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

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, (S-I)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

[0001]NEW POLYMORPHS OF (S)-6-CHLORO-2,3,4,9-TETRAHYDRO-1H-CARBAZOLE-1- CARBOXAMIDE IN CRYSTALLINE FORM DescriptionThe present invention provides for novel polymorphs of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide in crystalline form. Furthermore, thepresent invention provides for novel crystalline solvates of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide as well as for methods for the preparationthereof.BACKGROUND OF THE INVENTIONThe compound 6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-l-carboxamide offormula (I), also known as Selisistat or EX-527 (CAS-Nr. 49843-98-3) is known from WO2005 / 026112 A2 to possess anti-SIRT1 activity, and as such may be useful in thepreparation of medicaments for any condition which may benefit from the inhibitionof SIRT1. Such conditions may include, for example, cancer, metabolic diseases suchas metabolic syndrome, type I diabetes or type II diabetes, obesity, dislipidemia,hyperlipidemia, Alzheimer's disease, Parkinson's disease, amyotrophic lateralsclerosis, neurodegenerative conditions that are caused at least in part bypolyglutamine aggregation, such as Huntington's disease, spinalbulbar muscularatrophy (SBMA or Kennedy's disease), dentatorubro-pallidoluysian atrophy (DRPLA),spinocerebellar ataxia 1 (SCA1), spinocerebellar ataxia 2 (SCA2), Machado-Josephdisease (MJD;SCA3), spinocerebellar ataxia 6 (SCA6), spinocerebellar ataxia 7 (SCA7),and spinocerebellar ataxia 12 (SCA12).A synthesis for Selisistat in racemic form, hereinafter also referred to as “rac-SLS”, as well as polymorphs of racemic Selisistat have been described in WO2013 / 057258 A1.The molecule has an asymmetric carbon atom adjacent to the amidefunctionality and, accordingly, exists in the form of two enantiomers, namely (R)- 6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-l-carboxamide and (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-l-carboxamide of formula (S-I), hereinafter also referred to as “(S)-SLS”.While it is known that the enantiomeric forms of Selisistat differ significantlywith regard to their SIRT1 activity, current clinical trials are performed using theracemic mixture of both enantiomers of Selisistat. So far, enantiopure (S)-Selisistat isavailable in amorphous form only and can be prepared by chiral high-pressure liquidchromatography (HPLC) in limited amounts only.It is thus an object of the present invention to provide for new forms of (S)-Selisistat, in particular for new forms of (S)-Selisistat that are suitable forpharmaceutical purposes and that may be prepared conveniently in large scale.Further objects of the invention will be clear on the basis of the following descriptionof the invention, examples and claims.SUMMARY OF THE INVENTIONIn a first aspect, the invention relates to polymorphic forms of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) of formula (S-I) incrystalline form.In a second aspect, the present invention provides for a compositioncomprising a polymorphic form of (S)-SLS according to the first aspect of theinvention and further comprising any other solid-state form of (S)-SLS.In a third aspect, the invention provides for the polymorphic forms of (S)-SLSaccording to the first aspect of the invention or the composition according to thesecond aspect of the invention for use as a medicament, specifically for use in theprevention or treatment of a disease or condition associated with SIRT1.In a fourth aspect, the present invention provides for the use of thepolymorphic forms of (S)-SLS according to the first aspect of the invention or thecomposition according to the second aspect of the invention for the preparation of apharmaceutical composition.In a fifth aspect, the present invention relates to a pharmaceutical compositioncomprising a crystalline polymorphic form of (S)-SLS according to the first aspect orthe composition according to the second aspect of the invention and at least onepharmaceutically acceptable excipient.In yet further aspects, the present invention provides for solvates of (S)-SLS aswell as for methods for the preparation of the polymorphs and solvates of (S)-SLS asdisclosed herein.DESCRIPTION OF THE DRAWINGSFigure 1 depicts a diffractogram of an X-Ray Powder Diffraction (XRPD)analysis of a polymorph of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide in crystalline form (polymorph G).Figure 2 depicts a spectrum of an 1H-Nuclear Magnetic Resonance (1H-NMR)analysis of a polymorph of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide in crystalline form (polymorph G).Figure 3 depicts a spectrum of a Differential Scanning Calorimetry (DSC)analysis of a polymorph (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamidein crystalline form (polymorph G).Figure 4 depicts a diffractogram of an XRPD analysis of a polymorph of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide in crystalline form(polymorph K).Figure 5 depicts a spectrum of a DSC analysis of a polymorph (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-l-carboxamide in crystalline form (polymorph K).Figure 6 depicts a diffractogram of an XRPD analysis of a polymorph of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide in crystalline form(polymorph H).Figure 7 depicts a spectrum of a DSC analysis of a polymorph (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide in crystalline form (polymorph H).Figure 8 depicts a diffractogram of an XRPD analysis of a polymorph of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide in crystalline form(polymorph T).Figure 9 depicts a diffractogram of an XRPD analysis of an acetone solvate of(S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide in crystalline form(solvate J).Figure 10 depicts a Figure 2 depicts a spectrum of an 1H-Nuclear MagneticResonance (1H-NMR) analysis of an acetone solvate of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (solvate J).Figure 11 depicts a spectrum of a DSC analysis of an acetone solvate of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide in crystalline form (solvate J).Figure 12 depicts a diffractogram of an XRPD analysis of a dioxane solvate of(S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide in crystalline form(solvate M).Figure 13 depicts a spectrum of an 1H-Nuclear Magnetic Resonance (1H-NMR)analysis of a dioxane solvate of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (solvate M).Figure 14 depicts a spectrum of a DSC analysis of a dioxane solvate of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide in crystalline form (solvateM).Figure 15 depicts a diffractogram of an XRPD analysis of a N,N-dimethylformamide solvate of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide in crystalline form (solvate R).Figure 16 depicts a spectrum of an 1H-Nuclear Magnetic Resonance (1H-NMR)analysis of a N,N-dimethylformamide solvate of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (solvate R).Figure 17 depicts a diffractogram of an XRPD analysis of a cyclopentanonesolvate of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide in crystallineform (solvate Q).Figure 18 depicts a spectrum of an 1H-Nuclear Magnetic Resonance (1H-NMR)analysis of a cyclopentanone solvate of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (solvate Q).DETAILED DESCRIPTION OF THE INVENTIONIn the first aspect, the present invention provides for (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) of formula (S-I) (S-I)in crystalline form,wherein the (S)-SLS in crystalline form is a crystalline polymorphic form of (S)-SLSselected 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 (witha deviation of + / - 0.2 degree) ofa) 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), orc) 11.2, 13.0, 16.3 and 21.9 degrees (polymorph K).According to this first aspect, the present invention provides for three solidand crystalline polymorphic forms of crystalline (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide of formula (S-I), namely a first polymorph as listed underitem a) above and herein also referred to as “polymorph G”, a second polymorph aslisted under item b) above and herein also referred to “polymorph H”, as well as athird polymorph as listed under item c) above and herein also referred to “polymorphK”.More specifically, according to this first aspect the present invention relates to(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)-SLSselected 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 (witha deviation of + / - 0.2 degree) ofa) 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), andc) 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) as disclosed herein may be prepared as describedfurther below (see Example 1) and has been characterized in the form of whitecrystals. An X-Ray Powder Diffraction analysis (“XRPD” or “Powder X-Ray Diffractionanalysis, “PXRD” as used herein synonymously) showed prominent signals or, inother words, reflections at 2-theta (2- ^ ^ ^angle values of 10.8, 13.5, 21.7 and 23.8degrees (with a deviation of + / - 0.2 degree or preferably 0.1 degree when measuredat a temperature range of 20 °C to 30 °C, more specifically of 20 °C to 25 °C with Cu-K ^radiation having a wavelength of 0.15406 nm; for details of the analysis see Example2.1).The term "reflection" with regard to powder X-ray diffraction as used herein,means peaks in an X-ray diffractogram, which are caused at certain diffraction angles(Bragg angles) by constructive interference from X-rays scattered by parallel planesof atoms in solid material, which are distributed in an ordered and repetitive patternin a long-range positional order. Such a solid material is classified as crystallinematerial or, as used herein, “in crystalline form”, whereas amorphous material isdefined as solid material, which lacks long-range order and only displays short-rangeorder, thus resulting in broad scattering. According to literature, long-range order e.g.extends over approximately 100 to 1000 atoms, whereas short-range order is over afew atoms only (see "Fundamentals of Powder Diffraction and StructuralCharacterization of Materials' by Vitalij K. Pecharsky and Peter Y. Zavalij, KluwerAcademic Publishers, 2003, page 3).In some embodiments, the first polymorph (polymorph G) of (S)-SLS showedprominent signals or reflections at 2-theta (2- ^ ^ ^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. Morespecifically, the first polymorph (polymorph G) of (S)-SLS showed signals orreflections at 2-theta (2- ^ ^ ^angle values of substantially as listed in Table 1 (seeExample 2.1) and as shown in the XRPD diffractogram as depicted in Fig. 1.The second polymorph (polymorph H) of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) as disclosed herein may be prepared as describedfurther below (see Example 5) and has also been characterized in the form of whitecrystals. An X-Ray Powder Diffraction analysis showed prominent signals or, in otherwords, reflections at 2-theta (2- ^ ^ ^angle values of 6.7, 12.6, 13.4 and 18.5 degrees(with a deviation of + / - 0.2 degree or preferably 0.1 degree when measured at atemperature range of 20 °C to 30 °C, specifically of 20 °C to 25 °C with Cu-K ^ radiationhaving a wavelength of 0.15406; for details of the analysis see Example 2.1).In some embodiments, the second polymorph (polymorph H) of (S)-SLSshowed prominent signals or reflections at 2-theta (2- ^ ^ ^angle values of 6.7, 12.6,13.4, 18.5, 21.8, 24.9 and 26.9 degrees when measured as described above. Morespecifically, the second polymorph (polymorph H) of (S)-SLS showed signals orreflections at 2-theta (2- ^ ^ ^angle values of substantially as listed in Table 3 (seeExample 6.1) and as shown in the XRPD diffractogram as depicted in Fig. 6.The third polymorph (polymorph K) of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) as disclosed herein may be prepared as describedfurther below (see Example 3) and has also been characterized in the form of whitecrystals. An X-Ray Powder Diffraction analysis showed prominent signals or, in otherwords, reflections at 2-theta (2- ^ ^ ^angle values of 11.2, 13.0, 16.3 and 21.9 degrees(with a deviation of + / - 0.2 degree or preferably 0.1 degree) when measured at atemperature range of 20 °C to 30 °C, specifically of 20 °C to 25 °C with Cu-K ^ radiationhaving a wavelength of 0.15406; for details of the analysis see Example 2.1).In some embodiments, the third polymorph (polymorph K) of (S)-SLS showedprominent signals or reflections at 2-theta (2- ^ ^ ^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, thesecond polymorph (polymorph H) of (S)-SLS showed signals or reflections at 2-theta(2- ^ ^ ^angle values of substantially as listed in Table 2 (see Example 4.1) and asshown in the XRPD diffractogram as depicted in Fig. 4.The polymorphs of (S)-SLS of the present invention have been furtheranalysed by 1H-Nuclear magnetic resonance (1H-NMR). The 1H-NMR spectra of allthree polymorphs of the present invention were recorded using a dilute solutioncomprising about 5 to about 10 mg of the respective polymorph in about 0.7 mLdeuterated dimethylsulfoxide (DMSO-d6) (using a Varian Mercury 400 MHzspectrometer, equipped with a broadband probe ATB 1H / 19F / X of 5 mm). The 1H-NMR spectra of all three polymorphs were identical to the 1H-NMR spectrum ofracemic Selesistat (see Fig. 2, 1H-NMR spectrum of polymorph G) and showed noresidual organic solvents or other organic compounds.The polymorphs of (S)-SLS of the present invention have been furthercharacterized by Differential Scanning Calorimetry (DSC) in which correspondingsamples were heated from 25 °C to about 300 °C at a rate of about 10 °C / min (fordetails see Examples 2.3, 4.3 and 6.3). The corresponding spectra are depicted in Fig.3 (polymorph G), Fig. 5 (polymorph K) and Fig. 7 (polymorph H).The DSC spectrum of polymorph G (see Fig. 3) showed an endothermic peakwithin the range of from about 160 °C to about 170 °C, specifically from about 165 or166 °C to about 169 °C with an onset of about 167 °C, specifically of 167.1 °C and apeak at 168.7 °C. The corresponding melting enthalpy ( ^H) was determined as -92.6J / g (calculated as the area under curve of the endothermic peak and normalized tosample weight).The DSC spectrum of polymorph K (see Fig. 5) showed an endothermic peakwithin the range of from about 150 °C to about 175 °C, specifically from about 160 or165 °C to about 170 °C with an onset of about 167 °C, specifically of 167.3 °C and apeak at 170.2 °C. The corresponding melting enthalpy ( ^H) was determined as -64.6J / g (calculated as the area under curve of the endothermic peak and normalized tosample weight). In this case, the initial endothermic event was followed by anexothermic event with an onset at about 173 °C followed by a second endothermicpeak with an onset of about 184 °C.The DSC spectrum of polymorph H (see Fig. 7) showed an endothermic peakwithin the range of from about 150 °C to about 165 °C, specifically from about 155 or160 °C to about 165 °C with an onset of about 162 °C, specifically of 162.1 °C and apeak at 164.2 °C. In this case, the initial endothermic event is followed by anexothermic event with an onset at about 166 °C followed by a second endothermicpeak with an onset of about 185 °C.Accordingly, in a further embodiment the present invention provides for(S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) of formula (I)in crystalline form wherein the crystalline form of (S)-SLS is a crystalline polymorphicform of (S)-SLS selected from the group consisting of crystalline polymorphic formsa) to c) of (S)-SLS having a melting point (melting onset) ofa) 167 °C (polymorph G)b) 162 °C (polymorph H), andc) 167 °C (polymorph K).In yet a further embodiment, the present invention provides for (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) of formula (I) in crystallineform wherein the crystalline form of (S)-SLS is a crystalline polymorphic form of (S)-SLS is selected from the group consisting of crystalline polymorphic forms a) to c) of(S)-SLS having a melting enthalpy ( ^H) in the range of froma) 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), andc) from about - 67 J / g to about – 62 J / g (polymorph K),or in the range ofa) 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), andc) about - 65 J / g to about - 64 J / g (polymorph K), orofa) - 92.6 J / g (polymorph G),b) - 70.2 J / g (polymorph H), andc) - 64.6 J / g (polymorph K).In further embodiments, the present invention relates to a crystalline form of(S)-SLS of formula (I) wherein the crystalline form of (S)-SLS is a crystallinepolymorphic form of (S)-SLS selected from the group consisting of crystallinepolymorphic forms of (S)-SLS a) and b) having an X-ray powder diffraction patterncomprising 2-theta angle values (with a deviation of + / - 0.2 degree) ofa) 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6 and 30.6 (polymorph G), andb) 6.7, 12.6, 13.4, 18.5, 21.8, 24.9 and 26.9 degrees (polymorph H).In further embodiments, the present invention relates to the crystalline formof (S)-SLS of formula (I), wherein the crystalline form of (S)-SLS is a crystallinepolymorphic form of (S)-SLS having an X-ray powder diffraction pattern comprising2-theta angle values (with a deviation of + / - 0.2 degree) of 10.8, 13.5, 14.9, 21.7, 22.8,23.8, 26.6 and 30.6 (polymorph G).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 as described above,specifically polymorphs G, H and K do not comprise considerable amounts of water ororganic solvents enclosed or incorporated in the crystal structure, except for residualamounts of water or organic solvents of up to about 2.0 wt.-% or up to about 1 wt.-%or up to about 0.5 wt.-% with regard to the total weight of the respective crystallinematerial which may be, for example, associated to the surface of the crystallinematerial. Furthermore, the polymorphs of crystalline (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide as described above, specifically polymorphs G, H and Khave been found to be non-hygroscopic or, in other words, not to attract orincorporate water under defined storage conditions. Accordingly, in specificembodiments, the crystalline polymorphs of (S)-SLS as disclosed herein, specificallypolymorphs G, H and K are solvent free and / or non-hygroscopic.As mentioned above, the crystalline polymorphs of (S)-SLS as disclosed herein,specifically polymorphs G, H and K have been found to be stable under definedstorage conditions such as the storage conditions defined by the International Councilfor Harmonization of Technical Requirements for Pharmaceuticals for Human Use(ICH). More specifically, polymorphs G, H and K of (S)-SLS have been found stableunder accelerated ICH conditions for at least 7 days when stored in a suitable climatechamber at 40 °C+ / - 2 °C at 75 % + / - 5 % relative humidity (RH) as described inExample 7 below. Accordingly, in specific embodiments, the present inventionprovides for crystalline polymorphic forms of (S)-SLS, specifically polymorphs G, Hand K, which are stable at a temperature of 40 °C + / - 2 °C and a relative humidity(RH) of 75% + / - 5 % (accelerated ICH conditions) for a period of at least 7 days,wherein the term “stable” as used in this context means that at least 90 wt.-% or atleast 95 wt.-% or at least 98 wt.-% or at least 99 wt.-% of the specific polymorphremains in the specific polymorphic form without degradation or conversion toanother polymorphic or amorphous form. Accordingly, the crystalline polymorphicforms of (S)-SLS, specifically polymorphs G, H and K, are especially useful forpharmaceutical 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 crystallineform (hereinafter referred to as “polymorph T”). This further polymorph may beprepared as described further below (see Example 8) and has also been characterizedin the form of white crystals. An X-Ray Powder Diffraction analysis showedprominent signals or, in other words, reflections at 2-theta (2- ^ ^ ^angle values of 7.2,14.4, 21.7 and 24.1 degrees (with a deviation of + / - 0.2 degree or preferably 0.1degree when measured at a temperature range of 20 °C to 30 °C, specifically of 20 °Cto 25 °C with Cu-K ^ radiation having a wavelength of 0.15406; for details of theanalysis see Example 2.1). The corresponding XRPD diffractogram is depicted in Fig.8.The present invention, furthermore, discloses crystalline forms of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) of formula (S-I) inwhich (S)-SLS is comprised together with a solvent and, accordingly, is present in theform of a crystalline solvate, preferably a solid crystalline solvate.A first crystalline solvate of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide comprises acetone as the solvent (solvate J). This first crystalline solvateof (S)-SLS can be prepared as described in Example 10 below. An X-Ray PowderDiffraction analysis showed prominent signals or, in other words, reflections at 2-theta (2- ^ ^ ^angle values of 10.6, 17.2, 19.2 and 21.3 degrees, more specifically of 10.6,11.9, 15.6, 16.4, 17.2, 19.2, 21.3 and 25.2 degrees (with a deviation of + / - 0.2 degreeor preferably 0.1 degree when measured at a temperature range of 20 °C to 30 °C,specifically of 20 °C to 25 °C with Cu-K ^ radiation having a wavelength of 0.15406; fordetails of the analysis see Example 2.1). The complete list of reflections is listed inTable 5, Example 11.1; the corresponding XRPD diffractogram is depicted in Fig. 9.The 1H-NMR analysis as described in Example 11.2 below recorded indeuterated dimethylsulfoxide revealed a molar ratio of (S)-SLS to acetone of about3:1 (see Fig. 10). A Differential Scanning Calorimetry analysis as described in Example11.3 showed broad endothermic peaks with onsets of about 82 °C and about 106 °C(assumably indicating thermal desolvation) followed by a sharp endothermic peakwith an onset of 171 °C (see Fig. 11).The crystalline acetone solvate J of (S)-SLS has been found to be stable andnon-hygroscopic for a period of at least 7 days in a stability test under acceleratedICH conditions (storage at 40 °C + / -2 °C at 75% + / - 5% relative humidity (RH).A second crystalline solvate of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide comprises dioxane as the solvent (solvate M). This second crystallinesolvate of (S)-SLS can be prepared as described in Example 12 below. An X-RayPowder Diffraction analysis showed prominent signals or, in other words, reflectionsat 2-theta (2- ^ ^ ^angle values of 11.9, 16.1, 19.6 and 22.3 degrees, more specifically of9.9, 11.9, 16.1, 19.6, 19.8, 21.8, 22.3 and 22.9 degrees (with a deviation of + / - 0.2degree or preferably 0.1 degree when measured at a temperature range of 20 °C to 30°C, specifically of 20 °C to 25 °C with Cu-K ^ radiation having a wavelength of0.154419; for details of the analysis see Example 2.1). The complete list of reflectionsis listed in Table 6, Example 13.1; the corresponding XRPD diffractogram is depictedin Fig. 12.The 1H-NMR analysis as described in Example 13.2 below recorded indeuterated dimethylsulfoxide revealed a molar ratio of (S)-SLS to dioxane of about1:0.8 (see Fig. 13). A Differential Scanning Calorimetry analysis as described inExample 13.3 showed broad endothermic peaks with onsets of about 80 °C and about103 °C (assumably indicating thermal desolvation) followed by a sharp endothermicpeak with an onset of 188 °C (see Fig. 14).A third crystalline solvate of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide comprises N,N-dimethylformamide (DMF) as the solvent (solvate R).This third crystalline solvate of (S)-SLS can be prepared as described in Example 14below. X-Ray Powder Diffraction analysis showed prominent signals or, in otherwords, reflections at 2-theta (2- ^ ^ ^angle values of 10.9, 11.3, 17.0 and 17.8 degrees,more specifically of 5.6, 10.9, 11.3, 17.0, 17.3, 17.8, 19.2, 25.6 and 28.1 degrees (with adeviation of + / - 0.2 degree or preferably 0.1 degree when measured at a temperaturerange of 20 °C to 30 °C, specifically 20 °C to 25 °C with Cu-K ^ radiation having awavelength of 0.15406; for details of the analysis see Example 2.1). The complete listof reflections is listed in Table 7, Example 15.1; the corresponding XRPDdiffractogram is depicted in Fig. 15.The 1H-NMR analysis as described in Example 15.2 below recorded indeuterated dimethylsulfoxide revealed a molar ratio of (S)-SLS to N,N-dimethylformamide of about 1:0.5 (see Fig. 16).A fourth crystalline solvate of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide comprises cyclopentanone as the solvent (solvate Q). This fourthcrystalline solvate of (S)-SLS can be prepared as described in Example 16 below. X-Ray Powder Diffraction analysis showed prominent signals or, in other words,reflections at 2-theta (2- ^ ^ ^angle values of 11.1, 16.9, 20.6 and 21.0 degrees, morespecifically of 4.4, 11.1, 16.9, 19.2, 20.6, 21.0, 22.2 and 23.6 degrees (with a deviationof + / - 0.2 degree or preferably 0.1 degree when measured at a temperature range of20 °C to 30 °C specifically 20 °C to 25 °C with Cu-K ^ radiation having a wavelength of0.15406; for details of the analysis see Example 2.1). The complete list of reflections islisted in Table 8, Example 17.1; the corresponding XRPD diffractogram is depicted inFig. 17.The 1H-NMR analysis as described in Example 17.2 below recorded indeuterated dimethylsulfoxide revealed a molar ratio of (S)-SLS to cyclopentanone ofabout 1:1 (see Fig. 18).In a second aspect, the present invention provides for a compositioncomprising a crystalline form of (S)-SLS of formula (S-I), preferably a crystallinepolymorphic form of (S)-SLS as described above, more preferably polymorphs G, H orK 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 onthe weight of the composition. The term “solid-state form” as used in this context is tobe understood as form of (S)-SLS other than the polymorphs described herein,preferably polymorphs G, H and K, such as the further polymorphs and solvates asdisclosed above or an amorphous solid form of (S)-SLS.In a third aspect, the present invention provides for the crystallinepolymorphic forms of (S)-SLS as described above, preferably polymorphs G, H or K ofthe first aspect or the invention as described above for use as a medicament. In thiscontext, the present invention also relates to the use of the crystalline polymorphicforms of (S)-SLS of the first aspect of the invention, preferably polymorphs G, H or Kin the manufacture of a medicament. Furthermore, in this context the presentinvention also relates to a method of using the crystalline polymorphic forms of (S)-SLS of the first aspect of the invention, preferably polymorphs G, H or K as amedicament or for the treatment or prevention of a medical condition, preferably amedical condition of a warm-blooded animal or human, specifically of a human.In specific embodiments of this third aspect of the invention, a medicalcondition that may be treated or prevented may be a medical condition or diseaseassociated with or mediated by sirtuin, specifically a medical condition or diseaseassociated with or mediated by SIRT1. Accordingly, the present invention alsoprovides for the crystalline form of (S)-SLS of formula (S-I) according to the firstaspect of the invention as described above or the composition according to thesecond aspect of the invention for use in the prevention or treatment of a disease orcondition associated with or mediated by sirtuin, for example SIRT1.In specific embodiments, a disease or medical condition associated with ormediated by SIRT1 as referred to above that may be treated or prevented byadministration of the compounds or compositions of the present invention may beselected from cancer, metabolic diseases such as metabolic syndrome, type I diabetesor type II diabetes, obesity, dislipidemia, hyperlipidemia, Alzheimer's disease,Parkinson's disease, amyotrophic lateral sclerosis, neurodegenerative conditions thatare caused at least in part by polyglutamine aggregation, such as Huntington'sdisease, spinalbulbar muscular atrophy (SBMA or Kennedy's disease), dentatorubro-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia 1 (SCA1), spinocerebellarataxia 2 (SCA2), Machado-Joseph disease (MJD; SCA3), spinocerebellar ataxia 6(SCA6), spinocerebellar ataxia 7 (SCA7), and spinocerebellar ataxia 12 (SCA12),specifically Huntington’s disease.In a fourth aspect, the present invention relates to the use of a crystalline formof (S)-SLS of formula (S-I) according to the first aspect of the invention, specificallypolymorph G, H and / or K of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide or the composition according to the second aspect of the invention forthe preparation of a pharmaceutical composition.Accordingly, in a fifth aspect, the present invention relates to a pharmaceuticalcomposition comprising a crystalline form of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide, specifically polymorph G, H and / or K according to the firstaspect of the invention as described above or the composition comprising suchcrystalline polymorph of (S)-SLS, preferably in a predetermined and / orpharmaceutically effective amount, and at least one pharmaceutically acceptableexcipient wherein the term “pharmaceutically effective amount” as used hereinmeans that amount which, when administered to a warm-blooded animal or humanfor treating or preventing a disease, is sufficient to effect such treatment orprevention for the disease.In some embodiments, the predetermined and / or effective amount of thepreferably anhydrous and non-solvated crystalline form of (S)-SLS of the presentinvention or the composition comprising the same as defined in any one of the above-described aspects and their corresponding embodiments may be selected within therange of from about 1 mg to about 300 mg, or from about 20 mg to about 250 mg, orfrom about 1 mg to about 20 mg or from about 100 to about 200 mg per single doseamount, calculated as anhydrous and preferably non-solvated (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide in crystalline form.The term “excipient” as used herein means a pharmaceutically acceptableauxiliary substance, carrier or material that enables or facilitates the formulation ofan active pharmaceutical ingredient such as (S)-SLS in a crystalline polymorphic formas described herein as a composition or dosage form that may be manufacturedaccording to generally accepted quality standards, stored at common storageconditions and administered conveniently to subjects in need thereof, such as humanpatients. In this context, the term “pharmaceutically acceptable” means that thecompound or mixture it refers to is useful in preparing a pharmaceutical compositionthat is generally safe, non-toxic and neither biologically nor otherwise undesirableand includes that which is acceptable for human pharmaceutical use.The at least one pharmaceutically acceptable excipient, which is comprised inthe pharmaceutical composition of the present invention, is preferably selected fromthe group consisting of fillers, binders, disintegrants, lubricants, glidants, andcombinations thereof as known to those of skill in the art and as described, forexample, in current pharmacopoeias, such as the European Pharmacopoeia or theUnited States Pharmacopeia. Preferably, the at least one pharmaceutically acceptableexcipient is selected from the group consisting of one or more fillers, binders,disintegrants and lubricants. More preferably, the at least one pharmaceuticallyacceptable excipient is selected from the group consisting of microcrystallinecellulose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate andcombinations thereof.In some embodiments, the pharmaceutical compositions of this aspect of theinvention comprising a crystalline polymorph of (S)-SLS of the present invention,preferably polymorph G, H and / or K, especially in anhydrous and non-solvated formmay be a solid dosage form, such as a solid dosage form for oral administration.Examples for such solid dosage forms that are suitable for oral administration maycomprise but are not limited to tablets, capsules, granules and oral films. Morepreferably, the oral solid dosage form is a tablet or a capsule, such as a soft capsule ora hard capsule. In the case of a hard capsule, this may be filled with a powder mixtureor with granules or pellets comprising (S)-SLS. Optionally, the granules, the tablet orthe capsule may be coated.The pharmaceutical compositions of the present invention as defined in anyone of the above-described embodiments may be produced by standardmanufacturing processes, which are well-known to the skilled person including e.g.blending, granulation (wet or dry granulation), tablet compression, film-coating orcapsule filling and packaging. For example, the tablet may be prepared by mixing acrystalline form of (S)-SLS of the present invention or the composition comprising thesame as defined in any one of the above-described aspects and their correspondingembodiments with at least one excipient such as fillers, binders, disintegrants,lubricants, glidants or combinations thereof. Optionally, a granulation step such as adry or wet granulation step is performed before compression. The tablet cores maybe additionally film-coated.The polymorphs of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide according to the present invention may be prepared starting fromcommercially available racemic 6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide of formula (I). More specifically, polymorph G of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide may be prepared by co-crystallization of(S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide with a chiral tartaricacid derivative in enantiomerically enriched form as, for example described inExample 1 below. As the product of this co-crystallization, a diastereomericallyenriched or even diastereomerically pure cocrystal of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide with the chosen tartaric acid derivative asdescribed below may be isolated and optionally further purified by recrystallization.From this diastereomerically enriched or pure intermediate cocrystalenantiomerically enriched or enantiomerically pure (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide can be isolated by treatment with a base.Accordingly, in a further aspect the present invention provides for a processfor the preparation of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide((S)-SLS) of formula (S-I) in crystalline form, specifically of (S)-SLS in crystalline formhaving an X-ray powder diffraction pattern comprising 2-theta angle values (with adeviation of + / - 0.2 degree) 10.8, 13.5, 21.7 and 23.8, specifically of 10.8, 13.5, 14.9,21.7, 22.8, 23.8, 26.6 and 30.6 (polymorph G), the process comprising the steps ofa) providing a first mixture comprising rac-SLS of formula (I) and a compoundof formula (II) wherein R1, R2, R3, R4 and R5 can be the same or different and can independently beselected from H, C1-C4-alkyl, halogen, C1-C4-haloalkyl, -O-C1 -C4-alkyl, and -O-C1-C4-haloalkylin a first liquid medium,b) exposing the first mixture to conditions under which a rac-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and the compound of formula (II) at leastpartly dissolve in the first liquid medium to form an intermediate solution,c) exposing the intermediate solution as formed in step b) to conditions underwhich a solid intermediate product comprising a crystalline intermediate of (S)-SLSand the compound of formula (II) in the form of cocrystals is formed,d) optionally recrystallizing the crystalline intermediate in the form ofcocrystals in a second liquid medium to provide the solid intermediate productcomprising (S)-SLS and the compound of formula (II) in the form of cocrystals indiastereomerically enriched form, ande) exposing the crystalline intermediate in the form of cocrystals as formed instep 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 (S-I) in enantiomericallyenriched form.In the preferred compounds of formula (II) C1-C4-alkyl preferably means asaturated hydrocarbon substituent with one to four carbon atoms such as methyl,ethyl, n-propyl, isopropyl, n-butyl, s-butyl, tert.-butyl;halogen preferably means fluorine, chlorine, bromine, preferably fluorine or chlorine,especially chlorine;C1-C4-haloalkyl preferably means a saturated mono- or polyhalogenated hydrocarbonsubstituent with one to four carbon atoms such as trifluormethyl, pentafluoroethyl,heptafluor-isopropyl;-O-C1-C4-alkyl preferably means a saturated hydrocarbon substituent with one to fourcarbon atoms bound via an oxygen atom such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, s-butoxy, tert.-butoxy, preferably methoxy, isopropoxy andtert.-butoxy, especially methoxy; and-O-C1-C4-haloalkyl preferably means a saturated and halogenated hydrocarbonsubstituent with one to four carbon atoms bound via an oxygen atom such astrifluormethoxy, pentafluorethoxy, heptafluor-isopropoxy, especially trifluormethoxy.In some embodiments of the process according to this aspect of the invention,in the compound of formula (II) R1, R2, R3, R4 and R5 can be the same or different andcan independently be selected from H, C1-C4-alkyl, halogen and C1-C4-haloalkyl asdescribed above. In further specific embodiments, in the compound of formula (II) R1,R2, R3, R4 and R5 are H. In a preferred embodiment the compound of formula (II) is(2R, 3R)-(-)-Di-O-4-benzoyl-L-tartaric acid; CAS Nr. 2743-38-6, herein also referred toas “(-)-DBTA”.In yet further embodiments, in the compound of formula (II) R1, R2, R4 and R5are H and R3 is selected from C1-C4-alkyl and C1-C4-haloalkyl, preferably from C1-C4-alkyl, especially methyl. In a preferred embodiment the compound of formula (II) is(2R, 3R)-(-)-Di-O-4-toluoyl-L-tartaric acid; CAS Nr. 32634-66-5, herein also referredto as “(-)-DTTA”.The term “enantiomerically enriched form” as used herein in connection withthe tartaric acid derivative of formula (II) means that such tartaric acid derivative offormula (II) may be present in the form of its pure (-)-enantiomer in which bothchiral centers are in the R-configuration as depicted in formula (II) or, in other words,or in the form of non-racemic mixtures of the (-)-enantiomer of formula (II) with itscorresponding (+)-enantiomer in which the amount of (-)-enantiomer is larger thanthe amount of corresponding (+)-enantiomer. In some embodiments, the term“compound of formula (I) in enantiomerically enriched form” may refer to mixturescomprising the (-) enantiomer of the compound of formula (II) with an enantiomericexcess (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 terms “solid intermediate product comprising (S)-SLS and the compoundof formula (II) in the form of cocrystals” or just “cocrystals” as referred to herein mayalso be described as solids that are crystalline single-phase materials composed oftwo or more different molecular or ionic compounds, specifically composed of (S)-SLSand the compound of formula (II), generally in a stoichiometric ratio which areneither solvates nor simple salts.In further embodiments, the process for the preparation of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) of in enantiomericallyenriched form as described above may further comprise the steps of:c1) exposing the intermediate solution as formed in step b) to conditionsunder which a solid intermediate product comprising cocrystals of (S)-SLS and thecompound of formula (II) is formed; andc2) at least partially removing the first liquid medium from the solidintermediate product to provide cocrystals of (S)-SLS and the compound of formula(II).In yet a further specific embodiment, the process for the preparation of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) of inenantiomerically enriched form as described above may further comprise the stepsof:e1) exposing the crystalline intermediate product to an aqueous solution of aninorganic base to provide (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide of formula (S-I) in enantiomerically enriched form, ande2) isolating (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide offormula (S-I) in enantiomerically enriched form.In further embodiments of the process of this aspect of the invention, rac-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide of formula (I) and thecompound of formula (II) may be provided in the first liquid mixture in a molar ratioof about 1.5 : 1 to about 2.5 to 1, preferably from about 1.9 :1 to about 2.1 to 1.In specific embodiments, the first liquid medium as used in process step a)and / or the second liquid medium as used in the recrystallization according tooptional step d) may be an organic solvent or a mixture of organic solvents.Preferably, both liquid media comprise an organic solvent is an organic solvent ormixture of organic solvents, specifically comprising an organic solvent selected fromthe group consisting of C1-C4 alkyl acetates such as ethyl acetate, propyl acetate,isopropyl acetate isobutyl acetate, tert.-butyl acetate, acetonitrile, methyl isobutylketone, aromatic hydrocarbons such as toluene, or mixtures thereof.In further embodiments, the first liquid medium may comprise or essentiallyconsist of isobutyl acetate and acetonitrile such as a mixture of about 70 % to about95 % (v / v) isobutyl acetate an about 30 % to about 50 % (v / v) of acetonitrile (withregard to the volume of the final solvent mixture). In further specific embodiments,the second liquid medium according to the optional recrystallization of step d) maycomprise or essentially consist of acetonitrile.In some embodiments, the first liquid medium may be used in an amount ofabout 2 to about 10 mL or from about 5 to about 8 mL per mmol of rac-SLS as used instep a).According to process step b) the first liquid mixture is exposed to conditionsunder which a rac-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and thecompound of formula (II) at least partly dissolve in the first liquid medium to form anintermediate solution. In some embodiments, the first liquid mixture may, forexample, be heated, stirred or treated with ultrasound or both. In preferredembodiments, however, the first liquid mixture according to process step b) is heated,preferably to a temperature selected within the range of from about 60 °C to about100 °C or from about 80 °C to about 95 °C and further preferably until completedissolution of rac-SLS and the compound of formula (II) is observed. The solution asformed in step b) accordingly may then be exposed to conditions under which anintermediate mixture comprising a crystalline intermediate product comprising (S)-SLS and the chosen chiral compound of formula (II) in the form of cocrystals isformed. In specific embodiments, according to process step c) the solution as formedin step b) is cooled, preferably to a temperature within the range of from about 10°Cto about 30 °C, or from about 20°C to about 25 °C to form the intermediate cocrystalsof (S)-SLS and the compound of formula (II).In further embodiments, the crystalline intermediate product comprising (S)-SLS and the compound of formula (II) in the form of cocrystals as formed in step c)comprises (S)-SLS and the compound of formula (II) in a molar ratio of 2 : 1.According to an optional process step c3) the crystalline intermediate product(comprising the crystalline intermediate in the form of cocrystals) may then bewashed, preferably with solvent or mixture of solvents as described above for thefirst liquid medium.According to optional process step d), the crystalline intermediate productcomprising (S)-SLS and the chosen compound of formula (II) in the form of cocrystalsmay optionally be recrystallized in a second liquid medium as described above. Thesecond liquid medium as described above may be used in an amount within the rangeof from about 10 mL to about 40 mL or from about 15 mL to about 30 mL or to about20 mL per g of the crystalline intermediate product. The optional recrystallizationmay be performed as known to those of skill in the art. In some embodiments,however, the optional recrystallization of step d) may comprise the steps ofd1) providing a mixture of the crystalline intermediate product (comprisingthe intermediate cocrystals) in the second liquid medium,d2) exposing the mixture as formed in step d1) to conditions under which thecrystalline intermediate product (at least partly) dissolves in the third solvent orsolvent mixture, andd3) exposing the mixture as formed in step d2) in which the crystallineintermediate product is (at least partly) dissolved in the second liquid medium toconditions under which the dissolved intermediate product recrystallizes.In specific embodiments, step d2) may comprise heating of the mixture asprovided in step d1) to a temperature within the range of from about 60 °C to about90 °C or from about from about 70 °C to about 85 °C. Process step d3) may comprisecooling of the mixture as formed in step d2), preferably to a temperature within therange of from about 10 °C to about 30 °C. The recrystallized intermediate product inthe form of cocrystals may then be isolated and washed.According to process step e), the crystalline intermediate product as formed instep c) or d) is then exposed to an aqueous solution of an inorganic base selectedfrom the group of carbonates, hydrogen carbonates or hydroxides of alkaline or earthalkaline metals, such as aqueous solutions of sodium or potassium hydrogencarbonate or of sodium or potassium carbonate such as NaHCO3, KHCO3, Na2CO3,K2CO3, preferably to an aqueous solution of sodium hydrogen carbonate (NaHCO3). Insome embodiments of step e), the inorganic base may be used in an amount of at least1.5 equivalents with regard to the amount of intermediate cocrystals of (S)-SLS andthe compound of formula (II). In many cases, especially when conducted in a purelyaqueous liquid medium (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamideof formula (S-I) in enantiomerically enriched or enantiomerically pure form thencrystallizes in the reaction mixture, preferably in form of crystalline polymorph G,and may be isolated and washed by standard techniques.The process as described above allows for the preparation of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide of formula (S-I) in enantiomericallyenriched form. In specific embodiments, (S)-SLS, more specifically polymorph G of(S)-SLS may be prepared with an enantiomeric excess of at least about 70 % ee, or atleast 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. Infurther embodiments, the process comprises recrystallizing the intermediatecocrystals comprising (S)-SLS and the compound of formula (II) in a second liquidmedium according to step d).Starting from this crystalline polymorph G of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide the further crystalline polymorphs, specificallypolymorphs K and H can be prepared as described in Examples 3 and 5 below. Morespecifically, polymorph K of (S)-SLS may be prepared by recrystallization ofpolymorph G of (S)-SLS in nitromethane, whereas polymorph H of (S)-SLS may beprepared by suspending polymorph G of (S)-SLS in xylene.Accordingly, the present invention also provides for a process for thepreparation of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) in crystalline form,wherein the (S)-SLS in crystalline form is a crystalline polymorphic form of (S)-SLShaving an X-ray powder diffraction pattern comprising 2-theta angle values (with adeviation of + / - 0.2 degree) of 11.2, 13.0, 16.3 and 21.9 degrees (polymorph K), theprocess comprising the steps ofi) preparing (S)-SLS in crystalline form having an X-ray powder diffractionpattern comprising 2-theta angle values (with a deviation of + / - 0.2 degree) 10.8,13.5, 21.7 and 23.8, specifically of 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6 and 30.6(polymorph G) as described above; andii) recrystallizing polymorph G of (S)-SLS as prepared according to step i) innitromethane.Furthermore, the present invention provides for a process for the preparationof (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) incrystalline form,wherein the (S)-SLS in crystalline form is a crystalline polymorphic form of (S)-SLShaving an X-ray powder diffraction pattern comprising 2-theta angle values (with adeviation of + / - 0.2 degree) of 6.7, 12.6, 13.4 and 18.5 degrees (polymorph H), theprocess comprising the steps ofi') preparing (S)-SLS in crystalline form having an X-ray powder diffractionpattern comprising 2-theta angle values (with a deviation of + / - 0.2 degree) 10.8,13.5, 21.7 and 23.8, specifically of 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6 and 30.6(polymorph G) as described above; andii’) suspending polymorph G of (S)-SLS as prepared according to step i') inxylene.The following list of numbered items are embodiments comprised by thepresent invention:1. (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) offormula (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 polymorphicforms a) to c) of (S)-SLS having an X-ray powder diffraction patterncomprising 2-theta angle values (with a deviation of + / - 0.2 degree) ofa) 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), andc) 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) offormula (I) in crystalline form according to item 1,wherein the (S)-SLS in crystalline form is a crystalline polymorphic form of(S)-SLS selected from the group consisting of the crystalline polymorphicforms a) to c) of (S)-SLS having an X-ray powder diffraction patterncomprising 2-theta angle values (with a deviation of + / - 0.2 degree) ofa) 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6 and 30.6 degrees (polymorphG),b) 6.7, 12.6, 13.4, 18.5, 21.8, 24.9 and 26.9 degrees (polymorph H), andc) 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 item 1 or 2, whereinthe crystalline form of (S)-SLS is a crystalline polymorphic form of (S)-SLSselected from the group consisting of crystalline polymorphic forms a) to c) of(S)-SLS having a melting point (melting onset) ofa) 167 °C (polymorph G),b) 162 °C (polymorph H), andc) 167 °C (polymorph K).The crystalline form of (S)-SLS according to any one of the preceding items,whereinthe crystalline form of (S)-SLS is a crystalline polymorphic form of (S)-SLSselected from the group consisting of crystalline polymorphic forms a) to c) of(S)-SLS having a melting enthalpy ( ^H) ofa) - 92.6 J / g (polymorph G),b) - 70.2 J / g (polymorph H), andc) - 64.6 J / g (polymorph K).5. The crystalline form of (S)-SLS of formula (I) according to any one of thepreceding items, whereinthe crystalline form of (S)-SLS is a crystalline polymorphic form of (S)-SLSselected from the group consisting of crystalline polymorphic forms of (S)-SLSa) and d) having an X-ray powder diffraction pattern comprising 2-theta anglevalues (with a deviation of + / - 0.2 degree) ofa) 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6 and 30.6 (polymorph G), andb) 6.7, 12.6, 13.4, 18.5, 21.8, 24.9 and 26.9 degrees (polymorph H).6. The crystalline form of (S)-SLS of formula (I) according to any one of thepreceding items, whereinthe crystalline form of (S)-SLS is a crystalline polymorphic form of (S)-SLShaving an X-ray powder diffraction pattern comprising 2-theta angle values(with a deviation of + / - 0.2 degree) of 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6and 30.6 (polymorph G).7. The crystalline form of (S)-SLS according to any one of the preceding items,wherein the crystalline form of (S)-SLS is solvent-free and / or non-hygroscopic.8. The crystalline form of (S)-SLS according to any one 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 a period of at least 7 days.9. A composition comprising a crystalline form of (S)-SLS of formula (S-I)according to any one of the preceding items and further comprising up toabout 20 wt.-%, 10 wt.-%, 5 wt.-%, 4 wt.-%, 3 wt.-%, 2 wt.-% or 1 wt.-% ofany other solid-state form of (S)-SLS, based on the weight of the composition.10. The crystalline form of (S)-SLS of formula (S-I) according to any one of items 1to 8 or the composition according to item 9 for use as a medicament.11. The crystalline form of (S)-SLS of formula (S-I) according to any one of items 1to 8 or the composition according to item 9 for use in the prevention ortreatment of a disease or condition associated with SIRT1.12. The crystalline form of (S)-SLS of formula (S-I) according to any one of items 1to 8 or the composition according to item 9 for use in the prevention ortreatment of cancer, metabolic diseases such as metabolic syndrome, type Idiabetes or type II diabetes, obesity, dislipidemia, hyperlipidemia, Alzheimer'sdisease, Parkinson's disease, amyotrophic lateral sclerosis, neurodegenerativeconditions that are caused at least in part by polyglutamine aggregation, suchas Huntington's disease, spinalbulbar muscular atrophy (SBMA or Kennedy'sdisease) dentatorubro-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia1 (SCA1), spinocerebellar ataxia 2 (SCA2), Machado-Joseph disease (MJD;SCA3), spinocerebellar ataxia 6 (SCA6), spinocerebellar ataxia 7 (SCA7),and spinocerebellar ataxia 12 (SCA12).13. Use of a crystalline form of (S)-SLS of formula (S-I) according to any one ofitems 1 to 8 or the composition according to item 9 for the preparation of apharmaceutical composition.14. A pharmaceutical composition comprising a crystalline form of (S)-SLSaccording to any one of items 1 to 8 or the composition according to item 9and at least one pharmaceutically acceptable excipient.15. The pharmaceutical composition according to item 14, wherein thepharmaceutical composition is a solid dosage form for oral administration.16. The pharmaceutical composition according to item 14 or 15, wherein thecomposition is a tablet, capsule or oral film.17. A process for the preparation of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) of formula (S-I) in crystalline form, specifically of (S)-SLS in crystalline form having an X-ray powder diffraction pattern comprising2-theta angle values (with a deviation of + / - 0.2 degree) 10.8, 13.5, 21.7 and23.8, specifically of 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6 and 30.6 (polymorphG), the process comprising the steps ofa) providing a first mixture comprising rac-SLS of formula (I) and acompound of formula (II) wherein R1, R2, R3, R4 and R5 can be the same or different and canindependently be selected from H, C1-C4-alkyl, halogen, C1-C4-haloalkyl, -O-C1 -C4-alkyl, -O-C1-C4-haloalkylin a first liquid medium,b) exposing the first mixture to conditions under which a rac-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and the compound of formula(II) at least partly dissolve in the first liquid medium to form an intermediatesolution,c) exposing the intermediate solution as formed in step b) to conditionsunder which a solid intermediate product comprising a crystallineintermediate of (S)-SLS and the compound of formula (II) in the form ofcocrystals is formed,d) optionally recrystallizing the crystalline intermediate in the form ofcocrystals in a second liquid medium to provide the solid intermediateproduct comprising (S)-SLS and the compound of formula (II) in the form ofcocrystals in diastereomerically enriched form, ande) exposing the crystalline intermediate in the form of cocrystals asformed 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 (S-I)in enantiomerically enriched form.18. A process for the preparation of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) in crystalline form,wherein the (S)-SLS in crystalline form is a crystalline polymorphic form of(S)-SLS having an X-ray powder diffraction pattern comprising 2-theta anglevalues (with a deviation of + / - 0.2 degree) of 11.2, 13.0, 16.3 and 21.9 degrees(polymorph K), the process comprising the steps ofi) preparing (S)-SLS in crystalline form having an X-ray powderdiffraction pattern comprising 2-theta angle values (with a deviation of + / - 0.2degree) 10.8, 13.5, 21.7 and 23.8, specifically of 10.8, 13.5, 14.9, 21.7, 22.8,23.8, 26.6 and 30.6 (polymorph G) according to item 17; andii) recrystallizing polymorph G of (S)-SLS as prepared according to stepi) in nitromethane.19. A process for the preparation of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) in crystalline form,wherein the (S)-SLS in crystalline form is a crystalline polymorphic form of(S)-SLS having an X-ray powder diffraction pattern comprising 2-theta anglevalues (with a deviation of + / - 0.2 degree) of 6.7, 12.6, 13.4 and 18.5 degrees(polymorph H), the process comprising the steps ofi') preparing (S)-SLS in crystalline form having an X-ray powderdiffraction pattern comprising 2-theta angle values (with a deviation of + / - 0.2degree) 10.8, 13.5, 21.7 and 23.8, specifically of 10.8, 13.5, 14.9, 21.7, 22.8,23.8, 26.6 and 30.6 (polymorph G) as described above; andii’) suspending polymorph G of (S)-SLS as prepared according to step i')in xylene.The following examples serve to illustrate the invention, however, should notbe understood as restricting the scope of the invention in any respect. EXAMPLES Example 1: Preparation of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1- carboxamide ((S)-SLS) in crystalline form (polymorph G)1.1 Cocrystal formation of (S)-Selisistat ((S)-SLS) with (-)-DTTATo a 250 mL round-bottomed flask equipped with magnetic stirrer andcontaining 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 (-)-DTTA ((2R, 3R)-(-)-Di-O-4-toluoyl-L-tartaric acid; CAS Nr. 32634-66-5; 20.1 mmol, 0.5 eq.) 125 mL of a mixtureof acetonitrile and isobutyl acetate (2-methylpropyl ethanoate; CAS-Nr. 110-19-0)(15:85 (v / v)) was added. The resulting suspension was heated to reflux untilcomplete solution of the solid ingredients was observed. Then, the resulting solutionwas seeded with some cocrystals of (S)-SLS with (-)-DTTA with an enantiomericexcess of 99 % ee at high temperature, slowly cooled to room temperature (approx.22 °C) and stirred at room temperature for 2 h. The white mixture was filteredthrough a sintered funnel (porosity 3), washed two times with 20 mL each of a 15:85(v / v) mixture of acetonitrile and isobutyl acetate and dried under vacuum (approx. 1mbar) at room temperature overnight. Cocrystals of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) with (-)-DTTA (39.4% yield; 74.0% ee) wereobtained as a white solid.1.2 Recrystallization of the cocrystals of (S)-SLS with (-)-DTTATo a 250 mL round-bottomed flask equipped with magnetic stirrer andcontaining 6.50 g of the cocrystals of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) with (-)-DTTA (14.7 mmol) as prepared in step 1.1 above, 110mL of acetonitrile was added. The resulting suspension was heated to reflux untilcomplete solution was observed. The resulting solution was seeded with somecocrystals of (S)-SLS with (-)-DTTA with an enantiomeric excess of 99 % ee at hightemperature, slowly cooled to room temperature (approx. 22 °C) and stirred at roomtemperature for 2 h. The white mixture was filtered through a sintered funnel(porosity 3), washed two times with acetonitrile (13 mL each) and dried undervacuum (approx. 1 mbar) at room temperature overnight. Cocrystals of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) with (-)-DTTA (82.5 %yield; 99.1 % ee) were obtained as a white solid.1.3 Dissociation of cocrystals of (S)-SLS with (-)-DTTA To a 500 mL round-bottomed flask equipped with magnetic stirrer andcontaining 5 g of the cocrystals of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) with (-)-DTTA (11.3 mmol) as prepared under item 1.2 above,200 mL of water was added. The resulting suspension was stirred at roomtemperature (approx. 22°C) for 30 min and 25 mL of an aqueous solution of NaHCO3(0.86 M) was added. After stirring for 1 h the white resulting mixture was filteredthrough a sintered funnel (porosity 3), washed with water twice (20 mL each) anddried under vacuum (approx. 1 mbar) at room temperature overnight. (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (S)-SLS (polymorph G) (99.3 %yield; 32.3 % overall yield; 99.4 % ee) was obtained as a white solid.Example 2: Characterization of (S)-Selisistat in crystalline form (polymorph G)(S)-Selisistat in crystalline form having an enantiomeric purity of 99.4 % ee asprepared according to Example 1 above (polymorph G) was characterized by X-Raypowder diffraction (XRPD), 1H-NMR, Differential Scanning calorimetry (DSC) andchiral High-Pressure Liquid Chromatography (chiral HPLC).2.1 XPRD analysis of (S)-Selisistat in crystalline formXRPD analysis of (S)-Selisistat in crystalline form (polymorph G) wasperformed at ambient conditions on a PANalytical X'Pert PRO ^-^ diffractometer of240 mm of radius in reflection geometry, equipped with Cu Kα radiation and a PIXceldetector, operated at 45 kV and 40 mA. The crystalline sample was mounted on azero-background silicon holder and allowed to spin at 0.25 rev / s during the datacollection. The measurement angular range was 3.0-40.0° (2^) with a step size of0.013°. The scanning speed was 0.082 (40.80 s / step).The XRPD pattern measured for (S)-Selisistat in crystalline form (polymorphG) accordingly showed good crystallinity (see Fig. 1) and peaks as listed in Table 1below: Table 1: Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]6.7 13.1 610.1 8.7 410.8 8.2 10013.5 6.6 7614.9 6.0 1518.0 4.9 518.5 4.8 719.9 4.5 420.5 4.3 421.2 4.2 521.7 4.1 8222.8 3.9 1623.8 3.7 5025.3 3.5 426.6 3.4 1527.2 3.3 529.8 3.0 1130.6 2.9 1631.2 2.9 332.8 2.7 234.3 2.6 435.5 2.5 737.8 2.4 22.2 1H-NMR analysis of (S)-Selisistat in crystalline formA 1H-Nuclear magnetic resonance spectrum of (S)-Selisistat in crystalline form(polymorph G) was recorded in deuterated DMSO in a Varian Mercury 400 MHzspectrometer, equipped with a broadband probe ATB 1H / 19F / X of 5 mm (see Fig. 2).The spectrum was acquired dissolving approx. 5 to10 mg of sample in 0.7 mL ofdeuterated solvent.The 1H-NMR spectrum of (S)-Selisistat in crystalline form (polymorph G) wasidentical to the spectrum of the racemic starting material and showed no residualorganic solvents. 2.3 Differential Scanning Calorimetry (DSC) analysis of (S)-Selisistat incrystalline form (polymorph G)A DSC analysis of (S)-Selisistat in crystalline form was recorded with a MettlerToledo DSC2. The sample was weighed into a 40 μL aluminium crucible with apinhole lid and heated from 25 to 300 °C at a rate of 10 °C / min, under nitrogen (50mL / min).The recorded spectrum (see Fig. 3) showed an endothermic peak with anonset at 167.1 °C corresponding to the melting point of (S)-Selisistat in crystallineform (polymorph G).2.4 Chiral HPLC analysis of (S)-Selisistat in crystalline form (polymorph G)A chiral HPLC analysis of (S)-Selisistat in crystalline form (polymorph G) wasperformed using an Agilent HP1100 HPLC system equipped with a vacuum degasser,a quaternary pump, an autosampler, a thermostatic column and a VW detector.The enantiomeric excess of (S)-Selisistat in crystalline form was determinedunder the following conditions: Chiralpak IA 250 x 4.6 mm, 5 µm; sampleconcentration: 1 mg / mL in heptane / isopropyl alcohol (1:1); mobile phase: isopropylalcohol:ethanol-0.2% diethyl amine (50:50); temperature: 25 °C; flow rate: 0.4mL / min; wavelength: 210 nm; injection: 5 µL; run time: 30 min. The chromatogramdisplayed an enantiomeric purity of 99.4 % ee (peaks at retention times of 15.15 and19.62 min).Example 3: Preparation of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1- carboxamide (S)-SLS in crystalline form (polymorph K) 20 mg of (S)-SLS as prepared according to Example 1 (polymorph G) (0.080mmol) was suspended in 0.4 mL nitromethane. The suspension was heated until aclear solution was obtained. The resulting solution was cooled to room temperature(approx. 22 °C) and then stirred overnight. The resulting precipitate was filteredthrough a sintered funnel (porosity 3) and dried under vacuum at room temperatureto provide (S)-SLS (polymorph K) as a white solid.Example 4: Characterization of (S)-Selisistat in crystalline form (polymorph K)(S)-Selisistat in crystalline form (polymorph K) having an enantiomeric purityof 99.4 % ee as prepared according to Example 3 above (polymorph K) wascharacterized by X-Ray powder diffraction (XRPD), 1H-NMR and Differential Scanningcalorimetry (DSC).4.1 XRPD analysis of (S)-Selisistat in crystalline form (polymorph K)XRPD analysis of (S)-Selisistat in crystalline form (polymorph K) wasperformed as described under Example 2.1 above.The XRPD pattern measured for (S)-Selisistat in crystalline form (polymorphK) showed good crystallinity (see Fig. 4) and peaks as listed in Table 2 below:Table 2:Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]5.8 15.23 128.1 10.97 1711.2 7.88 4711.7 7.56 112.7 6.99 1413.0 6.81 10016.3 5.45 6317.6 5.03 517.9 4.96 918.5 4.79 919.0 4.66 420.6 4.30 721.4 4.16 1221.9 4.06 2622.6 3.93 2523.5 3.78 1124.3 3.66 2525.0 3.57 825.3 3.52 1026.2 3.40 1226.8 3.32 727.6 3.23 1028.8 3.10 729.2 3.06 629.6 3.01 130.2 2.96 930.8 2.90 731.8 2.82 133.6 2.67 634.3 2.61 534.9 2.57 136.3 2.48 637.2 2.41 137.6 2.39 134.2 1H-NMR analysis of (S)-Selisistat in crystalline form (polymorph K)A 1H Nuclear magnetic resonance spectrum of (S)-Selisistat in crystalline form(polymorph K) was recorded as described under Example 2.2.The 1H NMR spectrum of (S)-Selisistat in crystalline form (polymorph K) isconsistent with its chemical structure and showed no residual organic solvents.4.3 Differential Scanning calorimetry (DSC) analysis of (S)-Selisistat incrystalline form (polymorph K)A DSC analysis of (S)-Selisistat in crystalline form (polymorph K) was recordedas described under Example 2.3.The recorded spectrum (see Fig. 5) showed an endothermic peak with anonset at 167.3 °C corresponding to the initial melting point of (S)-Selisistat incrystalline form (polymorph K) followed by an exothermic event and followed by anendothermic peak having an onset at 184.5 °C.Example 5: Preparation of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (S)-SLS in crystalline form (polymorph H)50 mg of (S)-SLS as prepared according to Example 1 (polymorph G) (0.201mmol) was suspended in 0.5 mL of xylene. The suspension was stirred overnight atroom temperature (approx. 22°C). The resulting mixture was centrifuged, decantedand dried under vacuum at room temperature to provide (S)-SLS (polymorph H) as awhite solid.Example 6: Characterization of (S)-Selisistat in crystalline form (polymorph H)(S)-Selisistat in crystalline form (polymorph H) having an enantiomeric purityof 99.4 % ee as prepared according to Example 5 above (polymorph H) wascharacterized by X-Ray powder diffraction (XRPD), 1H-NMR and Differential Scanningcalorimetry (DSC).6.1 XRPD analysis of (S)-Selisistat in crystalline form (polymorph H)XPRD analysis of (S)-Selisistat in crystalline form (polymorph H) wasperformed as described under Example 2.1 above.The XPRD pattern measured for (S)-Selisistat in crystalline form (polymorphH) showed good crystallinity (see Fig. 6) and peaks as listed in Table 3 below:Table 3:Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]5.5 16.13 166.7 13.27 10012.2 7.24 912.6 7.03 7813.4 6.60 5214.8 6.00 815.1 5.88 1516.5 5.36 217.3 5.12 1218.2 4.89 1518.5 4.80 6519.0 4.66 519.2 4.62 1420.0 4.44 1020.3 4.38 1020.6 4.30 821.1 4.21 1121.3 4.17 1121.5 4.13 1621.8 4.08 2122.1 4.02 1222.7 3.92 1223.9 3.73 724.7 3.61 1224.9 3.58 2125.3 3.52 1326.0 3.42 1026.6 3.35 326.9 3.31 2127.6 3.23 828.9 3.09 1133.3 2.69 935.3 2.54 106.2 1H-NMR analysis of (S)-Selisistat in crystalline form (polymorph H)A 1H Nuclear magnetic resonance spectrum of (S)-Selisistat in crystalline form(polymorph H) was recorded as described under Example 2.2.The 1H NMR spectrum of (S)-Selisistat in crystalline form (polymorph H) wasidentical to the spectrum of the racemic starting material and showed no residualorganic solvents.6.3 Differential Scanning calorimetry (DSC) analysis of (S)-Selisistat incrystalline form (polymorph H)A DSC analysis of (S)-Selisistat in crystalline form (polymorph H) wasrecorded as described under Example 2.3.The recorded spectrum (see Fig. 7) showed an endothermic peak with anonset at ca. 162 °C corresponding to the initial melting point of (S)-Selisistat incrystalline form (polymorph H) followed by an exothermic event and followed by anendothermic peak having an onset at 185.1 °C.Example 7: Stability of polymorphs of (S)-Selisistat in crystalline form Samples of polymorphs G, H and K of (S)-Selisistat in crystalline form asprepared and characterized according to Examples 1 to 6 above were subjected to aaccelerated stability test under conditions as defined defined by the InternationalCouncil for Harmonization of Technical Requirements for Pharmaceuticals for HumanUse (ICH; accelerated ICH conditions: storage at 40 + / - 2 °C at 75 + / - 5 % relativehumidity) as follows: A crystal of each compound as prepared according to Examples1, 3 and 5, respectively, above was placed on an XRPD silicon sample holder andexposed to the above defined accelerated ICH conditions in a suitable climaticchamber.The samples were periodically analysed by XRPD to observe possiblecrystalline conversion or amorphization. All tested samples (polymorphs G, H and K)remained stable at 40 + / - 2 °C at 75 + / - 5 % relative humidity (RH) for at least 7 days.Example 8: Preparation of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (S)-SLS in crystalline form (polymorph T)20 mg of (S)-SLS as prepared according to Example 1 (polymorph G) (0.080mmol) was dissolved in 0.1 mL of dimethylsulfoxide (DMSO). 1 mL of anisole wasadded and the resulting mixture was centrifuged and decanted to provided (S)-SLS(polymorph T) in the form of a pasty solid.Example 9: Characterization of (S)-Selisistat in crystalline form (polymorph T)(S)-Selisistat in crystalline form (polymorph T) having an enantiomeric purityof 99.4 % ee as prepared according to Example 8 above was characterized by X-Raypowder diffraction (XRPD).9.1 XRPD analysis of (S)-Selisistat in crystalline form (polymorph T)XPRD analysis of (S)-Selisistat in crystalline form (polymorph T) wasperformed as described under Example 2.1 above.The XPRD pattern measured for (S)-Selisistat in crystalline form (polymorphT) showed low crystallinity (see Fig. 8) and peaks as listed in Table 4 below:Table 4:Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]7.2 12.34 10014.4 6.14 1621.7 4.10 2324.1 3.69 7 Example 10: Preparation of a solvate of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide with acetone in crystalline form (solvate J)50 mg of (S)-SLS as prepared according to Example 1 (polymorph G) (0.201mmol) was suspended in 0.25 mL of acetone and the resulting mixture was stirred atroom temperature overnight. The mixture was the filtered through a sintered funnel(porosity 3) and the precipitate dried under vacuum overnight to provided solvate Jof (S)-SLS as a white solidExample 11: Characterization of the acetone solvate of (S)-Selisistat incrystalline form (solvate J)The acetone solvate of (S)-Selisistat in crystalline form (solvate J) as preparedaccording to Example 10 above was characterized by X-Ray powder diffraction(XRPD), 1H-NMR and Differential Scanning calorimetry (DSC).11.1 XRPD analysis of the acetone solvate of (S)-Selisistat in crystalline form(solvate J)XRPD analysis of solvate J of (S)-Selisistat in crystalline form was performed asdescribed under Example 2.1 above.The XPRD pattern measured for solvate J of (S)-Selisistat in crystalline formshowed good crystallinity (see Fig. 9) and peaks as listed in Table 5 below:Table 5:Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]5.9 15.09 38.9 9.91 19.5 9.27 210.2 8.69 710.6 8.37 10011.2 7.93 411.9 7.45 1413.2 6.70 114.1 6.28 314.3 6.20 315.6 5.67 1416.2 5.48 516.4 5.41 1017.2 5.15 2717.5 5.05 217.9 4.95 818.2 4.87 318.9 4.70 219.2 4.63 1819.5 4.56 219.8 4.48 921.3 4.18 1922.6 3.94 223.1 3.86 323.4 3.81 124.0 3.71 424.2 3.68 125.2 3.54 1525.4 3.50 126.3 3.38 326.9 3.31 327.1 3.29 527.4 3.25 127.8 3.21 128.4 3.15 328.8 3.10 529.8 2.99 731.7 2.82 232.2 2.78 235.4 2.54 136.4 2.47 111.21H-NMR analysis of the acetone solvate of (S)-Selisistat in crystallineform (solvate J)A 1H-Nuclear magnetic resonance spectrum of solvate J of (S)-Selisistat incrystalline form (solvate J) was recorded as described under Example 2.2.The1H-NMR spectrum of acetone solvate J of (S)-Selisistat in crystalline form(see Fig. 10) showed signal of the starting material (polymorph G) and signals ofacetone at 2.1 ppm. Integration of the signals indicated a (molar) ratio of (S)-SLS toacetone of approx. 3:1. 11.3 Differential Scanning calorimetry (DSC) analysis of the acetone solvate of(S)-Selisistat in crystalline form (solvate J)A DSC analysis of the acetone solvate of (S)-Selisistat in crystalline form wasrecorded as described under Example 2.3.The recorded spectrum (see Fig. 11) showed two broad endothermic peakswith an onset at about 82 °C and about 106 °C, respectively, followed by a sharpendothermic peak with an onset at about 171 °C.Example 12: Preparation of a solvate of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide with dioxane in crystalline form (solvate M)50 mg of (S)-SLS as prepared according to Example 1 (polymorph G) (0.201mmol) was suspended in 1 mL of dioxane and the resulting mixture was stirred atroom temperature overnight. The mixture was the filtered through a sintered funnel(porosity 3) and the precipitate dried under vacuum overnight to provide dioxanesolvate M of (S)-SLS as a white solid.Example 13: Characterization of the dioxane solvate of (S)-Selisistat incrystalline form (solvate M)The dioxane solvate of (S)-Selisistat in crystalline form (solvate M) asprepared according to Example 12 above was characterized by X-Ray powderdiffraction (XRPD), 1H-NMR and Differential Scanning calorimetry (DSC).13.1 XRPD analysis of the dioxane solvate of (S)-Selisistat in crystalline form(solvate M)XRPD analysis of dioxane solvate M of (S)-Selisistat in crystalline form wasperformed as described under Example 2.1 above.The XPRD pattern measured for dioxane solvate M of (S)-Selisistat incrystalline form showed good crystallinity (see Fig. 12) and peaks as listed in Table 6below: Table 6: Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]5.9 15.01 29.9 8.96 2611.9 7.46 10014.3 6.20 416.1 5.49 3816.8 5.26 118.2 4.87 219.6 4.54 4219.8 4.47 2021.1 4.22 521.8 4.08 1822.3 3.98 3622.9 3.88 2124.1 3.70 825.0 3.57 425.2 3.53 425.5 3.49 226.3 3.39 528.1 3.18 428.4 3.14 429.7 3.01 230.0 2.98 330.7 2.91 731.0 2.88 531.4 2.85 332.0 2.80 432.6 2.74 234.1 2.63 334.8 2.58 135.5 2.53 136.2 2.48 136.9 2.44 238.7 2.33 113.21H-NMR analysis of the dioxane solvate of (S)-Selisistat in crystallineform (solvate M)A 1H Nuclear magnetic resonance spectrum of dioxane solvate M of (S)-Selisistat in crystalline form was recorded as described under Example 2.2.The 1H-NMR spectrum of dioxane solvate M of (S)-Selisistat in crystalline form(see Fig. 13) showed signal of the starting material (polymorph G) and signals ofdioxane at approx. 3.6 ppm. Integration of the signals indicated a (molar) ratio of (S)-SLS to dioxane of approx. 1:0.8.13.3 Differential Scanning calorimetry (DSC) analysis of the dioxane solvate of(S)-Selisistat in crystalline form (solvate M)A DSC analysis of the dioxane solvate of (S)-Selisistat in crystalline form wasrecorded as described under Example 2.3.The recorded spectrum (see Fig. 14) showed two broad endothermic peakswith an onset at about 80 °C and about 103 °C, respectively, followed by a sharpendothermic peak with an onset at about 188 °C.Example 14: Preparation of a solvate of (S)-6-Chloro-2,3,4,9-tetrahydro-1H- carbazole-1-carboxamide with N,N-dimethylformamide (DMF) in crystallineform (solvate R)100 mg of (S)-SLS as prepared according to Example 1 (polymorph G) (0.402mmol) was suspended in 0.15 mL of N,N-dimethylformamide and the resultingmixture was stirred at room temperature overnight. The mixture was the filteredthrough a sintered funnel (porosity 3) and the precipitate dried under vacuumovernight to provided solvate R of (S)-SLS as a white solid.Example 15: Characterization of the DMF solvate of (S)-Selisistat in crystallineform (solvate R)The DMF solvate of (S)-Selisistat in crystalline form (solvate R) as preparedaccording to Example 12 above was characterized by X-Ray powder diffraction(XRPD) and 1H-NMR.15.1 XRPD analysis of the DMF solvate of (S)-Selisistat in crystalline form(solvate R)XRPD analysis of DMF solvate R of (S)-Selisistat in crystalline form wasperformed as described under Example 2.1 above.The XPRD pattern measured for the DMF solvate R of (S)-Selisistat incrystalline form showed good crystallinity (see Fig. 15) and peaks as listed in Table 7below:Table 7:Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]4.9 18.14 125.6 15.92 157.3 12.17 119.5 9.28 910.2 8.70 410.9 8.12 10011.3 7.83 1813.0 6.81 313.3 6.66 814.1 6.27 215.4 5.76 1217.0 5.21 4617.3 5.11 1317.8 4.98 3318.5 4.80 1019.2 4.63 1319.8 4.48 120.9 4.24 121.6 4.11 221.9 4.05 1022.6 3.93 923.7 3.76 424.2 3.68 225.6 3.48 2226.2 3.40 226.6 3.35 227.3 3.27 828.1 3.18 1229.3 3.05 829.9 2.99 432.8 2.73 2 15.21H-NMR analysis of the DMF solvate of (S)-Selisistat in crystalline form(solvate R)A 1H-Nuclear magnetic resonance spectrum of DMF solvate R of (S)-Selisistatin crystalline form was recorded as described under Example 2.2.The 1H-NMR spectrum of DMF solvate R of (S)-Selisistat in crystalline form(see Fig. 16) showed signals of the starting material (polymorph G) and signals ofN,N-dimethylformamide at approx. 8.0, 2.9 and 2.7 ppm. Integration of the signalsindicated a (molar) ratio of (S)-SLS to DMF of approx. 1:0.5.Example 16: Preparation of a solvate of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide with cyclopentanone in crystalline form (solvate Q)100 mg of (S)-SLS as prepared according to Example 1 (polymorph G) (0.402mmol) was suspended in 0.15 mL of cyclopentanone and the resulting mixture wasstirred at room temperature overnight. The mixture was the filtered through asintered funnel (porosity 3) and the precipitate dried under vacuum overnight toprovided solvate R of (S)-SLS as a white solid.Example 17: Characterization of the cyclopentanone solvate of (S)-Selisistat incrystalline form (solvate Q)The cyclopentanone solvate of (S)-Selisistat in crystalline form (solvate Q) asprepared according to Example 16 above was characterized by X-Ray powderdiffraction (XRPD) and 1H-NMR.17.1 XRPD analysis of the cyclopentanone solvate of (S)-Selisistat incrystalline form (solvate Q)XRPD analysis of cyclopentanone solvate Q of (S)-Selisistat in crystalline formwas performed as described under Example 2.1 above.The XPRD pattern measured for the cyclopentanone solvate Q of (S)-Selisistatin crystalline form showed good crystallinity (see Fig. 17) and peaks as listed in Table8 below: Table 8: Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]4.4 20.02 144.8 18.43 85.1 17.34 45.5 16.06 16.4 13.80 67.3 12.12 79.6 9.25 79.9 8.89 511.1 8.00 10011.7 7.55 712.0 7.35 712.8 6.92 813.4 6.63 214.6 6.05 615.2 5.83 1016.9 5.26 5817.5 5.06 518.6 4.77 719.2 4.62 1420.6 4.32 2521.0 4.24 1621.7 4.09 822.2 4.00 1423.6 3.77 1524.2 3.67 425.1 3.55 1025.7 3.46 526.2 3.41 626.9 3.31 1327.5 3.25 829.6 3.02 1332.4 2.77 535.2 2.55 136.2 2.48 436.9 2.44 1 17.21H-NMR analysis of the cyclopentanone solvate of (S)-Selisistat incrystalline form (solvate Q)A 1H-Nuclear magnetic resonance spectrum of cyclopentanone solvate Q of (S)-Selisistat in crystalline form was recorded as described under Example 2.2.The 1H-NMR spectrum of cyclopentanone solvate Q of (S)-Selisistat incrystalline form (see Fig. 18) showed signals of the starting material (polymorph G)and signals of cyclopentanone at approx. 1.8 to 2.1 ppm. Integration of the signalsindicated a (molar) ratio of (S)-SLS to cyclopentanone of approx. 1:1.

Claims

Claims1. (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) offormula (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 polymorphicforms a) to c) of (S)-SLS having an X-ray powder diffraction patterncomprising 2-theta angle values (with a deviation of + / - 0.2 degree) ofa) 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), andc) 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) offormula (I) in crystalline form according to claim 1,wherein the (S)-SLS in crystalline form is a crystalline polymorphic form of(S)-SLS selected from the group consisting of the crystalline polymorphicforms a) to c) of (S)-SLS having an X-ray powder diffraction patterncomprising 2-theta angle values (with a deviation of + / - 0.2 degree) ofa) 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6 and 30.6 degrees (polymorphG),b) 6.7, 12.6, 13.4, 18.5, 21.8, 24.9 and 26.9 degrees (polymorph H), andc) 8.1, 11.2, 13.0, 16.3, 21.9, 22.6 and 24.3 degrees (polymorph K).

3. The crystalline form of (S)-SLS according to claim 1 or 2, whereinthe crystalline form of (S)-SLS is a crystalline polymorphic form of (S)-SLSselected from the group consisting of crystalline polymorphic forms a) to c) of(S)-SLS having a melting point (melting onset) ofa) 167 °C (polymorph G),b) 162 °C (polymorph H), andc) 167 °C (polymorph K).

4. The crystalline form of (S)-SLS according to any one of the preceding claims,whereinthe crystalline form of (S)-SLS is a crystalline polymorphic form of (S)-SLSselected from the group consisting of crystalline polymorphic forms a) to c) of(S)-SLS having a melting enthalpy ( ^H) in the range ofa) 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), andc) about - 65 J / g to about – 64 J / g (polymorph K).

5. The crystalline form of (S)-SLS of formula (I) according to any one of thepreceding claims, whereinthe crystalline form of (S)-SLS is a crystalline polymorphic form of (S)-SLSselected from the group consisting of crystalline polymorphic forms of (S)-SLSa) and d) having an X-ray powder diffraction pattern comprising 2-theta anglevalues (with a deviation of + / - 0.2 degree) ofa) 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6 and 30.6 (polymorph G), andb) 6.7, 12.6, 13.4, 18.5, 21.8, 24.9 and 26.9 degrees (polymorph H).

6. The crystalline form of (S)-SLS of formula (I) according to any one of thepreceding claims, whereinthe crystalline form of (S)-SLS is a crystalline polymorphic form of (S)-SLShaving an X-ray powder diffraction pattern comprising 2-theta angle values(with a deviation of + / - 0.2 degree) of 10.8, 13.5, 14.9, 21.7, 22.8, 23.8, 26.6and 30.6 (polymorph G).

7. The crystalline form of (S)-SLS according to any one of the preceding claims,wherein the crystalline form of (S)-SLS is solvent-free and / or non-hygroscopic.

8. The crystalline form of (S)-SLS according to any one of the preceding claims,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 a period of at least 7 days.

9. A composition comprising a crystalline form of (S)-SLS of formula (I)according to any one of the preceding claims and further comprising up toabout 20 wt.-%, 10 wt.-%, 5 wt.-%, 4 wt.-%, 3 wt.-%, 2 wt.-% or 1 wt.-% ofany other solid-state form of (S)-SLS, based on the weight of the composition.

10. The crystalline form of (S)-SLS of formula (I) according to any one of claims 1to 8 or the composition according to claim 9 for use as a medicament.

11. The crystalline form of (S)-SLS of formula (I) according to any one of claims 1to 8 or the composition according to claim 9 for use in the prevention ortreatment of a disease or condition associated with SIRT1.

12. The crystalline form of (S)-SLS of formula (I) according to any one of claims 1to 8 or the composition according to claim 9 for use in the prevention ortreatment of cancer, metabolic diseases such as metabolic syndrome, type Idiabetes or type II diabetes, obesity, dislipidemia, hyperlipidemia, Alzheimer'sdisease, Parkinson's disease, amyotrophic lateral sclerosis, neurodegenerativeconditions that are caused at least in part by polyglutamine aggregation, suchas Huntington's disease, spinalbulbar muscular atrophy (SBMA or Kennedy'sdisease) dentatorubro-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia1 (SCA1), spinocerebellar ataxia 2 (SCA2), Machado-Joseph disease (MJD;SCA3), spinocerebellar ataxia 6 (SCA6), spinocerebellar ataxia 7 (SCA7),and spinocerebellar ataxia 12 (SCA12).

13. Use of a crystalline form of (S)-SLS of formula (I) according to any one ofclaims 1 to 8 or the composition according to claim 9 for the preparation of apharmaceutical composition.

14. A pharmaceutical composition comprising a crystalline form of (S)-SLSaccording to any one of claims 1 to 8 or the composition according to claim 9and at least one pharmaceutically acceptable excipient.

15. The pharmaceutical composition according to claim 14, wherein thepharmaceutical composition is a solid dosage form for oral administration,preferably a tablet, a capsule or an oral film.

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