TW202509012A - New polymorphs of (s)-6-chloro-2,3,4,9-tetrahydro-1h-carbazole-1-carboxamide in crystalline form - Google Patents

Abstract

The invention provides ( S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (( S)-SLS) of formula (S-I) in crystalline form, wherein the ( S)-SLS in crystalline form is a crystalline polymorphic form of ( S)-SLS selected from the group consisting of the crystalline polymorphic forms a) to c) of ( S)-SLS having an X-ray powder diffraction pattern comprising 2-theta angle values (with a deviation of +/- 0.2 degree) of a) 10.8, 13.5, 21.7 and 23.8 degrees (polymorph G), b) 6.7, 12.6, 13.4 and 18.5 degrees (polymorph H), and c) 11.2, 13.0, 16.3 and 21.9 degrees (polymorph K).

Description

New polymorph of (S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide in crystalline form

The present invention provides a novel polymorph of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide in a crystalline form. In addition, the present invention provides a novel crystalline solvate of ( S )-6-chloro-2,3,4,9-tetrahydro- 1H -carbazole-1-carboxamide and a preparation method thereof.

The compound of formula (I) is 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide, (I), also known as Selisitat or EX-527 (CAS-Nr. 49843-98-3), is known from WO 2005/026112 A2 to have anti-SIRT1 activity and can therefore be used for the preparation of a medicament for any condition that may benefit from inhibition of SIRT1. Such conditions may include, for example, cancer, metabolic diseases such as metabolic syndromes, type I diabetes or type II diabetes, obesity, dyslipidemia, hyperlipidemia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, neurodegenerative diseases caused at least in part by polyglutamine aggregation, such as Huntington's disease, spinalbulbar muscular atrophy (SBMA or Kennedy's disease), dentatorubro-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia type 1 (SCA1), spinocerebellar ataxia type 2 (SCA2), Machado-Joseph disease (Machado-Joseph disease, MJD; SCA3), spinocerebellar ataxia type 6 (SCA6), spinocerebellar ataxia type 7 (SCA7), and spinocerebellar ataxia type 12 (SCA12).

The racemic form of Selisistat (hereinafter also referred to as " rac -SLS") and the synthesis of polymorphic forms of racemic Selisistat have been described in WO 2013/057258 A1.

The molecule has an asymmetric carbon atom adjacent to the amide functionality and therefore exists in two mirror image isomers, namely ( R )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-formamide and ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-formamide of formula ( S -I), ( S -I), hereinafter also referred to as "( S )-SLS".

Although the mirror image isomers of Selisistat are known to differ significantly with respect to their SIRT1 activities, current clinical trials have been conducted using a racemic mixture of the two mirror image isomers of Selisistat. To date, mirror image pure ( S )-Selisistat is only available in an amorphous form and can only be prepared in limited quantities using chiral high pressure liquid chromatography (HPLC).

One object of the present invention is therefore to provide a novel form of ( S )-Selisistat, in particular to provide a novel form of ( S )-Selisistat that is suitable for medical purposes and can be conveniently prepared on a large scale. Further objects of the present invention will become clear from the following description, examples and claims of the present invention.

In a first aspect, the present invention relates to polymorphs of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (( S )-SLS) of formula (SI) in crystalline form.

In a second aspect, the present invention provides a composition comprising a polycrystalline form of ( S )-SLS according to the first aspect of the present invention and further comprising any other solid state form of ( S )-SLS.

In a third aspect, the present invention provides a polymorph of ( S )-SLS according to the first aspect of the present invention or a composition according to the second aspect of the present invention for use as a medicament, in particular for the prevention or treatment of diseases or conditions associated with SIRT1.

In a fourth aspect, the present invention provides the use of the polymorphic form of ( S )-SLS according to the first aspect of the present invention or the composition according to the second aspect of the present invention for preparing a pharmaceutical composition.

In a fifth aspect, the present invention relates to a pharmaceutical composition comprising a polymorph of ( S )-SLS according to the first aspect or a composition according to the second aspect of the present invention and at least one pharmaceutically acceptable excipient.

In yet further aspects, the present invention provides solvent compositions of (S)-SLS and methods for preparing polymorphs and solvent compositions of ( S )-SLS as disclosed herein.

In a first aspect, the present invention provides a crystalline form of ( S )-6-chloro-2,3,4,9-tetrahydro- 1H -carbazole-1-carboxamide (( S )-SLS) of formula (SI): ( S -I), wherein the crystalline form of ( S )-SLS is a crystalline polymorph of ( S )-SLS selected from the group consisting of crystalline polymorphs a) to c) of ( S )-SLS having an X-ray powder diffraction pattern comprising the following 2θ angle values (with a deviation of +/- 0.2 degrees): a) 10.8, 13.5, 21.7 and 23.8 degrees (polymorph G), b) 6.7, 12.6, 13.4 and 18.5 degrees (polymorph H), or c) 11.2, 13.0, 16.3 and 21.9 degrees (polymorph K).

According to this first aspect, the present invention provides three solid and crystalline polymorphs of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide of crystalline formula (SI), namely, the first polymorph listed in item a) above and also referred to herein as "polymorph G", the second polymorph listed in item b) above and also referred to herein as "polymorph H", and the third polymorph listed in item c) above and also referred to herein as "polymorph K".

More specifically, according to this first aspect, the present invention relates to a crystalline form of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (( S )-SLS) of formula (SI), wherein the crystalline form of ( S )-SLS is a crystalline polymorph of ( S )-SLS selected from the group consisting of crystalline polymorphs a) to c) of ( S )-SLS having an X-ray powder diffraction pattern comprising the following 2θ angle values (with a deviation of +/- 0.2 degrees): a) 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6 and 30.6 degrees (polymorph G), b) 6.7, 12.6, 13.4, 18.5, 21.8, 24.9 and 26.9 degrees (polymorph H), and c) 8.1, 11.2, 13.0, 16.3, 21.9, 22.6 and 24.3 degrees (polymorph K).

The first polymorph (polymorph G) of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (( S )-SLS) disclosed herein can be prepared as further described below (see Example 1) and is also characterized in the form of white crystals. X-ray powder diffraction analysis ("XRPD" or "powder X-ray diffraction analysis, "PXRD" are used synonymously herein) shows significant signals, or in other words reflections, at 2θ (2θ) angle values of 10.8, 13.5, 21.7 and 23.8 degrees (with a deviation of +/- 0.2 degrees or more particularly 0.1 degrees when measured using Cu-K _α radiation with a wavelength of 0.15406 nm in a temperature range of 20°C to 30°C (more particularly 20°C to 25°C); see Example 2.1 for details of the analysis).

The term "reflection" used herein with respect to powder X-ray diffraction refers to peaks in the X-ray diffraction pattern that arise from constructive interference of X-rays scattered by parallel atomic planes in the solid material at certain diffraction angles (Bragg angles), which are distributed in an orderly and repetitive pattern of long-range positional order. Such solid materials are classified as crystalline materials or, as used herein, "in crystalline form", while amorphous materials are defined as solid materials that lack long-range order and only show short-range order, thus resulting in extensive scattering. According to the literature, long-range order extends, for example, over about 100 to 1000 atoms, whereas short-range order extends only over a few atoms (see "Fundamentals of Powder Diffraction and Structural Characterization of Materials' by Vitalij K. Pecharsky and Peter Y. Zavalij, Kluwer Academic Publishers, 2003, page 3).

In some embodiments, the first polymorph of ( S )-SLS (polymorph G) exhibits significant signals or reflections at 2θ angle values of 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6, and 30.6 degrees when measured as described above. More specifically, the first polymorph of ( S )-SLS (polymorph G) exhibits signals or reflections at 2θ angle values substantially as listed in Table 1 (see Example 2.1) and as shown in the XRPD diffraction pattern depicted in Figure 1.

The second polymorph (polymorph H) of ( S )-6-chloro-2,3,4,9-tetrahydro- 1H -carbazole-1-carboxamide (( S )-SLS) as disclosed herein can be prepared as further described below (see Example 5) and has also been characterized in the form of white crystals. X-ray powder diffraction analysis showed significant signals, or in other words reflections, at 2θ angle values of 6.7, 12.6, 13.4 and 18.5 degrees (with a deviation of +/- 0.2 degrees or better 0.1 degrees when measured in the temperature range of 20°C to 30°C (especially 20°C to 25°C) using Cu- _Kα radiation with a wavelength of 0.15406; see Example 2.1 for details of the analysis).

In some embodiments, the second polymorph of ( S )-SLS (polymorph H) exhibits significant signals or reflections at 2θ angle values of 6.7, 12.6, 13.4, 18.5, 21.8, 24.9 and 26.9 degrees when measured as described above. More specifically, the second polymorph of ( S )-SLS (polymorph H) exhibits 2θ angle values substantially as listed in Table 3 (see Example 6.1) and signals or reflections as shown in the XRPD diffraction pattern described in Figure 6.

A third polymorph (polymorph K) of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (( S )-SLS) as disclosed herein can be prepared as further described below (see Example 3) and has also been characterized in the form of white crystals. X-ray powder diffraction analysis shows significant signals, or in other words reflections, at 2θ angle values of 11.2, 13.0, 16.3 and 21.9 degrees (with a deviation of +/- 0.2 degrees or better still 0.1 degrees) when measured using Cu- _Kα radiation having a wavelength of 0.15406 at a temperature range of 20°C to 30°C (in particular 20°C to 25°C); see Example 2.1 for details of the analysis).

In some embodiments, the third polymorph of ( S )-SLS (polymorph K) exhibits significant signals or reflections at 2θ angle values of 8.1, 11.2, 13.0, 16.3, 21.9, 22.6, and 24.3 degrees when measured as described above. More specifically, the second polymorph of ( S )-SLS (polymorph H) exhibits signals or reflections at 2θ angle values substantially as listed in Table 2 (see Example 4.1) and as shown in the XRPD diffraction pattern depicted in Figure 4.

The polymorphs of ( S )-SLS of the present invention have been further analyzed by ^1H -nuclear magnetic resonance ( ^1H -NMR). ^1H -NMR spectra of all three polymorphs of the present invention were recorded using a dilute solution containing about 5 to about 10 mg of each polymorph in about 0.7 mL of deuterated dimethylsulfoxide (DMSO-d6) (using a Varian Mercury 400 MHz spectrometer equipped with a 5 mm wideband probe ATB 1H/19F/X). The ^1H -NMR spectra of the three polymorphs were all identical to the ^1H -NMR spectrum of racemic Selesistat (see FIG. 2 , ^1H -NMR spectra of the three polymorphs G) and showed no residual organic solvents or other organic compounds.

The polymorphs of ( S )-SLS of the present invention have been further characterized by differential scanning calorimetry (DSC), wherein the corresponding samples were heated from 25°C to about 300°C at a rate of about 10°C/min (see Examples 2.3, 4.3 and 6.3 for details). The corresponding spectra are depicted in Figure 3 (polymorph G), Figure 5 (polymorph K) and Figure 7 (polymorph H).

The DSC spectrum of polymorph G (see FIG. 3 ) shows an endothermic peak in the range from about 160° C. to about 170° C. (particularly from about 165 or 166° C. to about 169° C.), with an onset at about 167° C., particularly peaks at 167.1° C. and at 168.7° C. The corresponding melting enthalpy (ΔH) was determined to be -92.6 J/g (calculated as the area under the curve of the endothermic peak and normalized to the sample weight).

The DSC spectrum of polymorph K (see FIG. 5 ) shows endothermic peaks in the range from about 150° C. to about 175° C. (particularly from about 160 or 165° C. to about 170° C.), starting at about 167° C., particularly peaks at 167.3° C. and at 170.2° C. The corresponding melting enthalpy (ΔH) was determined to be -64.6 J/g (calculated as the area under the curve of the endothermic peak and normalized to the sample weight). In this case, the initial endothermic event is followed by an exothermic event starting at about 173° C., followed by a second endothermic peak starting at about 184° C.

The DSC spectrum of polymorph H (see FIG. 7 ) shows endothermic peaks in the range of from about 150° C. to about 165° C. (particularly from about 155 or 160° C. to about 165° C.), starting at about 162° C., particularly peaks at 162.1° C. and at 164.2° C. In this case, the initial endothermic event is followed by an exothermic event starting at about 166° C., followed by a second endothermic peak starting at about 185° C.

Therefore, in a further embodiment, the present invention provides a crystalline form of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (( S )-SLS) of formula (I), wherein the crystalline form of ( S )-SLS is a crystalline polymorph of ( S )-SLS, which is selected from the group consisting of crystalline polymorphs a) to c) of ( S )-SLS having the following melting points (onset of melting): a) 167°C (polymorph G), b) 162°C (polymorph H), and c) 167°C (polymorph K).

In yet another embodiment, the present invention provides a crystalline form of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (( S )-SLS) of formula (I), wherein the crystalline form of ( S )-SLS is a crystalline polymorph of ( S )-SLS selected from the group consisting of crystalline polymorphs a) to c) of ( S )-SLS having a melting enthalpy (ΔH) in the following ranges: a) from about -95 J/g to about -90 J/g (polymorph G), b) from about -73 J/g to about -68 J/g (polymorph H), and c) from about -67 J/g to about -62 J/g (polymorph K), or in the following ranges a) from about -93 J/g to about -93 J/g (polymorph K). J/g to about -92 J/g (polymorph G), b) from about -71 J/g to about -70 J/g (polymorph H), and c) about -65 J/g to about -64 J/g (polymorph K), or the following a) -92.6 J/g (polymorph G), b) -70.2 J/g (polymorph H), and c) -64.6 J/g (polymorph K).

In a further embodiment, the present invention relates to a crystalline form of ( S )-SLS of formula (I), wherein the crystalline form of ( S )-SLS is a crystalline polymorph of ( S )-SLS selected from the group consisting of the following crystalline polymorphs a) and b) of ( S )-SLS having X-ray powder diffraction patterns comprising the following 2θ angle values (with a deviation of +/- 0.2 degrees): a) 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6 and 30.6 (polymorph G), and b) 6.7, 12.6, 13.4, 18.5, 21.8, 24.9 and 26.9 degrees (polymorph H).

In a further embodiment, the present invention relates to a crystalline form of ( S )-SLS of formula (I), wherein the crystalline form of (S)-SLS is a crystalline polymorphic form (polymorph G) of ( S )-SLS having an X-ray powder diffraction pattern comprising 2θ angle values of 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6 and 30.6 (with a deviation of +/- 0.2 degrees).

As described in Examples 2, 4 and 6 below, the polymorphs of crystalline ( S )-6-chloro-2,3,4,9-tetrahydro- 1H -carbazole-1-carboxamide described above, in particular polymorphs G, H and K, do not contain significant amounts of water or organic solvents occluded or incorporated in the crystal structure, except for residual amounts of water or organic solvents of at most about 2.0 wt.-%, or at most about 1 wt.-%, or at most about 0.5 wt.-%, relative to the total weight of the respective crystalline material which may, for example, be bound to the surface of the crystalline material. Furthermore, it has been found that the polymorphic forms of crystalline ( S )-6-chloro-2,3,4,9-tetrahydro- 1H -carbazole-1-carboxamide as described above, in particular polymorphs G, H and K, are non-hygroscopic or, in other words, do not attract or incorporate water under defined storage conditions. Thus, in certain embodiments, the crystalline polymorphic forms of ( S )-SLS as disclosed herein, in particular polymorphs G, H and K, are solvent-free and/or non-hygroscopic.

As described above, the crystalline polymorphic forms of ( S )-SLS as disclosed herein, particularly polymorphs G, H and K, have been found to be stable under defined storage conditions, such as those defined by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). More specifically, it has been found that polymorphs G, H and K of ( S )-SLS are stable under accelerated ICH conditions for at least 7 days when stored in a suitable climate chamber at 40°C +/- 2°C, 75% +/- 5% relative humidity (RH) as described in Example 7 below. Thus, in a particular embodiment, the present invention provides crystalline polymorphs of (S)-SLS, in particular polymorphs G, H and K, which are stable for at least 7 days at a temperature of 40°C +/- 2°C and a relative humidity (RH) of 75% +/- 5% (accelerated ICH conditions), wherein the term "stable" as used herein means that at least 90 wt.-% or at least 95 wt.-% or at least 98 wt.-% or 99 wt.-% of the particular polymorph remains in the particular polymorph without degradation or conversion to another polymorphic or amorphous form. Thus, crystalline polymorphs of ( S )-SLS, in particular polymorphs G, H and K, are particularly useful for medical purposes and applications.

The present disclosure also relates to a further polymorph of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (( S )-SLS) of formula (I) in crystalline form (hereinafter referred to as "polymorph T"). This further polymorph can be prepared as further described below (see Example 8) and is also shown in the form of white crystals. X-ray powder diffraction analysis shows significant signals, or in other words reflections, at 2θ angle values of 7.2, 14.4, 21.7 and 24.1 degrees (with a deviation of +/- 0.2 degrees or better 0.1 degrees when measured in a temperature range of 20°C to 30°C (especially 20°C to 25°C) using Cu-K _α radiation with a wavelength of 0.15406; see Example 2.1 for details of the analysis). The corresponding XRPD diffraction pattern is depicted in Figure 8.

In addition, the present invention discloses a crystalline form of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (( S )-SLS) of formula (SI), wherein ( S )-SLS is contained together with a solvent and, therefore, exists in the form of a crystalline solvent complex, more preferably a solid crystalline solvent complex.

The first crystallization solvent of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide contains acetone as a solvent (Solvent J). The first crystallization solvent of ( S )-SLS can be prepared as described in Example 10 below. X-ray powder diffraction analysis shows significant signals or, in other words, reflections at 2θ angle values of 10.6, 17.2, 19.2 and 21.3 degrees, more specifically 10.6, 11.9, 15.6, 16.4, 17.2, 19.2, 21.3 and 25.2 degrees (with a deviation of +/- 0.2 degrees or better 0.1 degrees when measured in the temperature range of 20°C to 30°C (especially 20°C to 25°C) using Cu-K _α radiation with a wavelength of 0.15406; see Example 2.1 for details of the analysis). A complete list of reflections is listed in Table 5, Example 11.1; the corresponding XRPD diffraction pattern is depicted in Figure 9.

^1H -NMR analysis recorded in deuterated dimethyl sulfoxide as described in Example 11.2 below revealed a molar ratio of ( S )-SLS to acetone of about 3:1 (see Figure 10). Differential scanning calorimetry analysis as described in Example 11.3 showed broad endotherms starting at about 82°C and about 106°C (presumably indicative of thermal desolvation), followed by a sharp endotherm starting at 171°C (see Figure 11).

Crystalline acetone solvent complex J of ( S )-SLS was found to be stable and non-hygroscopic for at least 7 days in stability testing under accelerated ICH conditions (storage at 40°C +/- 2°C, 75% +/- 5% relative humidity (RH)).

The second crystallization solvent of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide contains dioxane as a solvent (solvent M). This second crystallization solvent of ( S )-SLS can be prepared as described in Example 12 below. X-ray powder diffraction analysis shows significant signals, or in other words reflections, at 2θ angle values of 11.9, 16.1, 19.6 and 22.3 degrees, more specifically 9.9, 11.9, 16.1, 19.6, 19.8, 21.8, 22.3 and 22.9 degrees (with a deviation of +/- 0.2 degrees or better 0.1 degrees when measured in the temperature range of 20°C to 30°C (especially 20°C to 25°C) using Cu-K _α radiation with a wavelength of 0.15406; see Example 2.1 for details of the analysis). A complete list of reflections is listed in Table 6, Example 13.1; the corresponding XRPD diffraction pattern is depicted in Figure 12.

^1H -NMR analysis recorded in deuterated dimethyl sulfoxide as described in Example 13.2 below revealed a molar ratio of ( S )-SLS to dioxane of about 1:0.8 (see Figure 13). Differential scanning calorimetry analysis as described in Example 13.3 showed broad endotherms starting at about 80°C and about 103°C (presumably indicating thermal desolvation), followed by a sharp endotherm starting at 188°C (see Figure 14).

The third crystalline solvent of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide comprises N , N - dimethylformamide (DMF) as a solvent (Solvent R). ( S )-SLS of the third crystalline solvent can be prepared as described in Example 14 below. X-ray powder diffraction analysis showed significant signals or, in other words, reflections at 2θ angle values of 10.9, 11.3, 17.0 and 17.8 degrees, more specifically 5.6, 10.9, 11.3, 17.0, 17.3, 17.8, 19.2, 25.6 and 28.1 degrees (with a deviation of +/- 0.2 degrees or better 0.1 degrees when measured in the temperature range of 20°C to 30°C (especially 20°C to 25°C) using Cu-K _α radiation with a wavelength of 0.15406; see Example 2.1 for details of the analysis). A complete list of reflections is listed in Table 7, Example 15.1; the corresponding XRPD diffraction pattern is depicted in Figure 15.

¹ H-NMR analysis recorded in deuterated dimethyl sulfoxide as described in Example 15.2 below revealed a molar ratio of ( S )-SLS to N , N -dimethylformamide of approximately 1:0.5 (see FIG. 16 ).

The fourth crystalline solvent complex of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide comprises cyclopentanone as a solvent (Solvent complex Q). This fourth crystalline solvent complex of ( S )-SLS can be prepared as described in Example 16 below. X-ray powder diffraction analysis shows significant signals, or in other words reflections, at 2θ angle values of 11.1, 16.9, 20.6 and 21.0 degrees, more specifically 4.4, 11.1, 16.9, 19.2, 20.6, 21.0, 22.2 and 23.6 degrees (with a deviation of +/- 0.2 degrees or better 0.1 degrees when measured in the temperature range of 20°C to 30°C (especially 20°C to 25°C) using Cu-K _α radiation with a wavelength of 0.15406; see Example 2.1 for details of the analysis). A complete list of reflections is listed in Table 8, Example 17.1; the corresponding XRPD diffraction pattern is depicted in Figure 17.

¹ H-NMR analysis recorded in deuterated dimethyl sulfoxide as described in Example 17.2 below revealed a molar ratio of ( S )-SLS to cyclopentanone of approximately 1:1 (see FIG. 18 ).

In a second aspect, the present invention provides a composition comprising a crystalline form of ( S )-SLS of formula (SI), preferably a crystalline polymorph of ( S )-SLS as described above, more preferably polymorph G, H or K as described above, and further comprising up to about 20 wt.-%, 10 wt.-%, 5 wt.-%, 4 wt.-%, 3 wt.-%, 2 wt.-% or 1 wt.-% of any other solid-state form of ( S )-SLS based on the weight of the composition. The term "solid-state form" as used herein is understood to mean forms of ( S )-SLS other than the polymorphs described herein, preferably polymorphs G, H and K, other polymorphs and solvates or amorphous solid forms of ( S )-SLS as disclosed above.

In a third aspect, the present invention provides a crystalline polymorph of ( S )-SLS as described above, preferably the first aspect or polymorph G, H or K of the present invention, for use as a drug. In this regard, the present invention also relates to the use of the crystalline polymorph of ( S )-SLS of the first aspect of the present invention (preferably polymorph G, H or K) in the manufacture of a drug. In addition, in this regard, the present invention also relates to a method of using the crystalline polymorph of ( S )-SLS of the first aspect of the present invention (preferably polymorph G, H or K) as a drug or for treating or preventing medical conditions (preferably warm-blooded animals or humans, especially medical conditions in humans).

In a specific embodiment of this third aspect of the present invention, the medical condition that can be treated or prevented may be a medical condition or disease associated with or mediated by sirtuin, in particular a medical condition or disease associated with or mediated by SIRT1. Therefore, the present invention also provides a crystalline form of ( S )-SLS of formula (SI) according to the first aspect of the present invention as described above or a composition according to the second aspect of the present invention, which is used to prevent or treat diseases or conditions associated with or mediated by sirtuin (e.g., SIRT1).

In certain embodiments, the SIRT1-related or SIRT1-mediated diseases or medical conditions described above can be treated or prevented by administering the compounds or compositions of the present invention, and can be selected from cancer, metabolic diseases such as metabolic syndrome, type I diabetes or type II diabetes, obesity, dyslipidemia, hyperlipidemia, Alzheimer's disease, Parkinson's disease, lateral sclerosis, neurodegenerative diseases caused at least in part by polyglutamine aggregation, such as Huntington's disease, spinal bulbar muscular atrophy (SBMA or Kennedy's disease), dentate-rubrospasmodic Lewy body atrophy (DRPLA), spinocerebellar ataxia type 1 (SCA1), spinocerebellar ataxia type 2 (SCA2), Machado-Joseph disease (MJD; SCA3), spinocerebellar ataxia type 6 (SCA6), spinocerebellar ataxia type 7 (SCA7), and spinocerebellar ataxia type 12 (SCA12), particularly Huntington's disease.

In a fourth aspect, the present invention relates to the use of a crystalline form of ( S )-SLS of formula (SI) according to the first aspect of the present invention, in particular polymorphs G, H and/or K of ( S )-6-chloro-2,3,4,9-tetrahydro- 1H -carbazole-1-carboxamide or a composition according to the second aspect of the present invention for preparing a pharmaceutical composition.

Therefore, in a fifth aspect, the present invention relates to a pharmaceutical composition comprising a crystalline form of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide according to the first aspect of the present invention as described above (particularly polymorphs G, H and/or K or a crystalline polymorph comprising the ( S )-SLS, preferably in a predetermined and/or pharmaceutically effective amount) and at least one pharmaceutically acceptable excipient, wherein the term "pharmaceutically effective amount" as used herein means an amount sufficient to achieve treatment or prevention of a disease when administered to a warm-blooded animal or a human being for the treatment or prevention of the disease.

In some embodiments, the predetermined and/or effective amount of the preferably anhydrous and insoluble crystalline form of ( S )-SLS of the present invention or a composition comprising the same as defined in any of the above embodiments and their corresponding embodiments can be selected in the range of from about 1 mg to about 300 mg, or from about 20 mg to about 250 mg, or from about 1 mg to about 20 mg, or from about 100 to about 200 mg per single dose, calculated as anhydrous and more preferably insoluble crystalline form of ( S )-6-chloro-2,3,4,9-tetrahydro- 1H -carbazole-1-carboxamide.

The term "excipient" as used herein means a pharmaceutically acceptable auxiliary substance, carrier or material that enables or facilitates the formulation of an active pharmaceutical ingredient (such as a crystalline polymorphic form of ( S )-SLS as described herein) in a composition or dosage form that is manufactured according to generally accepted quality standards, stored under ordinary storage conditions, and conveniently administered to an individual in need thereof (such as a human patient). In this context, the term "pharmaceutically acceptable" means that the compound or mixture to which it refers can be used to prepare a pharmaceutical composition, which is generally safe, non-toxic and not biologically or otherwise undesirable and includes those that are acceptable for human medical use.

At least one pharmaceutically acceptable excipient contained in the pharmaceutical composition of the present invention is preferably selected from the group consisting of fillers, binders, disintegrants, lubricants, glidants, and combinations thereof as known to those skilled in the art and as described, for example, in current pharmacopoeias (such as the European Pharmacopoeia or the United States Pharmacopoeia). Preferably, at least one pharmaceutically acceptable excipient is selected from the group consisting of one or more of the following: fillers, binders, disintegrants, and lubricants. More preferably, at least one pharmaceutically acceptable excipient is selected from the group consisting of microcrystalline cellulose, colloidal silicon dioxide, cross-linked carboxymethyl cellulose sodium, magnesium stearate, and combinations thereof.

In some embodiments, the pharmaceutical composition of this aspect of the invention comprising a crystalline polymorph of ( S )-SLS of the invention (preferably polymorphs G, H and/or K, especially in anhydrous and non-solventized form) may be a solid dosage form, such as a solid dosage form for oral administration. Examples of such solid dosage forms suitable for oral administration may include, but are not limited to, tablets, capsules, granules and oral films. More preferably, the oral solid dosage form is a tablet or a capsule, such as a soft capsule or a hard capsule. In the case of a hard capsule, it may be filled with a powder mixture or with granules or pellets comprising ( S )-SLS. Optionally, the granules, tablets or capsules may be coated.

The pharmaceutical composition of the present invention as defined in any of the above embodiments can be manufactured by standard manufacturing methods, which are well known to those skilled in the art, including, for example, blending, granulation (wet or dry granulation), tablet compression, film coating or capsule filling and packaging. For example, tablets can be prepared by mixing a crystalline form of ( S )-SLS of the present invention as defined in any of the above embodiments and their corresponding embodiments or a composition comprising the same and at least one excipient such as a filler, a binder, a disintegrant, a lubricant, a glidant or a combination thereof. Optionally, a granulation step, such as a dry or wet granulation step, is performed before compression. Tablet cores can additionally be film-coated.

The polymorphs of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide according to the present invention can be prepared starting from the commercially available racemic 6-chloro-2,3,4,9-tetrahydro- 1H -carbazole-1-carboxamide of formula (I). More specifically, the polymorph G of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide can be prepared by co-crystallization of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and a chiral tartaric acid derivative rich in mirror image isomerism, as described in Example 1 below. As a product of this co-crystalization, a non-mirror isomerically enriched or even non-mirror isomerically pure cocrystal of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and a selected tartaric acid derivative can be isolated as described below and further purified by recrystallization if necessary. The mirror isomerically enriched or mirror isomerically pure ( S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide can be isolated from this non-mirror isomerically enriched or pure intermediate cocrystal by treating with alkali .

Thus, in another aspect the present invention provides a method for preparing a crystalline form of ( S )-6-chloro-2,3,4,9-tetrahydro- 1H -carbazole-1-carboxamide (( S )-SLS) of formula (SI) having an X-ray powder diffraction pattern (polymorph G) comprising 2θ angle values of 10.8, 13.5, 21.7 and 23.8, in particular 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6 and 30.6 (with a deviation of +/- 0.2 degrees), the method comprising the following steps: a) providing a first mixture comprising rac -SLS of formula (I) and a compound of formula (II) in a first liquid medium, (II) wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ may be the same or different and may be independently selected from H, C ₁ -C ₄ -alkyl, halogen, C ₁ -C ₄ -halogenoalkyl, -OC ₁ -C ₄ -alkyl, and -OC ₁ -C ₄ -halogenoalkyl, b) exposing the first mixture to conditions where rac -6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and the compound of formula (II) are at least partially dissolved in the first liquid medium to form an intermediate solution, c) exposing the intermediate solution formed in step b) to conditions where a solid intermediate product comprising a co-crystal of ( S )-SLS and a crystalline intermediate of the compound of formula (II) is formed, d) Optionally, recrystallizing the co-crystal intermediate in a second liquid medium to provide a solid intermediate product comprising co-crystal ( S )-SLS and a compound of formula (II) enriched in mirror image isomerism, and e) exposing the co-crystal intermediate formed in step c) or d) to an aqueous solution of an inorganic base to provide ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide of formula (SI) enriched in mirror image isomerism.

In the preferred compounds of formula (II), C ₁ -C ₄ -alkyl preferably means saturated hydrocarbon substituents having one to four carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl; halogen preferably means fluorine, chlorine, bromine, preferably fluorine or chlorine, especially chlorine; C ₁ -C ₄ -haloalkyl preferably means saturated mono- or poly-halogenated saturated hydrocarbon substituents having one to four carbon atoms such as trifluoromethyl, pentafluoroethyl, heptafluoroisopropyl; -OC ₁ -C ₄ -alkyl preferably means saturated alkyl substituents having one to four carbon atoms bonded via an oxygen atom such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, preferably methoxy, isopropoxy and t-butoxy, especially methoxy; and -OC ₁ -C ₄ -haloalkyl preferably means saturated and halogenated alkyl substituents having one to four carbon atoms bonded via an oxygen atom such as trifluoromethoxy, pentafluoroethoxy, heptafluoroisopropoxy, especially trifluoromethoxy.

In some embodiments of the method according to this aspect of the invention, in the compound of formula (II), R ¹ , R ² , R ³ , R ⁴ and R ⁵ may be the same or different and may be independently selected from H, C ₁ -C ₄ -alkyl, halogen and C ₁ -C ₄ -haloalkyl as described above. In further specific embodiments, in the compound of formula (II), R ¹ , R ² , R ³ , R ⁴ and R ⁵ are H. In a preferred embodiment, the compound of formula (II) is (2 R , 3 R )-(-)-di-O-4-benzoyl-L-tartaric acid; CAS No. 2743-38-6, also referred to herein as "(-)-DBTA".

In a further embodiment, in the compound of formula (II), R ¹ , R ² , R ⁴ and R ⁵ are H, and R ³ is selected from C ₁ -C ₄ -alkyl and C ₁ -C ₄ -haloalkyl, preferably selected from C ₁ -C ₄ -alkyl, especially methyl. In a preferred embodiment, the compound of formula (II) is (2 R , 3 R )-(-)-di-O-4-toluoyl-L-tartaric acid; CAS No. 32634-66-5, also referred to herein as "(-)-DTTA".

The term "enantiomerically enriched form" in relation to the tartaric acid derivative of formula (II) as used herein means that the tartaric acid derivative of formula (II) may exist in the form of its pure (-)-enantiomer, wherein both chiral centers are in the R -configuration as described in formula (II), or in other words, in the form of a non-racemic mixture of a (-)-enantiomer of formula (II) and its corresponding (+)-enantiomer, wherein the amount of the (-)-enantiomer isomer is greater than the amount of the corresponding (+)-enantiomer. In some embodiments, the term "a compound of Formula (I) enriched in a mirror image isomer" may refer to a mixture comprising a (-) mirror image isomer of a compound of Formula (II) having a mirror image isomer excess (ee) of at least about 70% ee, or at least about 80% ee, or at least about 90% ee, such as from about 90 to about 99.9% ee, or from about 95 to about 99.8% ee, about 97 to about 99.7% ee, or from about 98 to about 99.8% ee.

The term "solid intermediate of ( S )-SLS and a compound of formula (II) in co-crystal form" or simply "co-crystal" as used herein may also describe a solid of a crystalline single-phase material composed of two or more different molecular or ionic compounds, in particular ( S )-SLS and a compound of formula (II), usually in a stoichiometric ratio, which is neither a solvate nor a simple salt.

In a further embodiment, the method for preparing the mirror image isomer-enriched ( S )-6-chloro-2,3,4,9-tetrahydro- 1H -carbazole-1-carboxamide (( S )-SLS) as described above may further comprise the following steps: c1) exposing the intermediate solution formed in step b) to conditions to form a solid intermediate product comprising a co-crystal of ( S )-SLS and a compound of formula (II); and c2) at least partially removing the first liquid medium from the solid intermediate product to provide a co-crystal of ( S )-SLS and a compound of formula (II).

In another specific embodiment, the method for preparing the ( S )-6-chloro-2,3,4,9-tetrahydro- 1H -carbazole-1-carboxamide (( S )-SLS) enriched in mirror image isomerism as described above may further comprise the following steps: e1) exposing the crystalline intermediate product to an aqueous solution of an inorganic base to provide ( S )-6-chloro-2,3,4,9-tetrahydro- 1H -carbazole-1-carboxamide enriched in mirror image isomerism, and e2) isolating ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide enriched in mirror image isomerism.

In a further embodiment of the method of this aspect of the invention, rac -6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide of formula (I) and the compound of formula (II) can be provided in the first liquid mixture in a molar ratio of about 1.5:1 to about 2.5 to 1, preferably from about 1.9:1 to about 2.1 to 1.

In a particular embodiment, the first liquid medium, such as used in process step a) and/or the second liquid medium, such as used in the recrystallization in step d) as required, may be an organic solvent or a mixture of organic solvents. Preferably, the two liquid media contain an organic solvent, such as an organic solvent or a mixture of organic solvents, in particular an organic solvent selected from the group consisting of C ₁ -C ₄ alkyl acetates such as ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, tert-butyl acetate, acetonitrile, methyl isobutyl ketone, aromatic hydrocarbons such as toluene, or mixtures thereof.

In further embodiments, the first liquid medium may comprise isobutyl acetate and acetonitrile or consist essentially of isobutyl acetate and acetonitrile, such as a mixture of about 70% to about 95% (v/v) isobutyl acetate and about 30% to about 50% (v/v) acetonitrile (relative to the volume of the final solvent mixture). In another specific embodiment, the second liquid medium for optional recrystallization according to step d) may comprise acetonitrile or consist essentially of acetonitrile.

In some embodiments, the first liquid medium may be used in an amount of about 2 to about 10 mL or from about 5 to about 8 mL per mmol of rac-SLS used in step a).

According to method step b), the first liquid mixture is exposed to conditions in which rac -6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and the compound of formula (II) are at least partially dissolved in the first liquid medium to form an intermediate solution. In some embodiments, for example, the first liquid mixture can be heated, stirred, or treated with ultrasound or both. However, in preferred embodiments, the first liquid mixture according to method step b) is heated, preferably to a temperature selected in the range of from about 60° C. to about 100° C. or from about 80° C. to about 95° C., and further preferably until complete dissolution of rac-SLS and the compound of formula (II) is observed. The solution formed in step b) can then be exposed to conditions that form an intermediate mixture comprising a crystalline intermediate product comprising ( S )-SLS and the selected chiral compound of formula (II) in co-crystal form. In a specific embodiment, according to process step c), the solution formed in step b) is cooled, preferably to a temperature in the range of from about 10°C to about 30°C, or from about 20°C to about 25°C to form an intermediate co-crystal of ( S )-SLS and the compound of formula (II).

In a further embodiment, the crystalline intermediate product comprising ( S )-SLS and the compound of formula (II) in the form of a co-crystal formed in step c) comprises ( S )-SLS and the compound of formula (II) in a molar ratio of 2:1. According to the optional method step c3), the crystalline intermediate product (including the crystalline intermediate in the form of a co-crystal) can then be washed, preferably with a solvent or a mixture of solvents as described above with respect to the first liquid medium.

According to the optional method step d), the crystalline intermediate product comprising ( S )-SLS in co-crystal form and the selected compound of formula (II) can be optionally recrystallized in a second liquid medium as described above. The amount of the second liquid medium as described above can be in the range of from about 10 mL to about 40 mL, or from about 15 mL to about 30 ml, or to about 20 mL per g of the crystalline intermediate product. The optional recrystallization can be performed as known to those skilled in the art. However, in some embodiments, the optional recrystallization of step d) may include the following steps: d1) providing a mixture of a crystallized intermediate product (including an intermediate eutectic) in a second liquid medium, d2) exposing the mixture formed in step d1) to conditions where the crystallized intermediate product is (at least partially) dissolved in a third solvent or solvent mixture, and d3) exposing the mixture formed in step d2) (wherein the crystallized intermediate product is (at least partially) dissolved in the second liquid medium) to conditions where the dissolved intermediate product recrystallizes.

In certain embodiments, step d2) may comprise heating the mixture as provided in step d1) to a temperature in the range of from about 60° C. to about 90° C. or from about 70° C. to about 85° C. Process step d3) may comprise cooling the mixture as formed in step d2), preferably to a temperature in the range of from about 10° C. to about 30° C. The recrystallized intermediate product in the eutectic form may then be separated and washed.

According to the method step e), the crystalline intermediate product formed in step c) or d) is then exposed to an aqueous solution of an inorganic base selected from the following group: an alkali metal or alkali earth metal carbonate, bicarbonate or hydroxide, such as an aqueous solution of sodium bicarbonate or potassium bicarbonate or an aqueous solution of sodium carbonate or potassium carbonate such as NaHCO ₃ , KHCO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , preferably an aqueous solution of sodium bicarbonate (NaHCO ₃ ). In some embodiments of step e), the amount of the inorganic base used may be at least 1.5 equivalents relative to the amount of the intermediate eutectic of ( S )-SLS and the compound of formula (II). In many cases, especially when carried out in a purely aqueous liquid medium, ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide of formula (SI) is enriched in the enantiomerically or enantiomerically pure form and then crystallizes in the reaction mixture, preferably in the form of crystalline polymorph G, and can be separated and washed by standard techniques.

The method described above allows the preparation of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide of formula (SI) enriched in mirror image isomers. In particular embodiments, (S)-SLS, more specifically polymorph G of (S)-SLS, having a mirror image isomer excess of at least about 70% ee, or at least about 80% ee, or at least about 90% ee, such as from about 90 to about 99.8% ee, or from about 95 to about 99.6% ee, or from about 97 to about 99.5 % ee can be prepared . In further embodiments, the method comprises recrystallizing an intermediate eutectic comprising (S ) -SLS and a compound of formula (II) in a second liquid medium according to step d).

Starting from this crystalline polymorph G of ( S )-6-chloro-2,3,4,9-tetrahydro- 1H -carbazole-1-carboxamide, further crystalline polymorphs, more specifically polymorphs K and H, can be prepared as described in Examples 3 and 5 below. More specifically, polymorph K of ( S )-SLS can be prepared by recrystallization in nitromethane, while polymorph H of ( S )-SLS can be prepared by suspending polymorph G of ( S )-SLS in xylene.

Therefore, the present invention also provides a method for preparing a crystalline form of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (( S )-SLS), wherein the crystalline form of ( S )-SLS is a crystalline polymorph of (S)-SLS (polymorph K) having an X-ray powder diffraction pattern of 2θ angle values comprising 11.2, 13.0, 16.3 and 21.9 degrees (with a deviation of +/- 0.2 degrees), the method comprising the following steps: i) preparing the crystalline form of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) having an X-ray powder diffraction pattern of 2θ angle values comprising 10.8, 13.5, 21.7 and 23.8, in particular 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6 and 30.6 (with a deviation of +/- 0.2 degrees); 0.2 degree deviation) of the X-ray powder diffraction pattern of ( S )-SLS (polymorph G) in the crystalline form; and ii) polymorph G of ( S )-SLS prepared according to step i) by recrystallization in nitromethane.

In addition, the present invention provides a method for preparing a crystalline form of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (( S )-SLS), wherein the crystalline form of ( S )-SLS is a crystalline polymorph of (S)-SLS (polymorph H) having an X-ray powder diffraction pattern of 2θ angle values comprising 6.7, 12.6, 13.4 and 18.5 degrees (with a deviation of +/- 0.2 degrees), and the method comprises the following steps: i') preparing the crystalline form of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) having an X-ray powder diffraction pattern of 2θ angle values comprising 10.8, 13.5, 21.7 and 23.8, in particular 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6 and 30.6 (with a deviation of +/- 0.2 degrees); ii') suspending the polymorph G of ( S ) -SLS prepared according to step i') in xylene.

The following is a list of numbered items that are embodiments of the present invention: 1. ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (( S )-SLS) of formula (SI) in a crystalline form, ( S -I) wherein the crystalline form of ( S )-SLS is a crystalline polymorph of ( S )-SLS selected from the group consisting of crystalline polymorphs a) to c) of ( S )-SLS having an X-ray powder diffraction pattern comprising the following 2θ angle values (with a deviation of +/- 0.2 degrees): a) 10.8, 13.5, 21.7 and 23.8 degrees (polymorph G), b) 6.7, 12.6, 13.4 and 18.5 degrees (polymorph H), and c) 11.2, 13.0, 16.3 and 21.9 degrees (polymorph K). 2. ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (( S )-SLS) of formula (I) according to claim 1, wherein the crystalline form of (S)-SLS is a crystalline polymorph of ( S )-SLS selected from the group consisting of crystalline polymorphs a) to c) of ( S )-SLS having an X-ray powder diffraction pattern comprising the following 2θ angle values (with a deviation of +/- 0.2 degrees): a) 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6 and 30.6 degrees (polymorph G), b) 3. The crystalline form of ( S )-SLS according to item 1 or 2, wherein the crystalline form of (S)-SLS is a crystalline polymorph of ( S )-SLS selected from the group consisting of: crystalline polymorphs of ( S )-SLS a) to c) having the following melting points (onset of melting): a ) 167°C (polymorph G), b) 162°C (polymorph H), and c) 167°C (polymorph K). 4. The crystalline form of ( S )-SLS according to any of the preceding items, wherein the crystalline form of ( S )-SLS is a crystalline polymorph of ( S )-SLS, which is selected from the group consisting of crystalline polymorphs a) to c) of ( S )-SLS having the following melting enthalpy (ΔH): a) - 92.6 J/g (polymorph G), b) - 70.2 J/g (polymorph H), and c) 64.6 J/g (polymorph K). 5. A crystalline form of ( S )-SLS of formula (I) according to any one of the preceding items, wherein the crystalline form of ( S )-SLS is a crystalline polymorph of ( S )-SLS selected from the group consisting of crystalline polymorphs a) and d) of ( S )-SLS having an X-ray powder diffraction pattern comprising the following 2θ angle values (with a deviation of +/- 0.2 degrees): a) 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6 and 30.6 (polymorph G), and b) 6.7, 12.6, 13.4, 18.5, 21.8, 24.9 and 26.9 degrees (polymorph H). 6. A crystalline form of ( S )-SLS of formula (I) according to any of the preceding items, wherein the crystalline form of ( S )-SLS is a crystalline polymorph of ( S )-SLS (polymorph G) having an X-ray powder diffraction pattern comprising 2θ angle values of 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6 and 30.6 (with a deviation of +/- 0.2 degrees). 7. A crystalline form of ( S )-SLS according to any of the preceding items, wherein the crystalline form of ( S )-SLS is solvent-free and/or non-hygroscopic. 8. A crystalline form of ( S )-SLS according to any of the preceding items, wherein the crystalline form of ( S )-SLS is stable at a temperature of 40°C +/- 2°C and a relative humidity (RH) of 75% +/- 5% (accelerated ICH conditions) for at least 7 days. 9. A composition comprising a crystalline form of ( S )-SLS according to formula (SI) of any of the preceding items and further comprising up to about 20 wt.-%, 10 wt.-%, 5 wt.-%, 4 wt.-%, 3 wt.-%, 2 wt.-% or 1 wt.-% of any other solid form of ( S )-SLS based on the weight of the composition. 10. A crystalline form of ( S )-SLS of formula (SI) according to any one of items 1 to 8 or a composition according to item 9 for use as a medicament. 11. A crystalline form of ( S )-SLS of formula (SI) according to any one of items 1 to 8 or a composition according to item 9 for use in the prevention or treatment of a disease or condition associated with SIRT1. 12. A crystalline form of ( S )-SLS of formula (SI) according to any one of items 1 to 8 or a composition according to item 9 for use in the prevention or treatment of cancer, metabolic diseases such as metabolic syndrome, type I diabetes or type II diabetes, obesity, dyslipidemia, hyperlipidemia, Alzheimer's disease, Parkinson's disease, lateral sclerosis, neurodegenerative diseases caused at least in part by polyglutamine aggregation, such as Huntington's disease, spinal bulbar muscular atrophy (SBMA or Kennedy's disease), glomerular dystrophy with Lewy bodies (DRPLA), spinocerebellar ataxia type 1 (SCA1), spinocerebellar ataxia type 2 (SCA2), Machado-Joseph Disease (MJD; SCA3), spinocerebellar ataxia type 6 (SCA6), spinocerebellar ataxia type 7 (SCA7), and spinocerebellar ataxia type 12 (SCA12). 13. Use of a crystalline form of ( S )-SLS of formula (SI) according to any one of items 1 to 8 or a composition according to item 9 for preparing a pharmaceutical composition. 14. A pharmaceutical composition comprising a crystalline form of ( S )-SLS of formula (SI) according to any one of items 1 to 8 or a composition according to item 9 and at least one pharmaceutically acceptable formulation. 15. The pharmaceutical composition according to item 14, wherein the pharmaceutical composition is a solid dosage form for oral administration. 16. The pharmaceutical composition according to item 14 or 15, wherein the composition is a tablet, a capsule or an oral film. 17. A method for preparing a crystalline form of ( S )-6-chloro-2,3,4,9-tetrahydro- 1H -carbazole-1-carboxamide (( S )-SLS) of formula (SI), in particular a crystalline form of (S)-SLS (polymorph G) having an X -ray powder diffraction pattern comprising 2θ angle values of 10.8, 13.5, 21.7 and 23.8, in particular 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6 and 30.6 (with a deviation of +/- 0.2 degrees), the method comprising the following steps: a) providing a first mixture comprising a rac -SLS of formula (I) and a compound of formula (II) in a first liquid medium, (II) wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ may be the same or different and may be independently selected from H, C ₁ -C ₄ -alkyl, halogen, C ₁ -C ₄ -halogenalkyl, -OC ₁ -C ₄ -alkyl, -OC ₁ -C ₄ -halogenalkyl, b) exposing the first mixture to conditions where rac -6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and the compound of formula (II) are at least partially dissolved in a first liquid medium to form an intermediate solution, c) exposing the intermediate solution formed in step b) to conditions where a solid intermediate product comprising ( S )-SLS in a co-crystal form and a crystalline intermediate of the compound of formula (II) is formed, d) Optionally, recrystallizing the co-crystal intermediate in a second liquid medium to provide a solid intermediate product comprising co-crystal ( S )-SLS and a compound of formula (II) enriched in a non-mirror image isomer, and e) exposing the co-crystal intermediate formed in step c) or d) to an aqueous solution of an inorganic base to provide ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide of formula (SI) enriched in a mirror image isomer. 18. A method for preparing a crystalline form of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (( S )-SLS), wherein the crystalline form of ( S )-SLS is a crystalline polymorph of ( S )-SLS (polymorph K) having an X-ray powder diffraction pattern comprising 2θ angle values of 11.2, 13.0, 16.3 and 21.9 degrees (with a deviation of +/- 0.2 degrees), the method comprising the following steps: i) Prepare according to item 17 a crystalline form of ( S )-SLS (polymorph G) having an X-ray powder diffraction pattern comprising 2θ angle values of 10.8, 13.5, 21.7 and 23.8, in particular 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6 and 30.6 (with a deviation of +/- 0.2 degrees); and ii) recrystallize in nitromethane the polymorph G of ( S )-SLS prepared according to step i). 19. A method for preparing a crystalline form of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (( S )-SLS), wherein the crystalline form of ( S )-SLS is a crystalline polymorph of ( S)-SLS (polymorph H) having an X-ray powder diffraction pattern comprising 2θ angle values of 6.7, 12.6, 13.4 and 18.5 degrees (with a deviation of +/- 0.2 degrees), the method comprising the following steps: i') preparing a crystalline form of (S ) -6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide as described above ii') suspending the polymorph G of ( S )-SLS prepared according to step i ') in xylene.

The following examples are used to illustrate the present invention, however, they should not be construed as limiting the scope of the present invention in any aspect. Examples Example 1 : Preparation of ( S )-6- chloro -2,3,4,9 - tetrahydro -1H- carbazole -1- carboxamide (( S )-SLS) ( polymorph G) in crystalline form 1.1 Cocrystal formation of ( S )-Selisistat (( S )-SLS) and (-)-DTTA

125 mL of acetonitrile and isobutyl acetate (mixture of 2-methylpropyl acetate; CAS-Nr. 110-19-0) (15:85 (v/v)) was added to a 250 mL round-bottom flask equipped with a magnetic stirrer and containing a mixture of 10.0 g of racemic 6-chloro-2,3,4,9-tetrahydro- 1H -carbazole-1-carboxamide ( rac -SLS) (40.2 mmol) and 7.77 g of (-)-DTTA (( 2R , 3R )-(-)-di-O-4-methylphenylmethyl-L-tartaric acid; CAS Nr. 32634-66-5; 20.1 mmol, 0.5 eq.). The resulting suspension was heated to reflux until complete dissolution of the solid component was observed. The resulting solution was then seeded with some co-crystals of ( S )-SLS and (-)-DTTA with a mirror image isomer excess of 99% ee at high temperature, slowly cooled to room temperature (about 22°C) and stirred at room temperature for 2 h. The white mixture was filtered through a sintering funnel (porosity 3), washed twice with 20 mL each of a 15:85 (v/v) mixture of acetonitrile and isobutyl acetate and dried overnight under vacuum (about 1 mbar) at room temperature. Co-crystals of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (( S )-SLS) and (-)-DTTA were obtained as white solids (39.4% yield; 74.0% ee). 1.2 Recrystallization of the eutectic of ( S )-SLS and (-)-DTTA

110 mL of acetonitrile was added to a 250 mL round bottom flask equipped with a magnetic stirrer and containing 6.50 g of the cocrystals of ( S )-6-chloro-2,3,4,9-tetrahydro-1 H -carbazole-1-carboxamide (( S )-SLS) and (-)-DTTA (14.7 mmol) prepared in step 1.1 above. The resulting suspension was heated to reflux until complete dissolution was observed. The resulting solution was seeded at high temperature with some cocrystals of ( S )-SLS and (-)-DTTA with a spectroscopic isomer excess of 99% ee, slowly cooled to room temperature (about 22°C) and stirred at room temperature for 2 h. The white mixture was filtered through a sintered funnel (porosity 3), washed twice with acetonitrile (13 mL each) and dried overnight at room temperature under vacuum (about 1 mbar). Cocrystals of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (( S )-SLS) and (-)-DTTA were obtained as white solids (82.5% yield; 99.1% ee). 1.3 Dissociation of cocrystals of ( S )-SLS and (-)-DTTA

200 mL of water was added to a 500 mL round-bottom flask equipped with a magnetic stirrer and containing 5 g of the cocrystal of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (( S )-SLS) and (-)-DTTA (11.3 mmol) prepared as described above in Item 1.2. The resulting suspension was stirred at room temperature (about 22°C) for 30 min and 25 mL of an aqueous solution of NaHCO ₃ (0.86 M) was added. After stirring for 1 h, the white resulting mixture was filtered through a sintered funnel (porosity 3), washed twice with water (20 mL each) and dried overnight at room temperature under vacuum (about 1 mbar). ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ( S )-SLS (polymorph G) was obtained as a white solid (99.3% yield; 32.3% overall yield; 99.4% ee). Example 2 : Characterization of the crystalline form of ( S )-Selisistat ( polymorph G)

The crystalline form of ( S )-Selisistat (polymorph G) prepared according to Example 1 above with a mirror image purity of 99.4% ee was characterized by X-ray powder diffraction (XRPD), ^1H -NMR, differential scanning calorimetry (DSC) and chiral high pressure liquid chromatography (chiral HPLC). 2.1 XPRD analysis of crystalline form of ( S )-Selisistat

XRPD analysis of the crystalline form of ( S )-Selisistat (polymorph G) was performed under ambient conditions using a PANalytical X'Pert PRO ϴ-ϴ diffractometer with a radius of 240 mm in reflection geometry, equipped with Cu K _α radiation and a PIXcel detector, operating at 45 kV and 40 mA. The crystalline sample was mounted on a zero-background silicon holder and rotated at 0.25 rev/s during data collection. The measurement angle range was 3.0-40.0° (2θ) using a step size of 0.013°. The scanning speed was 0.082 (40.80 s/step).

Accordingly, the XRPD pattern of ( S )-Selisistat (polymorph G) measured in crystalline form showed good crystallinity (see FIG. 1 ) and the peaks listed in Table 1 below: Table 1: Position [°2 θ ] [°2Th.] d -spacing [Å] Relative strength [%] 6.7 13.1 6 10.1 8.7 4 10.8 8.2 100 13.5 6.6 76 14.9 6.0 15 18.0 4.9 5 18.5 4.8 7 19.9 4.5 4 20.5 4.3 4 21.2 4.2 5 21.7 4.1 82 22.8 3.9 16 23.8 3.7 50 25.3 3.5 4 26.6 3.4 15 27.2 3.3 5 29.8 3.0 11 30.6 2.9 16 31.2 2.9 3 32.8 2.7 2 34.3 2.6 4 35.5 2.5 7 37.8 2.4 2 2.2 ¹ H-NMR analysis of the crystalline form of ( S )-Selisistat

The ^1H -NMR spectra of crystalline ( S )-selisistat (polymorph G) in deuterated DMSO were recorded on a Varian Mercury 400 MHz spectrometer equipped with a 5 mm broadband probe ATB 1H/19F/X (see Figure 2). Approximately 5 to 10 mg of sample was dissolved in 0.7 mL of deuterated solvent to obtain the spectrum.

The ¹ H-NMR spectrum of the crystalline form of ( S )-Selisistat (polymorph G) was identical to that of the racemic starting material and showed no residual organic solvent. 2.3 Differential Scanning Calorimetry (DSC) Analysis of the Crystalline Form of ( S )-Selisistat ( polymorph G)

DSC analysis of ( S )-Selisistat was recorded using a Mettler Toledo DSC2 to record the crystalline morphology. The sample was weighed into a 40 μL aluminum crucible with a pinhole cap and heated from 25°C to 300°C at a rate of 10°C/min under nitrogen (50 mL/min).

The recorded spectrum (see Figure 3) shows an endothermic peak starting at 167.1°C, corresponding to the melting point of the crystalline form of ( S )-Selisistat (polymorph G). 2.4 Chiral HPLC Analysis of Crystalline Form of ( S )-Selisistat ( polymorph G)

Chiral HPLC analysis of ( S )-Selisistat in crystalline form (polymorph G) was performed using an Agilent HP1100 HPLC system equipped with a vacuum degasser, quaternary pump, autosampler, thermostatic column, and VW detector.

The mirror image isomer excess of ( S )-Selisistat in crystalline form was determined under the following conditions: Chiralpak IA 250 x 4.6 mm, 5 µm; sample concentration: 1 mg/mL in heptane/isopropanol (1:1); mobile phase: isopropanol:ethanol-0.2% diethylamine (50:50); temperature: 25°C; flow rate: 0.4 mL/min; wavelength: 210 nm; injection: 5 µL; run time: 330 min. The chromatogram showed a mirror image isomer purity of 99.4 % ee (peaks at retention times of 15.15 and 19.62 min). Example 3 : Preparation of crystalline ( S )-6- chloro -2,3,4,9- tetrahydro - 1H - carbazole -1- carboxamide ( S )-SLS ( polymorph K)

20 mg of ( S )-SLS (polymorph G) (0.080 mmol) prepared according to Example 1 was suspended in 0.4 mL of nitromethane. The suspension was heated until a clear solution was obtained. The resulting solution was cooled to room temperature (about 22°C) and then stirred overnight. The resulting precipitate was filtered through a sintering funnel (porosity 3) and dried under vacuum at room temperature to provide ( S )-SLS (polymorph K) as a white solid. Example 4 : Characterization of ( S )-Selisistat ( polymorph K) in crystalline form

The crystalline form of ( S )-Selisistat (polymorph K) prepared according to Example 3 above with a spectroscopic purity of 99.4% ee was characterized by X-ray powder diffraction (XRPD), 1H-NMR and differential scanning calorimetry (DSC). 4.1 XRPD analysis of crystalline form of ( S )-Selisistat ( polymorph K)

XRPD analysis of the crystalline form of ( S )-Selisistat (polymorph K) was performed as described in Example 2.1 above.

The XRPD pattern of ( S )-Selisistat (polymorph K) measured in crystalline form showed good crystallinity (see FIG. 4 ) and the peaks listed in Table 2 below: Table 2: Position [°2 θ ] d -spacing [Å] Relative strength [%] 5.8 15.23 12 8.1 10.97 17 11.2 7.88 47 11.7 7.56 1 12.7 6.99 14 13.0 6.81 100 16.3 5.45 63 17.6 5.03 5 17.9 4.96 9 18.5 4.79 9 19.0 4.66 4 20.6 4.30 7 21.4 4.16 12 21.9 4.06 26 22.6 3.93 25 23.5 3.78 11 24.3 3.66 25 25.0 3.57 8 25.3 3.52 10 26.2 3.40 12 26.8 3.32 7 27.6 3.23 10 28.8 3.10 7 29.2 3.06 6 29.6 3.01 1 30.2 2.96 9 30.8 2.90 7 31.8 2.82 1 33.6 2.67 6 34.3 2.61 5 34.9 2.57 1 36.3 2.48 6 37.2 2.41 1 37.6 2.39 13 4.2 ¹ H-NMR analysis of crystalline ( S )-Selisistat ( polymorph K)

The ¹ H NMR spectrum of the crystalline form of ( S )-selisistat (polymorph K) was recorded as described in Example 2.2.

The ¹ H NMR spectrum of the crystalline form of ( S )-Selisistat (polymorph K) is consistent with its chemical structure and shows no residual organic solvent. 4.3 Differential Scanning Calorimetry (DSC) Analysis of Crystalline Form of ( S )-Selisistat ( polymorph K)

DSC analysis of the crystalline form of ( S )-Selisistat (polymorph K) was recorded as described in Example 2.3.

The recorded spectrum (see FIG. 5 ) shows an endothermic peak starting at about 167.3° C., corresponding to the initial melting point of the crystalline form of ( S )-Selisistat (polymorph K), followed by an exothermic event with an endothermic peak starting at 184.5° C. Example 5 : Preparation of ( S )-6- chloro -2,3,4,9 - tetrahydro -1H- carbazole -1- carboxamide ( S )-SLS ( polymorph H) in crystalline form

50 mg of ( S )-SLS (polymorph G) (0.201 mmol) prepared according to Example 1 was suspended in 0.5 mL of xylene. The suspension was stirred at room temperature (about 22°C) overnight. The resulting mixture was centrifuged, decanted and dried under vacuum at room temperature to provide ( S )-SLS (polymorph H) as a white solid. Example 6 : Characterization of ( S )-Selisistat ( polymorph H) in crystalline form

The crystalline form of ( S )-Selisistat (polymorph H) prepared according to Example 5 above with a telescopic purity of 99.4% ee was characterized by X-ray powder diffraction (XRPD), ¹ H-NMR and differential scanning calorimetry (DSC). 6.1 XRPD analysis of crystalline form of ( S )-Selisistat ( polymorph H)

XPRD analysis of the crystalline form of ( S )-Selisistat (polymorph H) was performed as described in Example 2.1 above.

The XRPD pattern of ( S )-Selisistat (polymorph H) measured in crystalline form showed good crystallinity (see FIG6 ) and the peaks listed in Table 3 below: Table 3: Position [°2 θ ] d -spacing [Å] Relative strength [%] 5.5 16.13 16 6.7 13.27 100 12.2 7.24 9 12.6 7.03 78 13.4 6.60 52 14.8 6.00 8 15.1 5.88 15 16.5 5.36 2 17.3 5.12 12 18.2 4.89 15 18.5 4.80 65 19.0 4.66 5 19.2 4.62 14 20.0 4.44 10 20.3 4.38 10 20.6 4.30 8 21.1 4.21 11 21.3 4.17 11 21.5 4.13 16 21.8 4.08 twenty one 22.1 4.02 12 22.7 3.92 12 23.9 3.73 7 24.7 3.61 12 24.9 3.58 twenty one 25.3 3.52 13 26.0 3.42 10 26.6 3.35 3 26.9 3.31 twenty one 27.6 3.23 8 28.9 3.09 11 33.3 2.69 9 35.3 2.54 10 6.2 ¹ H-NMR Analysis of Crystalline ( S )-Selisistat ( Polymorph H)

The ¹ H NMR spectrum of the crystalline form of ( S )-Selisistat (polymorph H) was recorded as described in Example 2.2.

The ¹ H NMR spectrum of the crystalline form of ( S )-Selisistat (polymorph H) was identical to that of the racemic starting material and showed no residual organic solvent. 6.3 Differential Scanning Calorimetry (DSC) Analysis of the Crystalline Form of ( S )-Selisistat ( polymorph H)

DSC analysis of the crystalline form of ( S )-Selisistat (polymorph H) was recorded as described in Example 2.3.

The recorded spectrum (see FIG. 7 ) shows an endothermic peak starting at about 162° C., corresponding to the initial melting point of the crystalline form of ( S )-Selisistat (polymorph H), followed by an exothermic event and then an endothermic peak starting at 185.1° C. Example 7 : Stability of the polymorphs of crystalline form of ( S )-Selisistat

Samples of polymorphs G, H and K of ( S )-Selisistat prepared according to Examples 1 to 6 above and in exemplary crystalline forms were subjected to accelerated stability testing under conditions as defined by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) (ICH; accelerated ICH conditions: storage at 40 +/- 2°C, 75 +/- 5% relative humidity) as follows: Crystals of each compound prepared according to Examples 1, 3 and 5, respectively, were placed on an XRPD silicon sample holder and exposed to the accelerated ICH conditions defined above in an appropriate climate chamber.

Samples were analyzed periodically by XRPD to observe possible crystalline transformation or amorphization. All tested samples (polymorphs G, H and K) remained stable for at least 7 days at 40 +/- 2°C, 75 +/- 5% relative humidity (RH). Example 8 : Preparation of ( S )-6- chloro -2,3,4,9- tetrahydro - 1H - carbazole -1- carboxamide ( S )-SLS ( polymorph T) in crystalline form

20 mg of ( S )-SLS (polymorph G) (0.080 mmol) prepared according to Example 1 was dissolved in 0.1 mL of dimethyl sulfoxide (DMSO). 1 mL of anisole was added and the resulting mixture was centrifuged and decanted to provide ( S )-SLS (polymorph T) in the form of a pasty solid. Example 9 : Characterization of ( S )-Selisistat ( polymorph T) in crystalline form

The crystalline form of ( S )-Selisistat (polymorph T) prepared according to Example 8 above with a spectroscopic purity of 99.4% ee was characterized by X-ray powder diffraction (XRPD). 9.1 XRPD analysis of crystalline form of ( S )-Selisistat ( polymorph T)

XPRD analysis of the crystalline form of ( S )-Selisistat (polymorph T) was performed as described in Example 2.1 above.

The XRPD pattern of ( S )-Selisistat (polymorph T) measured in crystalline form showed low crystallinity (see FIG8 ) and the peaks listed in Table 4 below: Table 4: Position [°2 θ ] d -spacing [Å] Relative strength [%] 7.2 12.34 100 14.4 6.14 16 21.7 4.10 twenty three 24.1 3.69 7 Example 10 : Preparation of a crystalline solvent of ( S )-6- chloro- 2,3,4,9- tetrahydro -1H- carbazole -1- carboxamide and acetone ( Solvent J)

50 mg of ( S )-SLS (polymorph G) (0.201 mmol) prepared according to Example 1 was suspended in 0.25 mL of acetone and the resulting mixture was stirred at room temperature overnight. The mixture was filtered through a sintering funnel (porosity 3) and the precipitate was dried under vacuum overnight to provide ( S )-SLS solvent complex J as a white solid. Example 11 : Characterization of crystalline form of ( S )-Selisistat in acetone solvent complex ( solvent complex J)

The crystalline ( S )-Selisistat in acetone solvent (Solvent J) prepared according to Example 10 was characterized by X-ray powder diffraction (XRPD), ¹ H-NMR and differential scanning calorimetry (DSC). 11.1 XRPD analysis of crystalline ( S )-Selisistat in acetone solvent ( Solvent J)

XRPD analysis of the crystalline form of ( S )-Selisistat in solvent complex J was performed as described in Example 2.1 above.

The XPRD pattern of solvent J of ( S )-Selisistat measured for crystalline form showed good crystallinity (see FIG. 9 ) and the peaks listed in Table 5 below: Table 5: Position [°2 θ ] d -spacing [Å] Relative strength [%] 5.9 15.09 3 8.9 9.91 1 9.5 9.27 2 10.2 8.69 7 10.6 8.37 100 11.2 7.93 4 11.9 7.45 14 13.2 6.70 1 14.1 6.28 3 14.3 6.20 3 15.6 5.67 14 16.2 5.48 5 16.4 5.41 10 17.2 5.15 27 17.5 5.05 2 17.9 4.95 8 18.2 4.87 3 18.9 4.70 2 19.2 4.63 18 19.5 4.56 2 19.8 4.48 9 21.3 4.18 19 22.6 3.94 2 23.1 3.86 3 23.4 3.81 1 24.0 3.71 4 24.2 3.68 1 25.2 3.54 15 25.4 3.50 1 26.3 3.38 3 26.9 3.31 3 27.1 3.29 5 27.4 3.25 1 27.8 3.21 1 28.4 3.15 3 28.8 3.10 5 29.8 2.99 7 31.7 2.82 2 32.2 2.78 2 35.4 2.54 1 36.4 2.47 1 11.2 ¹ H-NMR analysis of crystalline ( S )-selisistat in acetone solvent ( solvent J)

The ¹ H-NMR spectrum of ( S )-Selisista in Solvent J in the crystalline form (Solvent J) was recorded as described in Example 2.2.

The ^1H -NMR spectrum of the crystalline form of ( S )-Selisistat in acetone solvent J (see Figure 10) shows the signal of the starting material (polymorph G) at 2.1 ppm and the signal of acetone. The integration of the signals indicates a ( S )-SLS to acetone (molar) ratio of about 3:1. 11.3 Differential Scanning Calorimetry (DSC) Analysis of Crystalline Form of ( S )-Selisistat in Acetone Solvent ( Solvent J)

DSC analysis of the crystalline form of ( S )-Selisistat in acetone solvent was recorded as described in Example 2.3.

The recorded spectrum (see FIG. 11 ) shows two broad endothermic peaks starting at about 82° C. and about 106° C., respectively, followed by a sharp endothermic peak starting at about 171° C. Example 12 : Preparation of a crystalline solvent complex of ( S )-6- chloro -2,3,4,9 - tetrahydro -1 H -carbazole -1- carboxamide and dioxane ( solvent complex M)

50 mg of ( S )-SLS (polymorph G) (0.201 mmol) prepared according to Example 1 was suspended in 1 mL of dioxane and the resulting mixture was stirred at room temperature overnight. The mixture was filtered through a sintering funnel (porosity 3) and the precipitate was dried under vacuum overnight to provide ( S )-SLS dioxane solvent complex M as a white solid. Example 13 : Characterization of dioxane solvent complex ( solvent complex M) of crystalline form of ( S )-Selisistat

The crystalline ( S )-Selisistat in dioxane solvent (Solvent M) prepared according to Example 12 was characterized by X-ray powder diffraction (XRPD), ¹ H-NMR and differential scanning calorimetry (DSC). 13.1 XRPD analysis of crystalline ( S )-Selisistat in dioxane solvent ( Solvent M)

XRPD analysis of the crystalline form of ( S )-Selisistat in dioxane solvent M was performed as described in Example 2.1 above.

The XRPD pattern of the dioxane solvent complex M of ( S )-Selisistat measured in crystalline form showed good crystallinity (see FIG. 12 ) and the peaks listed in Table 6 below: Table 6: Position [°2 θ ] d -spacing [Å] Relative strength [%] 5.9 15.01 2 9.9 8.96 26 11.9 7.46 100 14.3 6.20 4 16.1 5.49 38 16.8 5.26 1 18.2 4.87 2 19.6 4.54 42 19.8 4.47 20 21.1 4.22 5 21.8 4.08 18 22.3 3.98 36 22.9 3.88 twenty one 24.1 3.70 8 25.0 3.57 4 25.2 3.53 4 25.5 3.49 2 26.3 3.39 5 28.1 3.18 4 28.4 3.14 4 29.7 3.01 2 30.0 2.98 3 30.7 2.91 7 31.0 2.88 5 31.4 2.85 3 32.0 2.80 4 32.6 2.74 2 34.1 2.63 3 34.8 2.58 1 35.5 2.53 1 36.2 2.48 1 36.9 2.44 2 38.7 2.33 1 13.2 ¹ H-NMR Analysis of the Dioxane Solvent Complex of ( S )-Selisistat in Crystalline Form ( Solvent Complex M)

The ¹ H NMR spectrum of the crystalline form of M( S )-Selisistat in dioxane solvent was recorded as described in Example 2.2.

The ^1H -NMR spectrum of the crystalline form of M ( S )-Selisistat in dioxane solvent (see FIG. 13) shows the signal of the starting material (polymorph G) and the signal of dioxane at about 3.6 ppm. The integration of the signals indicates a ( S )-SLS to dioxane (molar) ratio of about 1:0.8. 13.3 Differential Scanning Calorimetry (DSC) Analysis of Crystalline Form of ( S )-Selisistat in Dioxane Solvent ( Solvent M)

DSC analysis of the crystalline form of ( S )-Selisistat in dioxane solvent was recorded as described in Example 2.3.

The recorded spectrum (see FIG. 14 ) shows two broad endothermic peaks starting at about 80° C. and about 103° C., respectively, followed by a sharp endothermic peak starting at about 188° C. Example 14 : Preparation of a crystalline solvent complex of ( S )-6- chloro - 2,3,4,9 - tetrahydro -1H - carbazole -1- carboxamide and N , N -dimethylformamide (DMF) ( Solvent complex R)

100 mg of ( S )-SLS (polymorph G) (0.402 mmol) prepared according to Example 1 was suspended in 0.15 mL of dimethylformamide and the resulting mixture was stirred at room temperature overnight. The mixture was filtered with a sintering funnel (porosity 3) and the precipitate was dried under vacuum overnight to provide ( S )-SLS solvent complex R as a white solid. Example 15 : Characterization of ( S )-Selisistat in DMF solvent complex ( solvent complex R) in crystalline form

The crystalline form of ( S )-Selisistat in DMF solvent (Solvent R) prepared according to Example 12 above was characterized by X-ray powder diffraction (XRPD) and ¹ H-NMR. 15.1 XRPD analysis of crystalline form of ( S )-Selisistat in DMF solvent ( Solvent R)

XRPD analysis of the crystalline form of ( S )-Selisistat in DMF solvent R was performed as described in Example 2.1 above.

The XRPD pattern of ( S )-Selisistat in DMF solvent R, which measured the crystalline form, showed good crystallinity (see FIG. 15 ) and the peaks listed in Table 7 below: Table 7: Position [°2 θ ] d -spacing [Å] Relative strength [%] 4.9 18.14 12 5.6 15.92 15 7.3 12.17 11 9.5 9.28 9 10.2 8.70 4 10.9 8.12 100 11.3 7.83 18 13.0 6.81 3 13.3 6.66 8 14.1 6.27 2 15.4 5.76 12 17.0 5.21 46 17.3 5.11 13 17.8 4.98 33 18.5 4.80 10 19.2 4.63 13 19.8 4.48 1 20.9 4.24 1 21.6 4.11 2 21.9 4.05 10 22.6 3.93 9 23.7 3.76 4 24.2 3.68 2 25.6 3.48 twenty two 26.2 3.40 2 26.6 3.35 2 27.3 3.27 8 28.1 3.18 12 29.3 3.05 8 29.9 2.99 4 32.8 2.73 2 15.2 ¹ H-NMR Analysis of Crystalline ( S )-Selisistat in DMF Solvent ( Solvent R)

The ¹ H-NMR spectrum of the crystalline form of ( S )-selisistat in DMF solvent R was recorded as described in Example 2.2.

The ^1H -NMR spectrum of the crystalline form of ( S )-Selisistat in DMF solvent complex R (see Figure 16) shows signals of the starting material (polymorph G) and N , N- dimethylformamide at about 8.0, 2.9 and 2.7 ppm. The integration of the signals indicates a ( S )-SLS to DMF (molar) ratio of about 1:0.5. Example 16 : Preparation of a crystalline form of ( S )-6- chloro -2,3,4,9 - tetrahydro -1H- carbazole -1- carboxamide and cyclopentanone solvent complex ( solvent complex Q)

100 mg of ( S )-SLS (polymorph G) (0.402 mmol) prepared according to Example 1 was suspended in 0.15 mL of cyclopentanone and the resulting mixture was stirred at room temperature overnight. The mixture was filtered with a sintering funnel (porosity 3) and the precipitate was dried under vacuum overnight to provide ( S )-SLS solvent complex R as a white solid. Example 17 : Characterization of cyclopentanone solvent complex ( solvent complex Q) of ( S )-Selisistat in crystalline form

The crystalline form of ( S )-Selisistat in cyclopentanone solvent (Solvent Q) prepared according to Example 16 was characterized by X-ray powder diffraction (XRPD) and ¹ H-NMR. 17.1 XRPD Analysis of Crystalline Form of ( S )-Selisistat in Cyclopentanone Solvent ( Solvent Q)

XRPD analysis of the crystalline form of ( S )-Selisistat in cyclopentanone solvent complex Q was performed as described in Example 2.1 above.

The XRPD pattern of ( S )-Selisistat in cyclopentanone solvent Q, which measured the crystalline form, showed good crystallinity (see FIG. 17 ) and the peaks listed in Table 8 below: Table 8: Position [°2 θ ] d -spacing [Å] Relative strength [%] 4.4 20.02 14 4.8 18.43 8 5.1 17.34 4 5.5 16.06 1 6.4 13.80 6 7.3 12.12 7 9.6 9.25 7 9.9 8.89 5 11.1 8.00 100 11.7 7.55 7 12.0 7.35 7 12.8 6.92 8 13.4 6.63 2 14.6 6.05 6 15.2 5.83 10 16.9 5.26 58 17.5 5.06 5 18.6 4.77 7 19.2 4.62 14 20.6 4.32 25 21.0 4.24 16 21.7 4.09 8 22.2 4.00 14 23.6 3.77 15 24.2 3.67 4 25.1 3.55 10 25.7 3.46 5 26.2 3.41 6 26.9 3.31 13 27.5 3.25 8 29.6 3.02 13 32.4 2.77 5 35.2 2.55 1 36.2 2.48 4 36.9 2.44 1 17.2    ¹ H-NMR analysis of crystalline ( S )-Selisistat in cyclopentanone solvent ( solvent Q)

The ¹ H-NMR spectrum of the crystalline form of ( S )-selisistat in cyclopentanone solvent Q was recorded as described in Example 2.2.

The ^1H -NMR spectrum of the cyclopentanone solvent complex of ( S )-Selisistat in crystalline form Q (see Figure 18) shows signals of the starting material (polymorph G) and cyclopentanone at about 1.8 to 2.1 ppm. The integration of the signals indicates a ( S )-SLS to cyclopentanone (molar) ratio of about 1:1.

without

FIG. 1 depicts a diffraction pattern of an X-ray powder diffraction (XRPD) analysis of a crystalline polymorph of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (polymorph G).

FIG. 2 depicts the ¹ H-nuclear magnetic resonance ( ¹ H-NMR) spectrum of a crystalline polymorph of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (polymorph G).

FIG3 depicts the spectrum of the crystalline polymorph of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (polymorph G) analyzed by differential scanning calorimetry (DSC).

FIG. 4 depicts a diffraction pattern of an XRPD analysis of a polymorph of crystalline ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (polymorph K).

FIG5 depicts the spectrum of DSC analysis of a crystalline polymorph of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (polymorph K).

FIG6 depicts a diffraction pattern of an XRPD analysis of a polymorph of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (polymorph H) in crystalline form.

FIG. 7 depicts the spectrum of DSC analysis of a crystalline polymorph of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (polymorph H).

FIG8 depicts a diffraction pattern of an XRPD analysis of a polymorph of crystalline ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (polymorph T).

FIG. 9 depicts the diffraction pattern of the XRPD analysis of the crystalline form of ( S )-6-chloro-2,3,4,9-tetrahydro-1 H -carbazole-1-carboxamide in acetone solvent (Solvent J).

FIG. 10 depicts the spectrum of ¹ H-nuclear magnetic resonance ( ¹ H-NMR) analysis of an acetone solvent complex (Solvent J) of ( S )-6-chloro-2,3,4,9-tetrahydro- 1H -carbazole-1-carboxamide depicted in FIG. 2 .

FIG. 11 depicts the spectrum of DSC analysis of a crystalline form of ( S )-6-chloro-2,3,4,9-tetrahydro-1 H -carbazole-1-carboxamide in acetone solvent (Solvent J).

FIG. 12 depicts the diffraction pattern of the XRPD analysis of a dioxane solvent complex ( S )-6-chloro-2,3,4,9-tetrahydro- 1H -carbazole-1-carboxamide in a crystalline form (S).

FIG. 13 depicts the spectrum of ¹ H-nuclear magnetic resonance ( ¹ H-NMR) analysis of a dioxane solvent complex (solvent M) of ( S )-6-chloro-2,3,4,9-tetrahydro-1 H -carbazole-1-carboxamide.

FIG. 14 depicts the spectrum of the DSC analysis of a dioxane solvent complex ( S )-6-chloro-2,3,4,9-tetrahydro- 1H -carbazole-1-carboxamide in a crystalline form (Solvent M).

FIG. 15 depicts a diffraction pattern of an XRPD analysis of a crystalline form of ( S )-6-chloro-2,3,4,9-tetrahydro-1 H -carbazole-1-carboxamide in N,N -dimethylformamide solvent (Solvent R).

FIG. 16 depicts the spectrum of ¹ H-nuclear magnetic resonance ( ¹ H-NMR) analysis of ( S )-6-chloro-2,3,4,9-tetrahydro-1 H -carbazole-1-carboxamide in N,N -dimethylformamide solvent (solvent R).

FIG. 17 depicts a diffraction pattern of an XRPD analysis of a crystalline form of ( S )-6-chloro-2,3,4,9-tetrahydro-1 H -carbazole-1-carboxamide of cyclopentanone solvent complex (Solvent complex Q).

FIG. 18 depicts the spectrum of ¹ H-nuclear magnetic resonance ( ¹ H-NMR) analysis of a cyclopentanone solvent complex (Solvent Complex Q) of ( S )-6-chloro-2,3,4,9-tetrahydro-1 H -carbazole-1-carboxamide.

without

Claims (15)

A crystalline form of ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (( S )-SLS) of formula ( S -I), ( S -I) wherein the crystalline form of ( S )-SLS is a crystalline polymorph of ( S )-SLS selected from the group consisting of crystalline polymorphs a) to c) of ( S )-SLS having an X-ray powder diffraction pattern comprising the following 2θ angle values (with a deviation of +/- 0.2 degrees): a) 10.8, 13.5, 21.7 and 23.8 degrees (polymorph G), b) 6.7, 12.6, 13.4 and 18.5 degrees (polymorph H), and c) 11.2, 13.0, 16.3 and 21.9 degrees (polymorph K). ( S )-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (( S )-SLS) of formula (I) according to claim 1, wherein the crystalline form of ( S )-SLS is a crystalline polymorph of (S)-SLS selected from the group consisting of crystalline polymorphs a) to c) of ( S )-SLS having an X-ray powder diffraction pattern comprising the following 2θ angle values (with a deviation of +/- 0.2 degrees): a) 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6 and 30.6 degrees (polymorph G), b) 6.7, 12.6, 13.4, 18.5, 21.8, 24.9 and 26.9 degrees (polymorph H), and c) 8.1, 11.2, 13.0, 16.3, 21.9, 22.6 and 24.3 degrees (polymorph K). The crystalline form of ( S )-SLS according to claim 1 or 2, wherein the crystalline form of ( S )-SLS is a crystalline polymorphic form of ( S )-SLS, which is selected from the group consisting of crystalline polymorphic forms a) to c) of ( S )-SLS having the following melting points (start of melting): a) 167°C (polymorph G), b) 162°C (polymorph H), and c) 167°C (polymorph K). The crystalline form of ( S )-SLS according to any of the preceding claims, wherein the crystalline form of ( S )-SLS is a crystalline polymorph of ( S )-SLS selected from the group consisting of crystalline polymorphs a) to c) of ( S )-SLS having a melting enthalpy (ΔH) within the following ranges: a) from about -93 J/g to about -92 J/g (polymorph G), b) from about -71 J/g to about -70 J/g (polymorph H), and c) about -65 J/g to about -64 J/g (polymorph K). A crystalline form of ( S )-SLS of formula (I) according to any of the preceding claims, wherein the crystalline form of ( S )-SLS is a crystalline polymorph of ( S )-SLS selected from the group consisting of crystalline polymorphs a) and d) of ( S )-SLS having an X-ray powder diffraction pattern comprising the following 2θ angle values (with a deviation of +/- 0.2 degrees): a) 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6 and 30.6 (polymorph G), and b) 6.7, 12.6, 13.4, 18.5, 21.8, 24.9 and 26.9 degrees (polymorph H). A crystalline form of ( S )-SLS of formula (I) according to any of the preceding claims, wherein the crystalline form of ( S )-SLS is a crystalline polymorph of ( S )-SLS having an X -ray powder diffraction pattern comprising 2θ angle values of 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6 and 30.6 (with a deviation of +/- 0.2 degrees) (polymorph G). The crystalline form of ( S )-SLS according to any of the preceding claims, wherein the crystalline form of the ( S )-SLS is solvent-free and/or non-hygroscopic. The crystalline form of ( S )-SLS according to any of the preceding claims, wherein the crystalline form of ( S )-SLS is stable for at least 7 days at a temperature of 40°C +/- 2°C and a relative humidity (RH) of 75% +/- 5% (accelerated ICH conditions). A composition comprising a crystalline form of ( S )-SLS of formula (I) according to any of the preceding claims and further comprising up to about 20 wt.-%, 10 wt.-%, 5 wt.-%, 4 wt.-%, 3 wt.-%, 2 wt.-% or 1 wt.-% of any other solid form of ( S )-SLS, based on the weight of the composition. A crystalline form of ( S )-SLS of formula (I) according to any one of claims 1 to 8 or a composition according to claim 9 for use as a medicament. A crystalline form of ( S )-SLS of formula (I) according to any one of claims 1 to 8 or a composition according to claim 9 for use in preventing or treating a disease or condition associated with SIRT1. A crystalline form of ( S )-SLS of formula (I) according to any one of claims 1 to 8 or a composition according to claim 9 for use in the prevention or treatment of cancer, metabolic diseases such as metabolic syndrome, type I diabetes or type II diabetes, obesity, dyslipidemia, hyperlipidemia, Alzheimer's disease, Parkinson's disease, lateral sclerosis, neurodegenerative diseases caused at least in part by polyglutamine aggregation, such as Huntington's disease, spinal bulbar muscular atrophy (SBMA or Kennedy's disease), dentatorubro-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia type 1 (spinocerebellar ataxia 1, SCA1), spinocerebellar ataxia type 2 (SCA2), Machado-Joseph disease (Machado-Joseph disease, MJD; SCA3), spinocerebellar ataxia type 6 (SCA6), spinocerebellar ataxia type 7 (SCA7), and spinocerebellar ataxia type 12 (SCA12). A use of a crystalline form of ( S )-SLS of formula (I) according to any one of claims 1 to 8 or a composition according to claim 9 for preparing a pharmaceutical composition. A pharmaceutical composition comprising the crystalline form of ( S )-SLS according to any one of claims 1 to 8 or the composition according to claim 9 and at least one pharmaceutically acceptable excipient. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition is a solid dosage form for oral administration, preferably a tablet, a capsule or an oral film.