0.3 mi solvent</td><td>vapor diffusion, 23 ° C, 7 days, solution stirred</td><td>very similar to A (see Fig 11B)</td>

<td>acetonitrile</td><td>Water</td><td>212mgP1 0.4 mi solvent</td><td>vapor diffusion, 23 ° C, 6 days, solution stirred</td><td>viscous sticky dough</td>

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Evaporation experiments

The compound solutions were dried at room temperature (dry nitrogen flow) without stirring. The results of the evaporation experiments of solid form A are presented in Table 5.

Table 5:

<td>Start Form</td><td>Solvent</td><td>Concentration mg / ml</td><td>Terms</td><td>Produced form</td>

<td rowspan="2">TO</td><td rowspan="2">ethanol</td><td rowspan="2"> 100/2.0</td><td>23 ° C</td><td>(solution)</td>

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

<td rowspan="2">TO</td><td rowspan="2">ethyl acetate</td><td rowspan="2"> 109/2.0</td><td>23 ° C</td><td>(solution)</td>

<td>evaporated (N2 dry) 1 day / 23 ° C</td><td>very similar to A (see figure 12A)</td>

<td rowspan="2">TO</td><td rowspan="2">THF</td><td rowspan="2"> 183/2.0</td><td>23 ° C</td><td>(ssolution)</td>

<td>Evaporated (N2 dry) 5 days / 23 ° C</td><td>A + C (see figure 12A)</td>

Precipitation experiments

Precipitation experiments were carried out with 42 to 79 mg of the compound. The non-solvent was added to the solution. The samples obtained after filtration (P4 glass filter porosity) were dried with air at room temperature and for a short time only to avoid possible desolvation of solvents or labile hydrates. The results of the solid form A precipitation experiments are presented in Table 6.

Table 6

<td>Start Form</td><td>Solvent</td><td>Concentration mg / ml</td><td>Terms</td><td>Produced form</td>

<td rowspan="3">TO</td><td></td><td> 79/02</td><td>23 ° C</td><td>(solution)</td>

<td rowspan="2">ethanol</td><td rowspan="2"> 79/1.2</td><td>1.0 rnl n-heptane added</td><td>(phase separation)</td>

<td>stored 11 weeks / - 20 “C; removed solution and dried solid residue (N? 43 ml / min) 50 min RT</td><td>very similar to A</td>

<td rowspan="3">TO</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 mi n-heptane added</td><td>(viscous sticky mass)</td>

<td>stirred 14 h / 40 ° C filtered & air dried</td><td>TO</td>

<td rowspan="3">TO</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 m n-heptane aggregate</td><td>(viscous sticky mass)</td>

<td>stirred 14 h / 40 ° C filtered & air dried</td><td>TO</td>

<td rowspan="3">TO</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 m n-heptane aggregate</td><td>(viscous sticky mass)</td>

<td>fully stirred 13 h / 40 ° C filtered 8 air dried</td><td>TO</td>

Solution recrystallization

The compound was dissolved in different solvent systems at room temperature and cooled to + 5 ° C or -20 ° C. Post-filtration samples (P4 glass filter porosity) were air-dried at room temperature for a short time just to avoid desolvation.

100

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INSTITUTE MFXICAKC

DS THE POSSIBLE INDUSTRIAL PROPERTY of labile hydrates or solvents.

The results of the recrystallization experiments of solid form A are presented in Table 7.

Table 7:

<td>Start Form</td><td>Solvent</td><td>Concentration mg / ml</td><td>Terms</td><td>Produced form</td>