New cocrystals

Abstract

The invention provides a composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro- 1H-carbazole-1-carboxamide ((S)-SLS) of formula (S-I) (S-I) and a further pharmaceutically acceptable compound, wherein the composition is in the form of a cocrystal, and wherein the further pharmaceutically acceptable compound is selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid. The invention further provides for said compositions for use as a medicament as well as for pharmaceutical compositions comprising such cocrystalline compositions.

Description

[0001] TITLE: NEW COCRYSTALS

[0002] Description

[0003] The present invention provides for compositions comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) and a further pharmaceutically acceptable compound, wherein the composition is in the form of a cocrystal, and wherein the further pharmaceutically acceptable compound is selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid. The present invention also provides for pharmaceutical compositions comprising such cocrystalline compositions, the use thereof as a medicament as well as for methods for the preparation thereof.

[0004] BACKGROUND OF THE INVENTION

[0005] The compound 6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide of formula (I),

[0006] H2N H

[0007] N

[0008]

[0009] also known as Selisistat or EX-527 (CAS-Nr. 49843-98-3) is known from WO 2005 / 026112 A2 to possess anti-SIRTl (sirtuin 1) activity, and as such may be useful in the preparation of medicaments for any condition which may benefit from the inhibition of SIRT1. Such conditions may include, for example, cancer, metabolic diseases such as metabolic syndrome, type I diabetes or type II diabetes, obesity, dislipidemia, hyperlipidemia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, neurodegenerative conditions that are 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 1 (SCA1), spinocerebellar ataxia 2 (SCA2), Machado-Josephdisease (MJD;SCA3), spinocerebellar ataxia 6 (SCA6), spinocerebellar ataxia 7 (SCA7), and spinocerebellar ataxia 12 (SCA12).

[0010] 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 WO 2013 / 057258 Al.

[0011] The molecule has an asymmetric carbon atom adjacent to the amide functionality and, accordingly, exists in the form of two enantiomers, namely (7?)- 6- Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide and (S)-6-Chloro-2, 3,4,9-tetrahydro-lH-carbazole-l-carboxamide of formula (S-l),

[0012] H

[0013] N

[0014]

[0015] Cl

[0016] hereinafter also referred to as “(Sj-SLS”.

[0017] Amongst others, it is an object of the present invention to provide for new forms or derivatives of (S)-SLS that may be useful or advantageous for the preparation of a pharmaceutical composition and / or the treatment of a disease or condition associated with a sirtuin.

[0018] SUMMARY OF THE INVENTION

[0019] In a first aspect, the invention relates to a composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) of formula (S-I)

[0020]

[0021] and a further pharmaceutically acceptable compound,

[0022] wherein the composition is in the form of a cocrystal, andwherein the further pharmaceutically acceptable compound is selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid.

[0023] In a second aspect, the present invention provides for a pharmaceutical composition comprising the composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) and a further pharmaceutically acceptable compound in the form of a cocrystal according to the first aspect of the invention and at least one pharmaceutically acceptable excipient.

[0024] In a third aspect, the invention provides for the composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) and the further pharmaceutically acceptable compound in the form of a cocrystal according to the first aspect of the invention or the pharmaceutical composition according to the second aspect of the invention for use as a medicament, particularly for use in the prevention or treatment of a disease or medical condition associated with a sirtuin.

[0025] In a fourth aspect, the present invention provides for the use of the composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) and the further pharmaceutically acceptable compound in the form of a cocrystal according to the first aspect of the invention for the preparation of a pharmaceutical composition.

[0026] In a fifth aspect, the present invention provides for a method for the preparation of the composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) and the further pharmaceutically acceptable compound in the form of a cocrystal according to the first aspect of the invention.

[0027] DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 depicts a diffractogram of an X-Ray Powder Diffraction (XRPD) analysis of a polymorph of (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide in crystalline form (polymorph X).

[0029] Figure 2 depicts a spectrum of an1H-Nuclear Magnetic Resonance (1H-NMR) analysis of a polymorph of (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide in crystalline form (polymorph X).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-carboxamide in crystalline form (polymorph X).

[0030] Figure 4 depicts a diffractogram of an XRPD analysis of a cocrystal comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and gentisic acid.

[0031] Figure 5 depicts a spectrum of an1H-Nuclear Magnetic Resonance (1H-NMR) analysis of a cocrystal comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and gentisic acid.

[0032] Figure 6 depicts a spectrum of a DSC analysis of a cocrystal comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and gentisic acid.

[0033] Figure 7 depicts a diffractogram of an XRPD analysis of a cocrystal comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and nicotinamide.

[0034] Figure 8 depicts a spectrum of an1H-Nuclear Magnetic Resonance (1H-NMR) analysis of a cocrystal comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and nicotinamide.

[0035] Figure 9 depicts a spectrum of a DSC analysis of a cocrystal comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and nicotinamide.

[0036] Figure 10 depicts a diffractogram of an XRPD analysis of a cocrystal comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and oxalic acid.

[0037] Figure 11 depicts a spectrum of an1H-Nuclear Magnetic Resonance (1H-NMR) analysis of a cocrystal comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and oxalic acid.

[0038] Figure 12 depicts a spectrum of an13C-Nuclear Magnetic Resonance (13C-NMR) analysis of a cocrystal comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and oxalic acid.

[0039] Figure 13 depicts a diffractogram of an XRPD analysis of a cocrystal comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and glycolic acid.Figure 14 depicts a spectrum of an1H-Nuclear Magnetic Resonance (1H-NMR) analysis of a cocrystal comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and glycolic acid.

[0040] Figure 15 depicts a spectrum of a DSC analysis of a cocrystal comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and glycolic acid.

[0041] Figure 16 depicts a graph showing measurements of the mean concentration (ng / mL) of orally administered Selisistat racemate and Selisistat cocrystals comprising (S) -Selisistat over a timespan of ten hours in male rat plasma.

[0042] DETAILED DESCRIPTION OF THE INVENTION

[0043] In the first aspect, the present invention provides for a composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) of formula (S-I)

[0044]

[0045] and a further pharmaceutically acceptable compound,

[0046] wherein the composition is in the form of a cocrystal, and

[0047] wherein the further pharmaceutically acceptable compound is selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid.

[0048] According to this first aspect, the present invention provides for a composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) of formula (S-I)

[0049]

[0050] and a further pharmaceutically acceptable compound. The compositions according to the present invention comprise, as the first constituent, 6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide in the form of its S-enantiomer ((S)-SLS) as depicted in formula (S-I) above in which the asymmetric carbon atom to which the carboxamide substituent is connected is present in the absolute S-configuration. In some embodiments, the compositions of the present invention comprise (S)-SLS in enantiomerically enriched or even enantiomerically pure form.

[0051] The term “(5) -SLS in enantiomerically enriched form” as used herein in connection with the S-enantiomer of SLS of formula (S-l) as described above means that such S-enantiomer of SLS of formula (S-l) may be present in the form of its pure (5) -enantiomer of formula (S-l) or, in other words, in enantiomerically pure form, or in the form of non-racemic mixtures of the (S)-enantiomer of formula (S-I) with its corresponding (R)-enantiomer, namely (R)- 6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide of formula (R-I) as depicted below

[0052] NH2

[0053] H

[0054] N

[0055]

[0056] (*R*-I)

[0057] in which the amount of (S) -enantiomer is larger than the amount of corresponding (7?) -enantiomer. In some embodiments, the term “(S)-SLS of formula (S-l) in enantiomerically enriched form” may refer to mixtures of (SJ-SLS with its corresponding R-enantiomer comprising the (S) -enantiomer of the compound of formula (S-l) with an enantiomeric 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 100 % e.e. or 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.

[0058] Accordingly, the term “(5) -SLS in enantiomerically pure form” as used herein may refer to “(5) -SLS in enantiomerically enriched form which is present in an very high enantiomeric purity together with only residual amounts of the (7?) -SLS, if present at all, or, in other words in an enantiomeric excess of from about 99.0 % e.e to about 100 % e.e, or from about 99.95 % e.e. to about 99.9 % e.e. or 99.8 % e.e.(S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) in enantiomerically enriched or even enantiomerically pure form may be prepared by preparative chiral high-pressure liquid chromatography (HPLC) starting from racemic 6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (rac-SLS) or by kinetic resolution of rac-SLS as described in further detail below.

[0059] As the second constituent, the compositions of the present invention comprise a further pharmaceutically acceptable compound (with S-SLS as described above being the first pharmaceutically acceptable compound) wherein the pharmaceutically acceptable compound is selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid. In other words, the compositions according to the present invention comprise S-SLS in enantiomerically enriched or pure form as described above and either one of gentisic acid (2,5-Dihydroxybenzoic acid; CAS Reg. No.490-79-9) of formula (11)

[0060] O OH

[0061]

[0062] HO OH

[0063] or nicotineamide (3-pyridinecarboxamide; CAS Reg. No. 98-92-0) of formula (111) O

[0064] f| NH2

[0065]

[0066] (III)

[0067] or oxalic acid (ethanedioic acid; CAS Reg. No. 144-62-7) of formula (IV)

[0068]

[0069] O (IV)

[0070] or glycolic acid (hydroxyacetic acid; CAS Reg. No. 79-14-1) of formula (V)

[0071]

[0072] as the further pharmaceutically acceptable compound, wherein the term “pharmaceutically acceptable” means that the compound it refers to is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for human pharmaceutical use.

[0073] In particular embodiments, the compositions of the present invention are of high chemical purity and comprise (SJ-SLS as described above and one of gentisic acid, nicotineamide, oxalic acid, or glycolic acid and only small or even negligible amounts of other compounds such as water, residual solvents, salts or other impurities. In particular embodiments, the compounds of the present invention comprise or essentially consist of S-SLS and the one further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotineamide, oxalic acid and glycolic acid to an extend of at least 80 % (w / w) or at least about 90 % (w / w) or even at least about 95 % (w / w), such as from about 95 % (w / w) or from about 97 % (w / w) to about 99 % (w / w) or to about 100 % (w / w), or from about 98 % (w / w) to about 99.9 % (w / w) or from about 98.5 % (w / w) to about 99.8 % (w / w), all with regard to the combined amount of (SJ-SLS and the chosen compound selected from the group consisting of gentisic acid, nicotine amide, oxalic acid and glycolic acid.

[0074] The compositions according to the present invention are in the form of a cocrystal. In other words, the compositions of the present invention are cocrystals comprising or essentially consisting of (5)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-1-carboxamide ((5)-SLS) of formula (S-l) as described above and the further pharmaceutically acceptable compound is selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid.

[0075] The terms “cocrystal” or “cocrystalline composition” or “composition in form of a cocrystal” as used herein synonymously refers to a preferably solid, crystalline material comprising S-SLS and the chosen further pharmaceutically acceptable compound and showing reflections (or “peaks”) when analyzed by X-ray powderdiffraction (hereinafter also referred to as “XRPD” or “Powder X-Ray Diffraction analysis, “PXRD” as used herein synonymously) wherein such reflections which are caused at certain diffraction angles (Bragg angles) by constructive interference from X-rays scattered by parallel planes of atoms in solid material, which are distributed in an ordered and repetitive pattern in a long-range positional order. Such a solid material is classified as “crystalline” material or, as used herein, “in crystalline form”, whereas amorphous material is defined as solid material, which lacks long-range order and only displays short-range order, thus resulting in broad scattering.

[0076] According to literature, long-range order e.g. extends over approximately 100 to 1000 atoms, whereas short-range order is over a few atoms only (see " Fundamentals of Powder Diffraction and Structural Characterization of Materials” by Vitalij K.

[0077] Pecharsky and Peter Y. Zavalij, Kluwer Academic Publishers, 2003, page 3).

[0078] In particular embodiments, the further pharmaceutically acceptable compound comprised by the compositions according to the present invention is selected from the group consisting of gentisic acid, nicotinamide and glycolic acid.

[0079] In further particular embodiments, the further pharmaceutically acceptable compound comprised by the compositions according to the present invention is selected from the group consisting of gentisic acid and nicotinamide.

[0080] In a particular embodiment, the further pharmaceutically acceptable compound comprised by the compositions of the present invention is gentisic acid. According to this particular embodiment, the present invention provides for a cocrystal comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-l) and gentisic acid of formula (11), preferably in a molar ratio selected within the range of from about 0.9: 1 to about 1.1: 1, such as from about 0.95: 1 to about 1.05:1, preferably in a molar ratio of about 1: 1.

[0081] The cocrystalline composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-l) and gentisic acid of formula (11) may be prepared as described in further detail below (see Examples 3 and 4) and has been characterized in the form of a white powder. An X-Ray Powder Diffraction analysis (“XRPD” or “Powder X-Ray Diffraction analysis, “PXRD” as used herein synonymously; see Example 5.1) provided an X-ray powder diffraction patterncomprising prominent signals or, in other words, reflections at 2-theta (2-0) angle values of at least one of or of all of 6.3, 15.4 and 16.9 degrees (with a deviation of + / -0.3 degree or of + / - 0.2 degree or preferably of 0.1 degree when measured at a temperature range of 20 °C to 30 °C, more specifically of 20 °C to 25 °C with Cu-Ka radiation having a wavelength of 0.15406 nm; for details of the analysis see Example 2.1).

[0082] In particular embodiments, the cocrystalline composition comprising (5) -6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-l) and gentisic acid of formula (11) showed prominent signals or reflections at 2-theta (2-0) angle values of at least one of or of all of 6.3, 11.3, 13.6, 15.4 and 16.9 degrees (with a deviation of + / - 0.3 degree or of + / - 0.2 degree or preferably 0.1 degree) when measured as described above. In further particular embodiments, the cocrystalline composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-l) and gentisic acid of formula (11) showed signals or reflections at 2-theta (2-0) angle values of substantially as listed in Table 2 (see Example 5.1) and as shown in the XRPD diffractogram as depicted in Fig. 4.

[0083] The cocrystalline composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-l) and gentisic acid of formula (11) has been further characterized by Differential Scanning Calorimetry (DSC) in which a corresponding sample was heated from 25 °C to about 300 °C at a rate of about 10 °C / min (for details see Example 2.3). The corresponding spectrum as depicted in Fig.

[0084] 6 showed a single sharp endothermic peak with an onset at about 159°C and with a peak at 160 °C corresponding to a melting point within the range of from about 159 °C to about 160 °C. Accordingly, in particular embodiments, the cocrystalline composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-l) and gentisic acid of formula (11) has a melting point selected within the range of from about 155 °C to about 165 °C, or from about 157 °C to about 163 °C, or from about 158 °C to about 162 °C, or from about 159 °C to about 161 °C.

[0085] The corresponding melting enthalpy (AH) was determined as -120 J / g (calculated as the area under curve of the endothermic peak and normalized tosample weight). Accordingly, in particular embodiments, the cocrystalline composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-I ) and gentisic acid of formula (11) has a (normalized) melting enthalpy (AH) selected within the range of from of about - 130 J / g to about -110 J / g or of from about - 125 J / g to about - 115 J / g or of about - 120 J / g- In a further particular embodiment, the further pharmaceutically acceptable compound comprised by the compositions of the present invention is nicotinamide. According to this particular embodiment, the present invention provides for a cocrystal comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-l) and nicotinamide of formula (111), preferably in a molar ratio selected within the range of from about 0.9: 1 to about 1.1: 1, such as from about 0.95: 1 to about 1.05:1, preferably in a molar ratio of about 1: 1.

[0086] The cocrystalline composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-l) and nicotinamide of formula (111) may be prepared as described in further detail below (see Examples 6 and 7) and has been characterized in the form of a white powder. An X-Ray Powder Diffraction analysis (see Example 8.1) provided an X-ray powder diffraction pattern comprising prominent signals or, in other words, reflections at 2-theta (2-Θ) angle values of at least one of or of all of 9.8, 16.9 and 24.1 degrees (with a deviation of + / - 0.3 degree or of + / - 0.2 degree or preferably of 0.1 degree when measured at a temperature range of 20 °C to 30 °C, more specifically of 20 °C to 25 °C with Cu-Kα radiation having a wavelength of 0.15406 nm; for details of the analysis see Example 2.1).

[0087] In particular embodiments, the cocrystalline composition comprising (5) -6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-l) and nicotinamide of formula (111) showed prominent signals or reflections at 2-theta (2-Θ) angle values of at least one of or of all of 9.8, 13.2, 16.9, 23.6 and 24.1 degrees (with a deviation of + / - 0.3 degree or of + / - 0.2 degree or preferably of 0.1 degree) when measured as described above. In further particular embodiments, the cocrystalline composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-1-carboxamide ((S)-SLS) of formula (S-l) and nicotinamide of formula (11) showedsignals or reflections at 2-theta (2-Θ) angle values of substantially as listed in Table 3 (see Example 8.1) and as shown in the XRPD diffractogram as depicted in Fig. 7.

[0088] The cocrystalline composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-l) and nicotinamide of formula (111) has been further characterized by Differential Scanning Calorimetry (DSC) in which a corresponding sample was heated from 25 °C to about 300 °C at a rate of about 10 °C / min (for details see Example 2.3). The corresponding spectrum as depicted in Fig.

[0089] 9 showed a single sharp endothermic peak with an onset at about 157 °C and with a peak at about 158.5 °C corresponding to a melting point within the range of from about 157 °C to about 159 °C. Accordingly, in particular embodiments, the cocrystalline composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-1-carboxamide ((S)-SLS) of formula (S-l) and nicotinamide of formula (111) has a melting point selected within the range of from about 153 °C to about 163 °C, or from about 155 °C to about 161 °C, or from about 156 °C to about 160 °C, or from about 157 °C to about 159 °C.

[0090] The corresponding melting enthalpy (ΔH) was determined as -160 J / g (calculated as the area under curve of the endothermic peak and normalized to sample weight). Accordingly, in particular embodiments, the cocrystalline composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-l) and nicotinamide of formula (111) has a (normalized) melting enthalpy (ΔH) selected within the range of from of about - 150 J / g to about -170 J / g or of from about - 155 J / g to about - 165 J / g or of about - 160 J / g. In a yet further particular embodiment, the further pharmaceutically acceptable compound comprised by the compositions of the present invention is oxalic acid. According to this particular embodiment, the present invention provides for a cocrystal comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-l) and oxalic acid of formula (IV), preferably in a molar ratio selected within the range of from about 0.9: 1 to about 1.1: 1, such as from about 0.95: 1 to about 1.05:1, preferably in a molar ratio of about 1: 1.The cocrystalline composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-l) and oxalic acid of formula (IV) may be prepared as described in further detail below (see Examples 9 and 10) and has been characterized in the form of a white powder. An X-Ray Powder Diffraction analysis (see Example 11.1) provided an X-ray powder diffraction pattern comprising prominent signals or, in other words, reflections at 2-theta (2-Θ) angle values of at least one of or of all of 5.0, 9.9 and 19.6 degrees (with a deviation of + / - 0.3 degree or of + / - 0.2 degree or preferably 0.1 of degree when measured at a temperature range of 20 °C to 30 °C, more specifically of 20 °C to 25 °C with Cu-Kα radiation having a wavelength of 0.15406 nm; for details of the analysis see Example 2.1).

[0091] In particular embodiments, the cocrystalline composition comprising (5) -6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-l) and oxalic acid of formula (II) showed prominent signals or reflections at 2-theta (2-Θ) angle values of at least one of or of all of 5.0, 9.9, 12.2, 19.6, and 25.0 degrees (with a deviation of + / - 0.3 degree or of + / - 0.2 degree or preferably of 0.1 degree) when measured as described above. In further particular embodiments, the cocrystalline composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-l) and oxalic acid of formula (IV) showed signals or reflections at 2-theta (2-Θ) angle values of substantially as listed in Table 4 (see Example 11.1) and as shown in the XRPD diffractogram as depicted in Fig. 10.

[0092] In yet a further particular embodiment, the further pharmaceutically acceptable compound comprised by the compositions of the present invention is glycolic acid. According to this particular embodiment, the present invention provides for a cocrystal comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-l) and glycolic acid of formula (V), preferably in a molar ratio selected within the range of from about 0.9: 1 to about 1.1: 1, such as from about 0.95: 1 to about 1.05:1, preferably in a molar ratio of about 1: 1.

[0093] The cocrystalline composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-l) and glycolic acid of formula (V) may be prepared as described in further detail below (see Examples 12 and 13) and has been characterized in the form of a white powder. An X-Ray Powder Diffractionanalysis (see Example 14.1) provided an X-ray powder diffraction pattern comprising prominent signals or, in other words, reflections at 2-theta (2-Θ) angle values of at least one of or of all of 10.5, 12.5, 17.6 and 23.1 degrees (with a deviation of + / - 0.3 degree or of + / - 0.2 degree or preferably of 0.1 degree when measured at a temperature range of 20 °C to 30 °C, more specifically of 20 °C to 25 °C with Cu-Kα radiation having a wavelength of 0.15406 nm; for details of the analysis see Example 2.1).

[0094] In further particular embodiments, the cocrystalline composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-1) and glycolic acid of formula (V) showed signals or reflections at 2-theta (2-Θ) angle values of substantially as listed in Table 5 (see Example 14.1) and as shown in the XRPD diffractogram as depicted in Fig. 13.

[0095] The cocrystalline composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-l) and glycolic acid of formula (V) has been further characterized by Differential Scanning Calorimetry (DSC) in which a corresponding sample was heated from 25 °C to about 300 °C at a rate of about 10 °C / min (for details see Example 2.3). The corresponding spectrum as depicted in Fig.

[0096] 15 showed a single sharp endothermic peak with an onset at about 137 °C and with a peak at about 138.5 °C corresponding to a melting point within the range of from about 137 °C to about 139 °C. Accordingly, in particular embodiments, the cocrystalline composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-1-carboxamide ((S)-SLS) of formula (S-l) and glycolic acid of formula (V) has a melting point selected within the range of from about 133 °C to about 143 °C, or from about 135 °C to about 141 °C, or from about 136 °C to about 140 °C, or from about 137 °C to about 139 °C.

[0097] The corresponding melting enthalpy (ΔH) was determined as -111 J / g (calculated as the area under curve of the endothermic peak and normalized to sample weight). Accordingly, in particular embodiments, the cocrystalline composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-l) and glycolic acid of formula (V) has a (normalized) melting enthalpy (ΔH) selected within the range of from of about - 100J / g to about -120 J / g or of from about - 105 J / g to about - 115 J / g or of about - 111 J / g- As described in Examples 5, 8, 11 and 14 below, the cocrystalline compositions comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid as described above do not comprise considerable amounts of water or organic solvents enclosed or incorporated in the crystal structure, except for residual amounts 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 cocrystalline material which may be, for example, associated to the surface of the cocrystalline material.

[0098] Furthermore, the cocrystalline compositions comprising (S)-6-Chloro-2, 3,4,9-tetrahydro-lH-carbazole-l-carboxamide and the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid as described above have been found to be non-hygroscopic or, in other words, not to attract or incorporate water under defined storage conditions. Accordingly, in specific embodiments, the cocrystalline compositions comprising (SJ-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide and the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid are solvent free and / or non-hygroscopic.

[0099] As mentioned above, the cocrystalline compositions comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid as described above, especially the cocrystalline compositions comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-1-carboxamide and the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid and nicotinamide as described above, have been found to be stable under defined storage conditions such as the storage conditions defined by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). More specifically, the cocrystallinecompositions comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and gentisic acid as well as the cocrystalline compositions comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and nicotinamide have been found stable under accelerated ICH conditions for at least 2 months when stored in a suitable climate chamber at 40 °C+ / - 2 °C at 75 % + / - 5 % relative humidity (RH) (see Example 15).

[0100] Accordingly, in specific embodiments, the present invention provides for cocrystalline compositions comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-1-carboxamide and the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid and nicotinamide, 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 2 months, wherein the term “stable” as used in this context means that at least about 90 wt.-% or at least about 95 wt.-% or at least about 98 wt.-% or at least about 99 wt.-% of the specific cocrystal remains in its specific crystalline form without degradation or conversion to another crystalline or amorphous form.

[0101] In further in specific embodiments, the present invention provides for cocrystalline compositions comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-1-carboxamide and the further pharmaceutically acceptable compound selected from the group consisting of oxalic acid and glycolic acid, 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 2 days (cocrystal of S-SLS and oxalic acid) or even at least 7 days (cocrystal of S-SLS and glycolic acid), wherein the term “stable” is used as described above.

[0102] Accordingly, the cocrystalline compositions comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid as described above, especially the cocrystalline compositions comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and the further pharmaceutically acceptable compound selected from the group consisting ofgentisic acid and nicotinamide are especially useful for pharmaceutical purposes and applications.

[0103] In a second aspect, the present invention provides for a pharmaceutical composition comprising the composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) and a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid in the form of a cocrystal according to the first aspect of the invention and at least one pharmaceutically acceptable excipient.

[0104] 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 the cocrystals comprising (S)-SLS and a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid as described herein as a composition or dosage form that may be manufactured according to generally accepted quality standards, stored at common storage conditions and administered conveniently to subjects in need thereof, such as human patients. In this context, the term “pharmaceutically acceptable” also means that the compound or mixture it refers to is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for human pharmaceutical use as already mentioned above.

[0105] The at least one pharmaceutically acceptable excipient, which is comprised in the pharmaceutical composition of the present invention, may, for example, be selected from the group of excipients useful for the manufacture of a solid dosage form such as a solid dosage form for oral administration comprising, but not limited to fillers, binders, disintegrants, lubricants, glidants, and combinations thereof as known to those of skill in the art and as described, for example, in current pharmacopoeias, such as the European Pharmacopoeia or the United States Pharmacopeia. In some embodiments, the at least one pharmaceutically acceptable excipient is selected from the group consisting of one or more fillers, binders, disintegrants and lubricants. In exemplary embodiments, the at least one pharmaceutically acceptable excipient is selected from the group consisting ofmicrocrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and combinations thereof.

[0106] In some embodiments, the pharmaceutical compositions according to this aspect of the invention may comprise, in addition to (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamid, oxalic acid and glycolic acid in the form of a cocrystal, preferably, (S)-6-Chloro-2, 3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((SJ-SLS) and a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid and nicotinamide, 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 (SJ-SLS, based on the weight of the pharmaceutical composition. The term “solid-state form” as used in this context is to be understood as a solid form of (SJ-SLS other than the cocrystals described herein, such as (SJ-SLS in amorphous or crystalline form.

[0107] In some embodiments, the pharmaceutical compositions of this aspect of the invention may comprise cocrystals of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) and a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamid, oxalic acid and glycolic acid, preferably, (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((SJ-SLS) and a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid and nicotinamide, especially in anhydrous and non-solvated form may 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 may comprise but are not limited to tablets, capsules, granules and oral films. More preferably, the oral solid dosage form may be a tablet or a capsule, such as a soft capsule or a hard capsule. In the case of a hard capsule, this may be filled with a powder mixture or with granules or pellets comprising the cocrystals of (SJ-SLS and a further pharmaceutically acceptable compound as described herein. Optionally, the granules, the tablet or the capsule may be coated.

[0108] The pharmaceutical compositions of the present invention as defined in any one 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 or capsule filling and packaging. For example, the tablet may be prepared by mixing a cocrystalline form of (SJ-SLS and a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamid, oxalic acid and glycolic acid, preferably, (5)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((Sj-SLS) and a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid and nicotinamide of the present invention or the pharmaceutical composition comprising the same as defined in any one of the above-described aspects and their corresponding embodiments with at least one excipient such as fillers, binders, disintegrants, lubricants, glidants or combinations thereof. Optionally, a granulation step such as a dry or wet granulation step may be performed before compression. The tablet cores may be additionally film-coated.

[0109] In particular embodiments, the pharmaceutical compositions according to this aspect of the invention comprising the cocrystals of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) and a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamid, oxalic acid and glycolic acid according to the first aspect of the invention as described above and at least one pharmaceutically acceptable excipient comprise the cocrystals (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) and a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamid, oxalic acid and glycolic acid or at least the (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) comprised therein in a predetermined and / or pharmaceutically effective amount, wherein the term “pharmaceutically effective amount” as used herein means that such amount which, when administered to a warm-blooded animal or human for treating or preventing a disease or medical condition, is sufficient to effect such treatment or prevention for the disease or medical condition.

[0110] In some embodiments, the predetermined and / or effective amount of the preferably anhydrous and non-solvated cocrystals of (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) and a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalicacid and glycolic acid of the present invention or the pharmaceutical composition comprising the same as defined in any one of the above-described aspects and their corresponding embodiments may be selected within 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 mg to about 200 mg per single dose amount, calculated as anhydrous and preferably non-solvated (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide.

[0111] In a third aspect, the present invention provides for the compositions comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) and a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid in the form of a cocrystal according to the first aspect of the invention as described above for use as a medicament, preferably as a medicament for oral administration or, in other words, in an oral dosage form.

[0112] In this context, the present invention also relates to the use of the compositions comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) and a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid in the form of a cocrystal according to the first aspect of the invention in the manufacture of a medicament. Furthermore, in this context the present invention also relates to a method of using the compositions comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) and a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid in the form of a cocrystal according to the first aspect of the invention as a medicament or for the treatment or prevention of a medical condition, preferably a medical condition of a warm-blooded animal or human, specifically of a human.

[0113] In this context, the present invention further relates to a method for the treatment or prevention of a disease or medical condition in a warm blooded animal or a human, specifically in a human, the method comprising the administration of compositions comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((SJ-SLS) and a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid in the form of a cocrystal according to the first aspect of the invention, specifically wherein the composition is administered orally.

[0114] In this context, the present invention further relates to a kit comprising a pharmaceutical composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((SJ-SLS) and a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid in the form of a cocrystal according to the first aspect of the invention, specifically in a solid dosage form such as an oral dosage form suitable for oral administration and instructions for use of the composition.

[0115] In particular embodiments of this third aspect of the invention, a medical condition or disease that may be treated or prevented may be a medical condition or disease associated with or mediated by a sirtuin, specifically a medical condition or disease associated with or mediated by at least one sirtuin selected from the group of sirtuins selected from SIRT1, SIRT2, SIRT3 and SIRT7, preferably at least one sirtuin selected from SIRT1 and SIRT2. Accordingly, the present invention also provides for the compositions comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((SJ-SLS) and a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid in the form of a cocrystal according to the first aspect of the invention as described above or the pharmaceutical composition according to the second aspect of the invention for use in the prevention or treatment of a disease or condition associated with or mediated by a sirtuin, for example SIRT1 and / or SIRT2, specifically SIRT1.

[0116] In further particular embodiments, a disease or medical condition associated with or mediated by a sirtuin, for example by at least one sirtuin selected from SIRT1, SIRT2, SIRT3 and SIRT7 as referred to above, that may be treated or prevented by administration of the compounds or compositions of the present invention may be selected, for example, from cancer, metabolic diseases such as metabolic syndrome, type 1 diabetes or type II diabetes, obesity, dislipidemia, hyperlipidemia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, neurodegenerativeconditions that are 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 1 (SCA1), spinocerebellar ataxia 2 (SCA2), Machado-Joseph disease (MJD; SCA3), spinocerebellar ataxia 6 (SCA6), spinocerebellar ataxia 7 (SCA7), and spinocerebellar ataxia 12 (SCA12), specifically Huntington’s disease.

[0117] In a fourth aspect, the present invention provides for the use of composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) and a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid, preferably selected from gentisic acid or nicotinamide, in the form of a cocrystal according to the first aspect of the invention for the preparation of a pharmaceutical composition according to the second aspect of the invention.

[0118] In a fifth aspect, the present invention provides for a method for the preparation of a composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) of formula (S-I)

[0119]

[0120] Cl(S-l)

[0121] and a further pharmaceutically acceptable compound, wherein the composition is in the form of a cocrystal, and wherein the pharmaceutically acceptable compound is selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid according to the first aspect of the invention, the method comprising the steps of:

[0122] a) Providing (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) in solid form;

[0123] b) Providing a pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid; andc) Contacting (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l- carboxamide ((S)-SLS) in solid form as provided in step a) and the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid as provided in step b) in the presence of an organic solvent to form a mixture comprising the composition comprising (S)-6-Chloro-2, 3,4,9- tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-l) and a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid in the form of a cocrystal.

[0124] In particular embodiments of the method according to this aspect of the invention, according to step a) (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) is provided in solid form such as in amorphous form and / or in crystalline form, preferably in crystalline form. In specific embodiments of the present method, (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) is provided, according to step a), in the form of a crystalline polymorph of (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide having an X-ray powder diffraction pattern comprising 2-theta angle values (with a deviation of + / - 0.2 degree) of 16.4, 19.8, 21.9 and 32.6 degrees (polymorph X), more specifically having an X-ray powder diffraction pattern comprising 2-theta angle values (with a deviation of + / - 0.2 degree) of at least one of or of all of 14.8, 16.4, 19.8, 21.9, 24.9, 30.4 and 32.6 degrees. Such crystalline polymorph of (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide may further be characterized by having a melting point (melting onset) of about 185 °C and / or a melting enthalpy (ΔH) within the range of from about -104 J / g to about -109 J / g or from about -105 J / g to about -108 J / g and / or substantially as described in Example 2 below.

[0125] In further particular embodiments, however, further crystalline polymorphs of S-SLS may also be used as a starting material for the preparation of the cocrystals comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-l) and a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid according to the present invention.In some embodiments, (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((SJ-SLS) in solid form, preferably in crystalline form to be used as a starting material for the preparation of the cocrystals comprising (S)-6-Chloro- 2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-I) and a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid according to the present invention may be prepared as described in Example 1 below by kinetic resolution of racemic 6-Chloro- 2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (rac-SLS) of formula (I) by cocrystallization with, e.g. ((27?, 37?)-(-)-Di-O-4-toluoyl-L-tartaric acid; CAS Nr. 32634-66-5; (-)-DTTA).

[0126] According to step b) of the method of this aspect of the present invention, the chosen pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid is provided, preferably in the form of solid, especially in the form of a crystalline solid. The molar ratio in which (S)-SLS and the one further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid to be provided according to steps a) and b) of the method of the present invention may be varied within a broad range and may range, in particular embodiments, from about 0.5 or from about 0.75 to about 5 molar equivalents of the chosen further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid with regard to the amount of (SJ-SLS. In preferred embodiments, however, the pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid is provided in at least equimolar amounts when compared to the molar amount of (S)-SLS as provided in step b), for example in a ratio from 1 : 1 to about 5 : 1 or from about 1: 1 to about 1 : 4 or to about 1 : 3 or to about 1 : 2.

[0127] According to step c) of the method of this aspect of the invention, (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) is provided in solid, preferably in crystalline form as provided in step a) and the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid as provided in step b) are contacted in thepresence of an organic solvent to form a mixture comprising the composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-l) and the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid in the form of a cocrystal.

[0128] The term “contacting” as used herein means that the respective compounds are brought into close contact with each other in solution or in solid state, preferably in solution, specifically that the compounds are mixed by methods as known to those of skill in the art using standard mixing equipment such as mechanical or magnetic stirrers or ultrasonic mixers or mixer mills. In some embodiments, the term “contacting comprises techniques known to those of skill in the art as “wet grinding”, “solvent drop grinding” (SDG), “liquid assisted grinding” (LAG) or “slurrying” as, for example, described in M. Solares- Briones et al., Pharmaceutics 2021, 13(6), 790.

[0129] According to step c) of the present method (S)-SLS and the selected further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid are contacted or mixed in the presence of an organic solvent. In particular embodiments, (S)-SLS and the selected further pharmaceutically acceptable compound selected from the group consisting of gentisic acid may be mixed in solid form such as in the form of crystals before the organic solvent is added. In alternative embodiments, however, (S)-SLS and the selected further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid in solid or crystalline form may be added to the organic solvent and contacted or mixed in the organic solvent.

[0130] The organic solvent that may be used according to step c) of the method according to this aspect of the invention may be selected from a broad range of suitable organic solvents, preferably of organic solvents or mixtures of such solvents in which preferably (S)-SLS is not completely soluble at room temperature (about 20 °C to about 25 °C, preferably about 22 °C to 23°C), specifically in which (S)-SLS is not completely soluble in a volume of such organic solvent of about 10 times the volume of (S)-SLS, for example acetonitrile, a C1- to C6-alcohol (i.e. a branched or unbranchedalcohol with one to six carbon atoms) for example methanol, ethanol or isopropyl alcohol, an ester of a C1- to C6-alcohol with an C1- to C6-carboxylic acid, for example ethyl acetate or isobutyl acetate, a C3- to C8-ketone, for example methyl isobutyl ketone, a C3- to C6-ether, for example methyl tert-butyl ether or tetrahydrofurane. In some embodiments, specifically tetrahydrofurane may be used as a suitable solvent according to step c) of the present process, especially in cases in which (S)-SLS is contacted with the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid by wet grinding. In further particular embodiments the term “organic solvent” comprises single organic solvents or mixtures of two or more suitable organic solvents. In preferred embodiments, the organic solvent to be used according to step c) (as a single solvent or in the form of a mixture of organic solvents) is selected from the group consisting of acetonitrile, isopropanol, ethyl acetate, isobutyl acetate and methyl isobutyl ketone, preferably acetonitrile or isobutyl acetate, especially acetonitrile.

[0131] In further embodiments, the amount of organic solvent or mixture of organic solvents to be used according to step c) may be varied within a broad range, for example from about 1 mL to about 10 mL per mmol of (S)-SLS, or from about 1.5 mL to about 8 mL per mmol of (S)-SLS, or 2 mL to about 6 mL per mmol of (S)-SLS.

[0132] The resulting mixture of (S)-SLS, the selected further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid and the chosen organic solvent or mixture of organic solvents, which, in preferred embodiments, is in the form of a suspension, may then be stirred at room temperature during which the composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide and the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid in the form of a cocrystal is formed.

[0133] According to optional process step d) the resulting composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide and the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid in the form of a cocrystal may then beseparated from the organic solvent or mixture of organic solvents. Such separation may be performed using methods known to those of skill in the art such as filtration, centrifugation, decantation or others to provide a crude product which may then be dried, if necessary, under reduced pressure to remove residual organic solvent.

[0134] The cocrystalline compositions comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic according to the first aspect of the invention, in in vitro experiments as described in Example 16 below have shown a comparable affinity of the (SJ-SLS comprised therein or used in the form of the cocrystals of the present invention to that of (S)-SLS used in pure form or, in other words, in the absence of the chosen further pharmaceutically acceptable compound.

[0135] The cocrystalline compositions comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic according to the first aspect of the invention, surprisingly, in in vivo experiments as described in Examples 17 and 18 below have been found to show a different pharmacokinetic profile which is assumed to be based on a modified metabolic profile of (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide when administered in the form of the cocrystalline compositions of the present invention compared to the metabolic profile of (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide when administered in the form of a pure compound, or, in other words, without the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid. More specifically, the formation of a key metabolite of (S)-6-Chloro-2, 3,4,9-tetrahydro-lH-carbazole-l-carboxamide resulting from oxidative deamination of the carboxamide substituent to the corresponding carboxylic acid derivative has been found to be delayed significantly when (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-1-carboxamide in the form of the cocrystals of (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide and the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid andglycolic acid after oral or intravenous administration to rats when compared to the corresponding administration of (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide in pure form (without the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid).

[0136] As a result, especially after oral (p.o.) administration of (S)-SLS in the form of a cocrystal according to the present invention comprising a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid an advantageous pharmacokinetic profile of (S)-SLS was observed, for example, showing a significantly prolonged half-life (T1 / 2) and bioavailability (BA) of (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS).

[0137] It has been shown, particularly in rat plasma, that cocrystals comprising (S)-SLS of formula (S-l), respectively the cocrystalline composition of (S)-SLS, according to the invention, has an improved inhibition of SIRT, particularly SIRT1 and SIRT2, and increased systemic exposure than the Selisistat racemate consisting of (S)-SLS and (R)-SLS. For this comparison, the Selisistat racemate is in a crystalline but not in a cocrystalline form.

[0138] Preferably, cocrystals comprising (S)-SLS, respectively the cocrystalline composition of (S)-SLS, according to the invention, has a higher efficacy than the Selisistat racemate consisting of (S)-SLS and (R)-SLS.

[0139] The IC50 for in vitro SIRT inhibition of the cocrystalline composition of (S)-SLS according to the invention is preferably 1.3 - 4.4, particularly 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, times lower than the in vitro SIRT inhibition of the Selisistat Racemate.

[0140] Particularly preferred, the IC50 for in vitro SIRT1 inhibition of the cocrystalline composition of (S)-SLS is 1.3 – 4.4, particularly 1.3, 2.0 or 4.4, times lower than the in vitro SIRT1 inhibition of the Selisistat Racemate.Determined values for IC50 [μM] for SIRT1 for the Selisistat racemate are 0.48, 0.93 and 0.63.

[0141] A determined value for IC50 [μM] for SIRT1 for a cocrystalline composition comprising Selisistat and gentisic acid is 0.24.

[0142] Determined values for IC50 [μM] for SIRT1 for a cocrystalline composition comprising Selisistat and nicotinamide are 0.21 and 0.41.

[0143] A determined value for IC50 [μM] for SIRT1 for a cocrystalline composition comprising Selisistat and oxalic acid is 0.24.

[0144] A determined value for IC50 [μM] for SIRT1 for a cocrystalline composition comprising Selisistat and gycolic acid is 0.36.

[0145] Preferably, the IC50 for in vitro SIRT2 inhibition of the cocrystalline composition of (S)-SLS is 1.8 – 4.4, particularly 1.8, 2, 3.6 or 4.4, times lower than the in vitro SIRT2 inhibition of the Selisistat Racemate.

[0146] The determined values for IC50 [μM] for SIRT2 for the Selisistat racemate are 2.7, 3.8 and 3.1.

[0147] A determined value for IC50 [μM] for SIRT2 for a cocrystalline composition comprising Selisistat and gentisic acid is 1.4.

[0148] Determined values for IC50 [μM] for SIRT2 for a cocrystalline composition comprising Selisistat and nicotinamide are 1.5 and 0.86.

[0149] A determined value for IC50 [μM] for SIRT2 for a cocrystalline composition comprising Selisistat and oxalic acid is 1.3.

[0150] A determined value for IC50 [μM] for SIRT2 for a cocrystalline composition comprising Selisistat and gycolic acid is 1.2.

[0151] The half maximal inhibitory concentration (IC50) is a measure of the potency of a substance in inhibiting a specific biological or biochemical function, indicating how much of a particular inhibitory substance is needed to inhibit in vitro a given biological process or biological component by 50%. Therefore, a lower value for ICso indicates a higher efficacy of a drug.A composition can be preferred, wherein the cocrystalline composition of (S)-SLS has an improved inhibition of SIRT, particularly SIRT1 and SIRT2, than a Selisistat racemate.

[0152] Further, a composition can be preferred, wherein the cocrystalline composition of (SJ-SLS has an increased systemic exposure than a Selisistat racemate.

[0153] A composition can be preferred, wherein the cocrystalline composition of (S)-SLS has an improved inhibition of SIRT, particularly SIRT1 and SIRT2, and increased systemic exposure than a Selisistat racemate.

[0154] A composition can be preferred, wherein the cocrystalline composition of (S)-SLS has an improved inhibition of SIRT, particularly SIRT1 and SIRT2, or increased systemic exposure than a Selisistat racemate.

[0155] A composition can be preferred, wherein the cocrystalline composition of (S)-SLS has an improved inhibition of SIRT, particularly SIRT1 and SIRT2, and / or increased systemic exposure than a Selisistat racemate.

[0156] A composition can be preferred, wherein the cocrystalline composition of (S)-SLS has a higher efficacy than a Selisistat racemate.

[0157] Said cocrystalline composition comprises a further pharmaceutically acceptable compound, which is selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid.

[0158] Further, a pharmaceutical composition with a cocrystalline composition of (S)-SLS and the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid and a further pharmaceutically acceptable excipient is preferred, wherein the cocrystalline composition has an improved inhibition of SIRT, particularly SIRT1 and SIRT2, than a Selisistat racemate.

[0159] Further, a pharmaceutical composition with a cocrystalline composition of (S)-SLS and the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid and a further pharmaceutically acceptable excipient is preferred, wherein the cocrystallinecomposition has an improved inhibition of SIRT, particularly SIRT1 and SIRT2, and / or increased systemic exposure than a Selisistat racemate.

[0160] Further, a pharmaceutical composition with a cocrystalline composition of (S)-SLS and the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid and a further pharmaceutically acceptable excipient is preferred, wherein the cocrystalline composition has a higher efficacy than a Selisistat racemate.

[0161] Fig.16 depicts a graph showing measurements of the mean concentration (ng / mL) of orally administered Selisistat racemate and Selisistat cocrystals comprising (SJ-Selisistat over a timespan of ten hours in male rat plasma. Hereby, Selisistat racemate is present in a ratio of approximately 50:50 of (SJ- Selisistat and (RJ- Selisistat.

[0162] Selisistat racemate is referred to as “Selisistat” in the graph. The given dose for all groups was 10 mg / kg, independent of the molecular weight of the individual compounds. The administered cocrystalline compositions comprise (S) -Selisistat and gentisic acid, (S) -Selisistat and glycolic acid, (S) -Selisistat and Imidazole, (S) -Selisistat and nictotinamide and (S) -Selisistat and oxalic acid. It can be seen, that the cocrystalline compositions comprising (S) -Selisistat exhibit a higher mean concentration after a given timespan than the Selisistat racemate.

[0163] The effects observed in in-vitro and in in-vivo studies suggest an improved efficacy of cocrystalline compositions of (S)-SLS than the Selisistat racemate.

[0164] The following is a list of numbered items 1 to 41 which are embodiments comprised by the present invention:

[0165] 1. A composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l- carboxamide ((SJ-SLS) of formula (S-l)

[0166]

[0167] and a further pharmaceutically acceptable compound,wherein the composition is in the form of a cocrystal, and

[0168] wherein the further pharmaceutically acceptable compound is selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid.

[0169] 2. The composition according to item 1, wherein the further pharmaceutically acceptable compound is selected from the group consisting of gentisic acid, nicotinamide and glycolic acid.

[0170] 3. The composition according to item 1 or 2, wherein the further pharmaceutically acceptable compound is selected from the group consisting of gentisic acid and nicotinamide.

[0171] 4. The composition according to any one of items 1 to 3, wherein the further pharmaceutically acceptable compound is gentisic acid.

[0172] 5. The composition according to item 4, wherein the cocrystalline composition has an X-ray powder diffraction pattern comprising 2-theta angle values (with a deviation of + / - 0.3 degree) of at least one of 6.3, 15.4 and 16.9 degrees, or of at least one of 6.3, 11.3, 15.4 and 16.9 degrees.

[0173] 6. The composition according to item 4 or 5, wherein the cocrystalline composition has a melting point within the range of from about 159 °C to about 160 °C.

[0174] 7. The composition according to any one of items 4 to 6, wherein the cocrystalline composition has a (normalized) melting enthalpy (AH) selected within the range of from of about - 130 J / g to about -110 J / g or of from about – 125 J / g to about – 115 J / g or of about - 120 J / g.

[0175] 8. The composition according to any one of items 1 to 3, wherein the further pharmaceutically acceptable compound is nicotinamide.

[0176] 9. The composition according to item 8, wherein the cocrystalline composition has an X-ray powder diffraction pattern comprising 2-theta angle values (with a deviation of + / - 0.2 degree) of at least one of 9.8, 16.9 and 24.1 degrees, or of at least one of 9.8, 13.2, 16.9, 23.6 and 24.1 degrees.The composition according to item 8 or 9, wherein the cocrystalline composition has a melting point within the range of from about 157 °C to about 159 °C.

[0177] The composition according to any one of items 8 to 10, wherein the cocrystalline composition has a (normalized) melting enthalpy (AH) selected within the range of from of about - 170 J / g to about -150 J / g or of from about - 165 J / g to about - 155 J / g or of about - 160 J / g.

[0178] The composition according to item 1, wherein the further pharmaceutically acceptable compound is oxalic acid.

[0179] The composition according to item 12, wherein the cocrystalline composition has an X-ray powder diffraction pattern comprising 2-theta angle values (with a deviation of + / - 0.3 degree) of at least one of 5.0, 9.9 and 19.6 degrees, or of at least one of 5.0, 9.9, 12.2, 19.6, and 25.0 degrees.

[0180] The composition according to any one of items 1 or 2, wherein the further pharmaceutically acceptable compound is glycolic acid.

[0181] The composition according to item 14, wherein the cocrystalline composition has an X-ray powder diffraction pattern comprising 2-theta angle values (with a deviation of + / - 0.3 degree) of at least one of 10.5, 12.5, 17.6 and 23.1 degrees.

[0182] The composition according to item 14 or 15, wherein the cocrystalline composition has a melting point within the range of from about 137 °C to about 139 °C.

[0183] The composition according to any one of items 14 to 16, wherein the cocrystalline composition has a (normalized) melting enthalpy (AH) selected within the range of from of about - 120 J / g to about -100 J / g or of from about – 115 J / g to about – 105 J / g or of about - 111 J / g.

[0184] The composition according to any one of the preceding items, wherein the composition comprises (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-I) and the further pharmaceuticallyacceptable compound in a molar ratio selected within the range of from about 0.9: 1 to about 1.1: 1, preferably in a molar ratio of about 1: 1.

[0185] 19. The composition according to any one of the preceding items, wherein the composition is solvent- free and / or non-hygroscopic.

[0186] 20. The composition according to any one of items 3 to 11, wherein the composition 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 2 months.

[0187] 21. The composition according to item 12 or 13, wherein the composition 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 2 days.

[0188] 22. The composition according to any one of items 14 to 17, wherein the composition 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.

[0189] 23. A pharmaceutical composition comprising the composition comprising (5) -6- Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) and a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid in the form of a cocrystal according to any one of items 1 to 22 and at least one pharmaceutically acceptable excipient.

[0190] 24. The pharmaceutical composition according to item 23, 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 pharmaceutical composition.

[0191] 25. The pharmaceutical composition according to item 23 or 24, wherein the pharmaceutical composition is a solid dosage form for oral administration, preferably a tablet, a capsule or an oral film.

[0192] 26. The composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l- carboxamide ((S)-SLS) and a further pharmaceutically acceptable compoundin the form of a cocrystal according to any one of items 1 to 22 or the pharmaceutical composition according to any one of items 23 to 25 for use as a medicament.

[0193] 27. The composition for use according to item 26, for use in the prevention or treatment of a disease or condition associated with a sirtuin.

[0194] 28 The composition for use according to item 27, wherein the sirtuin is selected from SIRT1, SIRT2, SIRT3 and SIRT7.

[0195] 29. The composition for use according to item 27or 28, wherein the sirtuin is selected from SIRT1 and SIRT2.

[0196] 30. The composition for use according to any one of items 26 to 29, for use in the prevention or treatment of a disease or medical condition associated with or mediated by a sirtuin, for example by at least one sirtuin selected from SIRT1, SIRT2, SIRT3 and SIRT7, for example cancer, metabolic diseases such as metabolic syndrome, type 1 diabetes or type II diabetes, obesity, dislipidemia, hyperlipidemia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, neurodegenerative conditions that are 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 1 (SCA1), spinocerebellar ataxia 2 (SCA2), Machado-Joseph disease (MJD; SCA3), spinocerebellar ataxia 6 (SCA6), spinocerebellar ataxia 7 (SCA7), and spinocerebellar ataxia 12 (SCA12).

[0197] 31. The composition for use according to any one of items 23 to 30, wherein the composition is for oral administration.

[0198] 32. Use of composition comprising (SJ-6-Chloro-2,3,4,9-tetrahydro-lH- carbazole-l-carboxamide ((SJ-SLSJ and at least one pharmaceutically acceptable compound in the form of a cocrystal according to any one of items 1 to 22 for the preparation of a pharmaceutical composition.

[0199] 33. A method for the preparation of a composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) of formula (S-I)

[0200]

[0201] and a further pharmaceutically acceptable compound,

[0202] wherein the composition is in the form of a cocrystal, and

[0203] wherein the further pharmaceutically acceptable compound is selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid according to any one of items 1 to 22, the method comprising the steps of: a] Providing (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l- carboxamide ((SJ-SLS) in solid form;

[0204] b] Providing a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid; and

[0205] c) Contacting (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) in solid form and the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid in the presence of an organic solvent to form a mixture comprising the composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l- carboxamide ((S)-SLS) of formula (S-I) and the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid in the form of a cocrystal.

[0206] The method according to item 33, wherein according to step a) (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((SJ-SLS) is provided in crystalline form.

[0207] The method according to item 33 or 34, wherein according to step a) (SJ-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((SJ-SLS) is provided in the form of a polymorph having an X-ray powder diffraction patterncomprising 2-theta angle values (with a deviation of + / - 0.2 degree) of 16.4, 19.8, 21.9 and 32.6 degrees (polymorph X).

[0208] 36. The method according to any one of items 33 to 35, wherein according to step a) (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) is provided in the form of a polymorph having an X-ray powder diffraction pattern comprising 2-theta angle values (with a deviation of + / - 0.2 degree) of 14.8. 16.4. 19.8, 21.9, 24.9, 30.4 and 32.6 degrees (polymorph X).

[0209] 37. The method according to any one of items 33 to 36, wherein according to step a) (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) is provided in the form of a polymorph having a melting point (melting onset) of about 185 °C (polymorph X).

[0210] 38. The method according to any one of items 33 to 37, wherein according to step a) (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) is provided in the form of a polymorph having a melting enthalpy (ΔH) within the range of from about -104 J / g to about -109 J / g or from about -105 J / g to about -108 J / g.

[0211] 39. The method according to any one of items 33 to 38, wherein the organic solvent used according to step c) is selected from the group consisting of acetonitrile, isopropanol, ethyl acetate, isobutyl acetate and methyl isobutyl ketone.

[0212] 40. The method according to any one of items 33 to 39, wherein the organic solvent used according to step c) is selected from acetonitrile or isobutyl acetate, specifically wherein the organic solvent used according to step c) is acetonitrile.

[0213] 41. The method according to any one of items 33 to 40, the method further comprising the step of

[0214] d) Separating the composition comprising (S)-6-Chloro-2, 3,4,9- tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) of formula (S-l) and a further pharmaceutically acceptable compound selected from thegroup consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid in the form of a cocrystal from the organic solvent.

[0215] The following examples serve to illustrate the invention, however, should not be understood as restricting the scope of the invention in any respect.

[0216] EXAMPLES

[0217] Example 1: Preparation of (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) in crystalline form (polymorph X) by resolution of rac-Selisistat (rac-SLS) using (-)- di-0,0'-para-toluoyl-tartaric acid ((-)-DTTA) 1.1 Cocrystal formation of (S)-Selisistat ((SJ-SLS) with (-)-DTTA

[0218] 100.0 g (402.0 mmol) rac-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (rac-SLS) and 400 mL isobutyl acetate (2 -methylpropyl ethanoate; CAS-Nr. 110-19-0) were added to a reactor having a volume of 2 L equipped with a mechanical stirrer, a thermometer and a condenser. To the resulting white suspension was added a solution of 77.7 g (201.0 mmol) (-)-DTTA ((27?, 37?)-(-)-Di-O-4-toluoyl-L-tartaric acid; CAS Nr. 32634-66-5) in 188 mL of acetonitrile followed by 660 mL of isobutyl acetate. The suspension was heated under stirring to a temperature of 92 °C at which the formation of a clear yellowish solution was observed.

[0219] Following that, the solution was slowly cooled to room temperature (approx.

[0220] 22 °C) ata cooling rate of about 0.3 °C / min. At an internal temperature of the solution of 80 °C some seed crystals of a cocrystal of (S)-SLS with (-)-DTTA with an enantiomeric excess of 99 % ee were added. After completion of the cooling process the resulting suspension was stirred for 1 h at room temperature and then filtered with a sintered funnel (porosity 3). The resulting solid was washed four times with 200 mL (each) of a mixture of isobutyl acetate and acetonitrile (85:15 (v / v)) to afford 113 g of a crude product comprising 70 g of solid cocrystals of (S)-6-Chloro-2, 3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) with (-)-DTTA (as estimated by1H-NMR) in the form of white crystals having an enantiomeric excess of 84.5 % ee containing residual amounts of isobutyl ethanoate and acetonitrile.

[0221] 1.2 Recrystallization of the cocrystals of (SJ-SLS with (-)-DTTA

[0222] 112 g of the crude product comprising 70 g of the solid cocrystals of (S)-SLS with (-)-DTTA as prepared under step 1.1 above was filled into a 2 L reaction vessel equipped with a mechanical stirrer, a thermometer and a condenser together with 1200 mL of acetonitrile. The resulting white suspension was heated to a temperature of 80 °C at which the formation of a clear solution was observed.

[0223] Following that, the solution was slowly cooled to room temperature (approx.

[0224] 22 °C) ata cooling rate of about 0.3 °C / min. At an internal temperature of the solution of 75 °C some seed crystals of a cocrystal of (S)-SLS with (-)-DTTA with an enantiomeric excess of 99 % ee were added. After completion of the cooling process the resulting suspension was stirred for 1 h at room temperature and then filtered with a sintered funnel (porosity 3). The resulting solid was washed two times with 144 mL (each) of acetonitrile and dried at a pressure of approx. 1 mbar at room temperature for approx. 12 h to afford 46.1 g of cocrystals of (S)-SLS with (-)-DTTA in the form of white crystals having an enantiomeric excess of 99.3 % ee.

[0225] 1.3 Dissociation of cocrystals of (SJ-SLS with (-)-DTTA

[0226] 45.0 g (102 mmol) of the cocrystals of (S)-SLS with (-)-DTTA were charged to a 2 L reaction vessel equipped with a mechanical stirrer together with 900 mL of water to afford a white emulsion. To the emulsion 235 ml of a 0.86 M aqueous solution of sodium hydrogen carbonate (NaHCO3) (comprising 2 equivalents of NaHCO3 with regard to the amount of cocrystals of (S)-SLS with (-)-DTTA) were added and the resulting mixture was stirred at room temperature for 2 h to provide a white suspension. The suspension was filtered with a sintered funnel (porosity 3) and the resulting filter cake was washed 5 times with 180 mL of water (each).

[0227] The resulting solid was dried at a pressure of approx. 1 mbar at room temperature for approx. 12 h to afford 24.5 g of (S)-Selisistat ((S)-SLS) in the form of white crystals having an enantiomeric excess of 99.3 % ee.1.4 Recovery of (-)-DTTA

[0228] 1.8 L of the aqueous phases received from the filtration step as well as subsequent washing as described under item 1.3 above were provided in a reaction vessel with a volume of 2 L and being equipped with a mechanical stirrer. 155 mL of a IM aqueous solution of hydrochloric acid were added to provide a mixture with a pH-value of 3 which was stirred at room temperature for a period of 1 h to afford a white suspension. The suspension was slowly filtered with a sintered funnel (porosity 3) and the resulting filter cake was wished twice with 180 mL of water (each) and dried under vacuum (approx. 1 mbar) for about 12 h to afford 5.6 g (-)-DTTA in the form of a white solid.

[0229] Example 2: Characterization of (S)-Selisistat in crystalline form (polymorph X) (S)-Selisistat in crystalline form having an enantiomeric purity of 99.3 % ee as prepared according to Example 1 above was characterized by X-Ray powder diffraction (XRPD), 1H-NMR, Differential Scanning calorimetry (DSC) and chiral High-Pressure Liquid Chromatography (chiral HPLC).

[0230] 2.1 XPRD analysis of (S)-Selisistat in crystalline form

[0231] XPRD analysis of (S)-Selisistat in crystalline form was performed at ambient conditions on a PANalytical X'Pert PRO 0-0 diffractometer of 240 mm of radius in reflection geometry, equipped with Cu Ka radiation and a PIXcel detector, operated at 45 kV and 40 mA. The crystalline sample was mounted on a zero-background silicon holder and allowed to spin at 0.25 rev / s during the data collection. The measurement angular range was 3.0-40.0° (20) with a step size of 0.013°. The scanning speed was 0.082 (40.80 s / step).

[0232] The XPRD pattern measured for (S)-Selisistat in crystalline form (polymorph X) accordingly showed good crystallinity (see Fig. 1) and peaks as listed in Table 1 below:Table 1:

[0233] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]

[0234] 11.5 7.70 2

[0235] 13.1 6.75 2

[0236] 14.8 6.00 19

[0237] 16.4 5.41 54

[0238] 18.5 4.78 2

[0239] 19.8 4.49 25

[0240] 20.8 4.27 8

[0241] 21.9 4.06 100

[0242] 22.4 3.97 7

[0243] 23.1 3.84 6

[0244] 24.3 3.66 8

[0245] 24.9 3.57 16

[0246] 25.0 3.57 5

[0247] 27.2 3.27 9

[0248] 27.7 3.22 15

[0249] 28.8 3.09 8

[0250] 29.0 3.07 1

[0251] 29.3 3.04 9

[0252] 29.8 2.99 1

[0253] 30.4 2.94 17

[0254] 31.2 2.86 1

[0255] 32.6 2.74 25

[0256] 33.6 2.67 1

[0257] 33.9 2.64 2

[0258] 34.5 2.59 6

[0259] 35.6 2.52 1

[0260] 36.2 2.48 1

[0261] 36.7 2.45 1

[0262]

[0263] 38.3 2.35 1

[0264] 2.21H-NMR analysis of (S)-Selisistat in crystalline form

[0265] A1H-Nuclear magnetic resonance spectrum of (S)-Selisistat in crystalline form (polymorph X) was recorded in deuterated DMSO in a Varian Mercury 400 MHz spectrometer, equipped with a broadband probe ATB 1H / 19F / X of 5 mm (see Fig. 2). The spectrum was acquired dissolving approx. 5 tolO mg of sample in 0.7 mL of deuterated solvent.The1H NMR spectrum of (S)-Selisistat in crystalline form was identical to the spectrum of the racemic starting material and showed no residual organic solvents.

[0266] 2.3 Differential Scanning calorimetry (DSC) analysis of (S)-Selisistat in crystalline form

[0267] A DSC analysis of (S)-Selisistat in crystalline form (polymorph X) was recorded with a Mettler Toledo DSC2. The sample was weighed into a 40 pL aluminium crucible with a pinhole lid and heated from 25 to 300 °C at a rate of 10 °C / min, under nitrogen (50 mL / min).

[0268] The recorded spectrum (see Fig. 3) showed an endothermic peak with an onset at about 185 °C corresponding to the melting point of (S)-Selisistat in crystalline form (polymorph X).

[0269] 2.4 Chiral HPLC analysis of (S)-Selisistat in crystalline form

[0270] A chiral HPLC analysis of (S)-Selisistat in crystalline form was performed using an Agilent HP 1100 HPLC system equipped with a vacuum degasser, a quaternary pump, an autosampler, a thermostatic column and a VW detector.

[0271] The enantiomeric excess of (S)-Selisistat in crystalline form was determined under the following conditions: Chiralpak 1A 250 x 4.6 mm, 5 pm; sample concentration: 1 mg / mL in heptane / isopropyl alcohol (1:1); mobile phase: isopropyl alcohol:ethanol-0.2% diethyl amine (50:50); temperature: 25 °C; flow rate: 0.4 mL / min; wavelength: 210 nm; injection: 5 pL; run time: 30 min. The chromatogram displayed an enantiomeric purity of 99.3 % ee (peaks at retention times of 15.16 and 19.86 min).

[0272] Example 3: Preparation of a cocrystalline compound comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (S)-SLS and gentisic acid ((S)-SLS: gentisic acid)

[0273] 0.50 mL of acetonitrile was added to a mixture of 51 mg of (S)-SLS as prepared according to Example 1 (polymorph X) (0.21 mmol) and gentisic acid (63 mg, 0.41 mmol, 2 eq.) in a glass test tube with screw cap and equipped with a magnetic stirrer. Then, the resulting suspension was stirred at room temperature (approx. 22 °C) overnight, was filtered through a sintered glass funnel (porosity 3) and washed three times with 0.1 mL of acetonitrile. The recovered solid was dried under vacuum at room temperature overnight affording 34 mg of cocrystals of (S)-SLS and gentisic acid in the form of a white powder (41% yield).

[0274] Example 4: Preparation of a cocrystalline compound comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (S)-SLS and gentisic acid ((S)-SLS: gentisic acid)

[0275] 25 mg (5)-SLS (0.1 mmol) and 8 mg gentisic acid (0.05 mmol, 0.5 eq.) was loaded into 2 mL Eppendorf tubes together with three stainless steel balls. Then, two drops of acetonitrile were added for wet grinding before milling for 45 minutes (3 cycles of 15 minutes each) at a rate of 30 Hz with a Retsch Ball Mill MM400. The resulting solids were dried at room temperature under vacuum affording cocrystals of (S)-SLS and gentisic acid as a mixture with crystalline (S)-SLS according to XRPD analysis.

[0276] Example 5: Characterization of the cocrystalline compound comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (S)-SLS and gentisic acid ((S)-SLS: gentisic acid)

[0277] The cocrystalline compound comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (S)-SLS and gentisic acid (CAS Reg. No. 490-79-9; ((S)-SLS: gentisic acid) as prepared according to Example 3 above was characterized by X-Ray powder diffraction (XRPD), 1H-NMR and Differential Scanning calorimetry (DSC).

[0278] 5.1 XRPD analysis of the cocrystalline compound comprising (S)-SLS and gentisic acid ((S)-SLS: gentisic acid)

[0279] An XRPD analysis of the cocrystalline compound comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (S)-SLS and gentisic acid ((S)-SLS: gentisic acid) was performed as described under Example 2.1 above.

[0280] The XRPD pattern measured for (S)-SLS: gentisic acid cocrystals displayed high crystallinity (see Fig.4) and peaks as listed in Table 2 below:Table 2:

[0281] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]

[0282] 6.3 13.92 32 7.3 12.12 4 7.7 11.51 7 11.3 7.83 84 12.1 7.32 32 13.6 6.51 92 14.6 6.07 97 15.4 5.74 16 16.9 5.25 100 17.4 5.10 9 17.8 4.99 9 18.4 4.81 17 19.3 4.59 25 19.6 4.54 7 20.1 4.42 12 20.4 4.36 22 20.9 4.24 25 22.0 4.04 24 22.3 3.99 17 22.7 3.91 18 23.3 3.83 12 23.4 3.80 16 23.9 3.72 4 24.2 3.68 10 24.4 3.64 18 24.8 3.60 15 25.1 3.55 12 25.4 3.50 61 25.8 3.45 39 26.4 3.38 11 26.7 3.34 3 27.4 3.25 20 27.7 3.22 12 27.9 3.19 7 28.4 3.14 12 29.2 3.06 15 29.8 3.00 13 30.3 2.95 4 31.2 2.87 3

[0283]

[0284] 31.3 2.85 631.6 2.83 9

[0285] 32.5 2.76 14

[0286] 32.8 2.73 8

[0287] 34.1 2.63 12

[0288] 34.6 2.59 9

[0289] 36.0 2.49 2

[0290] 37.0 2.43 6

[0291] 37.6 2.39 3

[0292] 38.3 2.35 3

[0293]

[0294] 38.8 2.32 6

[0295] 5.21H-NMR analysis of the cocrystalline compound comprising (S)-SLS and gentisic acid ((S)-SLS: gentisic acid)

[0296] A1H Nuclear magnetic resonance spectrum of the cocrystalline compound comprising (S)-SLS and gentisic acid ((S)-SLS: gentisic acid) was recorded as described under Example 2.2.

[0297] The1H NMR spectrum of (S)-SLS: gentisic acid cocrystals (see Fig. 5) is consistent with chemical structure comprising (S)-SLS and gentisic acid in a molar ratio of 1: 1 and showed no residual organic solvents.

[0298] 5.3 Differential Scanning calorimetry (DSC) analysis of the cocrystalline compound comprising (S)-SLS and gentisic acid ((S)-SLS: gentisic acid)

[0299] A DSC analysis of the cocrystals of (S)-Selisistat and gentisic acid was recorded as described under Example 2.3.

[0300] The recorded spectrum (see Fig. 6) showed a single sharp endothermic peak with an onset at about 159 °C and with a peak at about 160 °C corresponding to the melting point the cocrystalline compound comprising (S)-SLS and gentisic acid ((A)-SLS: gentisic acid) and a (normalized) melting enthalpy (AH) of about - 120 J / g.

[0301] Example 6: Preparation of a cocrystalline compound comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (S)-SLS and nicotinamide ((S)-SLS: nicotinamide)4.0 mL of acetonitrile was added to a mixture of 200 mg of (S)-SLS as prepared according to Example 1 (polymorph X) (0.80 mmol) and 99 mg of nicotinamide (CAS Reg. No.98-92-0; 0.8 mmol) in a 10 mL round bottom glass flask equipped with a magnetic stirrer. Then, the resulting suspension was stirred at room temperature (approx. 22 °C) for about 5 min before some seed crystals were added. Stirring was continued overnight before the mixture was filtered through a sintered glass funnel (porosity 4) and the obtained solids were washed three times with 0.4 mL of acetonitrile. The obtained solid was dried under vacuum at room temperature overnight affording 229 mg of cocrystals of (S)-SLS and nicotinamide in the form of a white powder (77 % yield).

[0302] Example 7: Preparation of a cocrystalline compound comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (S)-SLS and nicotinamide ((S)-SLS: nicotinamide)

[0303] 25 mg (S)-SLS (0.1 mmol) and 12 mg nicotinamide (0.1 mmol, 1 eq.) was loaded into 2 mL Eppendorf tubes together with three stainless steel balls. Then, two drops of isopropyl alcohol were added for wet grinding before milling for 45 minutes (3 cycles of 15 minutes each) at a rate of 30 Hz with a Retsch Ball Mill MM400. The resulting solids were dried at room temperature under vacuum affording cocrystals of (S)-SLS and nicotinamide according to XRPD.

[0304] Example 8: Characterization of the cocrystalline compound comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (S)-SLS and nicotinamide ((S)-SLS: nicotinamide)

[0305] The cocrystalline compound comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (S)-SLS and nicotinamide ((S)-SLS: nicotinamide) as prepared according to Example 6 above was characterized by X-Ray powder diffraction (XRPD), 1H-NMR and Differential Scanning calorimetry (DSC).8.1 XRPD analysis of the cocrystalline compound comprising (S)-SLS and nicotinamide ((S)-SLS: nicotinamide)An XRPD analysis of the cocrystalline compound comprising (S)-SLS: nicotinamide was performed as described under Example 2.1 above.The XRPD pattern measured for (S)-SLS: nicotinamide cocrystals displayed a pattern with high crystallinity (see Fig. 7) and peaks as listed in Table 3 below: Table 3:

[0306] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]

[0307] 7.0 12.71 3

[0308] 7.9 11.18 2

[0309] 9.8 9.04 43

[0310] 11.5 7.73 32

[0311] 13.2 6.69 57

[0312] 13.9 6.36 5

[0313] 15.9 5.57 6

[0314] 16.9 5.24 55

[0315] 17.4 5.09 18

[0316] 17.9 4.95 3

[0317] 18.3 4.84 7

[0318] 19.7 4.51 100

[0319] 20.8 4.28 27

[0320] 20.9 4.25 12

[0321] 21.6 4.12 22

[0322] 22.0 4.03 5

[0323] 23.1 3.86 12

[0324] 23.6 3.78 76

[0325] 23.8 3.74 15

[0326] 24.1 3.70 38

[0327] 24.4 3.65 11

[0328] 24.7 3.61 9

[0329] 25.6 3.48 4

[0330] 26.1 3.41 22

[0331] 26.5 3.36 35

[0332] 26.9 3.31 24

[0333] 27.1 3.29 9

[0334] 28.8 3.10 7

[0335] 29.2 3.06 3

[0336] 30.1 2.97 3

[0337]

[0338] 30.7 2.92 1131.4 2.85 5

[0339] 31.6 2.83 8

[0340] 32.2 2.78 5

[0341] 32.7 2.74 8

[0342] 33.1 2.70 4

[0343] 33.5 2.67 6

[0344] 34.3 2.61 2

[0345] 34.7 2.58 3

[0346] 35.0 2.56 2

[0347] 35.9 2.50 5

[0348] 36.6 2.45 11

[0349] 37.0 2.43 4

[0350] 37.8 2.38 1

[0351] 38.5 2.34 3

[0352]

[0353] 38.6 2.34 2

[0354] 8.21H-NMR analysis of the cocrystalline compound comprising (S)-SLS and nicotinamide ((S)-SLS: nicotinamide)

[0355] A1H Nuclear magnetic resonance spectrum of the cocrystalline compound comprising (S)-SLS and nicotinamide was recorded as described under Example 2.2.

[0356] The1H NMR spectrum of (S)-SLS: nicotinamide cocrystals (see Fig. 8) is consistent with chemical structure comprising (S)-SLS and nicotinamide in a molar ratio of 1: 1 and showed no residual organic solvents.

[0357] 8.3 Differential Scanning calorimetry (DSC) analysis of the cocrystalline compound comprising (S)-SLS and nicotinamide ((S)-SLS: nicotinamide)

[0358] A DSC analysis of the cocrystals of (S)-Selisistat and nicotinamide was recorded as described under Example 2.3.

[0359] The recorded spectrum (see Fig. 9) showed a single sharp endothermic peak with an onset at about 157 °C and with a peak at about 158.5 °C corresponding to the melting point the cocrystalline compound comprising (S)-SLS and nicotinamide ((S)-SLS: nicotinamide) and a (normalized) melting enthalpy (ΔH) of about – 160 J / g.Example 9: Preparation of a cocrystalline compound comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (S)-SLS and oxalic acid ((S)-SLS: oxalic acid)

[0360] 0.5 mL of acetonitrile was added to a mixture of 50 mg of (S)-SLS as prepared according to Example 1 (polymorph X) (0.20 mmol) and 56 mg of oxalic acid (CAS Reg. No. 144-62-7; 0.61 mmol) in a glass test tube with screw cap equipped with a magnetic stirrer. Then, the resulting suspension was stirred at room temperature (approx. 22 °C) overnight before the mixture was filtered through a sintered glass funnel (porosity 3) and the obtained solids were washed two times with 0.1 mL of cold acetonitrile. The obtained solid was dried under vacuum at room temperature overnight affording 14.5 mg of cocrystals of (S)-SLS and oxalic acid in the form of a white powder (21 % yield).

[0361] Example 10: Preparation of a cocrystalline compound comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (S)-SLS and oxalic acid ((S)-SLS: oxalic acid)

[0362] 25 mg (S)-SLS (0.1 mmol) and 9 mg oxalic acid (0.1 mmol, 1 eq.) was loaded into 2 mL Eppendorf tubes together with three stainless steel balls. Then, two drops of acetonitrile were added for wet grinding before milling for 45 minutes (3 cycles of 15 minutes each) at a rate of 30 Hz with a Retsch Ball Mill MM400. The resulting solids were dried at RT under vacuum affording cocrystals of (S)-SLS and oxalic acid according to XRPD analysis.

[0363] Example 11: Characterization of the cocrystalline compound comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (S)-SLS and oxalic acid ((S)-SLS: oxalic acid)

[0364] The cocrystalline compound comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (S)-SLS and oxalic acid ((S)-SLS: oxalic acid) as prepared according to Example 9 above was characterized by X-Ray powder diffraction (XRPD),1H-NMRand13C-NMR.11.1 XRPD analysis of the cocrystalline compound comprising (S)-SLS and oxalic acid ((S)-SLS: oxalic acid)

[0365] An XRPD analysis of the cocrystalline compound comprising (S)-SLS: oxalic acid was performed as described under Example 2.1 above.

[0366] The XRPD pattern measured for the (S)-SLS: oxalic acid cocrystals displayed a pattern with moderate crystallinity (see Fig. 10) and peaks as listed in Table 4 below: Table 4:

[0367] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]

[0368] 5.0 17.85 54

[0369] 6.1 14.52 7

[0370] 9.9 8.90 21

[0371] 12.2 7.26 26

[0372] 12.8 6.91 3

[0373] 14.9 5.93 100

[0374] 18.3 4.86 19

[0375] 19.6 4.53 16

[0376] 21.2 4.19 7

[0377] 21.5 4.12 5

[0378] 22.7 3.92 2

[0379] 23.1 3.85 7

[0380] 25.0 3.56 43

[0381] 25.5 3.49 8

[0382] 26.1 3.41 9

[0383] 28.4 3.14 4

[0384] 28.9 3.09 3

[0385] 30.1 2.97 7

[0386]

[0387] 30.8 2.90 7

[0388] 11.21H-NMR analysis of the cocrystalline compound comprising (S)-SLS and oxalic acid ((S)-SLS: oxalic acid)

[0389] A1H-Nuclear magnetic resonance spectrum of the cocrystalline compound comprising (S)-SLS and oxalic acid was recorded as described under Example 2.2.

[0390] The1H NMR spectrum of (S)-SLS: oxalic acid cocrystals (see Fig. 11) is consistent with chemical structure of (S)-SLS and showed no residual organic solvents.11.313C-NMR analysis of the cocrystalline compound comprising (S)-SLS and oxalic acid ((S)-SLS: oxalic acid)

[0391] A13C-Nuclear magnetic resonance spectrum of the cocrystalline compound comprising (S)-SLS and was recorded at a spectral width of -15 to 235 ppm in deuterated DMSO (DMSO-d6) using a Varian Mercury 100 MHz spectrometer, equipped with a broadband probe ATB 1H / 19F / X of 5 mm. The spectrum was acquired by dissolving 10 mg of sample in 0.7 mL of the deuterated solvent with 2000 scans, a relaxation delay of 3 s, a pulse angle of 45° and at a temperature of 25°C.

[0392] The13C-NMR spectrum of (S)-SLS: oxalic acid cocrystals (see Fig. 12) is consistent with chemical structure of (S)-SLS and oxalic acid (signal at 160.9 ppm).

[0393] Example 12: Preparation of a cocrystalline compound comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (S)-SLS and glycolic acid ((S)-SLS: glycolic acid)

[0394] 0.5 mL of isobutyl acetate was added to a mixture of 50 mg of (S)-SLS as prepared according to Example 1 (polymorph X) (0.20 mmol) and 15 mg of glycolic acid (CAS Reg. No. 89-14-1; 0.2 mmol) in a glass test tube with a screw cap equipped with a magnetic stirrer. Then, the resulting suspension was stirred at room temperature (approx. 22 °C) overnight before the mixture was filtered through a sintered glass funnel (porosity 3) and the obtained solids were washed three times with 0.1 mL of isobutyl acetate. The obtained solid was dried under vacuum at room temperature overnight affording 34 mg of cocrystals of (S)-SLS and glycolic acid in the form of a white powder (52 % yield).

[0395] Example 13: Preparation of a cocrystalline compound comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (S)-SLS and glycolic acid ((S)-SLS: glycolic acid)

[0396] 20 mg (S)-SLS (0.08 mmol) and 12 mg glycolic acid (0.16 mmol, 2 eq.) was loaded into 2 mL Eppendorf tubes together with three stainless steel balls. Then, twodrops of acetonitrile were added for wet grinding before milling for 45 minutes (3 cycles of 15 minutes each) at a rate of 30 Hz with a Retsch Ball Mill MM400. The resulting solids were dried at room temperature under vacuum affording cocrystals of (S)-SLS and glycolic acid according to XRPD analysis.

[0397] Example 14: Characterization of the cocrystalline compound comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (S)-SLS and nicotinamide ((S)-SLS: glycolic acid)

[0398] The cocrystalline compound comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (S)-SLS and glycolic acid ((S)-SLS: glycolic acid) as prepared according to Example 12 above was characterized by X-Ray powder diffraction (XRPD),1H-NMR and Differential Scanning calorimetry (DSC).

[0399] 14.1 XRPD analysis of the cocrystalline compound comprising (S)-SLS and glycolic acid ((S)-SLS: glycolic acid)

[0400] An XRPD analysis of the cocrystalline compound comprising (S)-SLS: glycolic acid was performed as described under Example 2.1 above.

[0401] The XRPD pattern measured for (S)-SLS: glycolic acid cocrystals displayed a pattern with high crystallinity (see Fig. 13) and peaks as listed in Table 5 below: Table 5:

[0402] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]

[0403] 10.5 8.39 81

[0404] 12.5 7.06 40

[0405] 14.9 5.96 10

[0406] 17.3 5.12 14

[0407] 17.6 5.04 100

[0408] 18.2 4.88 11

[0409] 18.4 4.83 7

[0410] 19.6 4.52 5

[0411] 20.1 4.41 2

[0412] 20.3 4.37 2

[0413] 21.2 4.20 60

[0414] 21.4 4.15 15

[0415] 23.1 3.86 57

[0416]

[0417] 24.7 3.60 825.2 3.53 18

[0418] 25.9 3.45 5

[0419] 26.3 3.39 6

[0420] 26.8 3.33 20

[0421] 27.5 3.24 15

[0422] 28.9 3.09 16

[0423] 30.0 2.98 3

[0424] 30.3 2.95 23

[0425] 32,0 2.80 10

[0426] 33.9 2.65 10

[0427] 35.0 2.56 4

[0428] 35.3 2.54 3

[0429] 35.6 2.52 3

[0430] 36.0 2.50 6

[0431] 36.8 2.44 2

[0432] 37.2 2.42 3

[0433] 38.4 2.35 2

[0434]

[0435] 39.4 2.29 2

[0436] 14.21H-NMR analysis of the cocrystalline compound comprising (S)-SLS and glycolic acid ((S)-SLS: glycolic acid)

[0437] A1H-Nuclear magnetic resonance spectrum of the cocrystalline compound comprising (S)-SLS and glycolic acid was recorded as described under Example 2.2.

[0438] The ’H NMR spectrum of (S)-SLS: glycolic acid cocrystals (see Fig. 14) is consistent with chemical structure comprising (S)-SLS and glycolic acid in a molar ratio of 1: 1 and showed no residual organic solvents.

[0439] 14.3 Differential Scanning calorimetry (DSC) analysis of the cocrystalline compound comprising (S)-SLS and nicotinamide ((S)-SLS: nicotinamide)

[0440] A DSC analysis of the cocrystals of (S)-Selisistat and glycolic was recorded as described under Example 2.3.

[0441] The recorded spectrum (see Fig. 15) showed a single sharp endothermic peak with an onset at about 137 °C and with a peak at about 138.5 °C corresponding to the melting point the cocrystalline compound comprising (S)-SLS and glycolic acid ((S)-SLS: glycolic acid) and a (normalized) melting enthalpy (AH) of about - 111 J / g.Example 15: Determination of the stability of the cocrystalline compounds comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((SJ-SLS) and a further pharmaceutically acceptable compound.

[0442] The cocrystalline compounds comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (S)-SLS and a further pharmaceutically acceptable compound as prepared according to Examples 3, 6, 9 and 12 above were subjected to a accelerated stability test under conditions as defined defined by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (1CH; accelerated ICH conditions: storage at 40 + / - 2 °C at 75 + / - 5 % relative humidity) as follows: A crystal of each compound as prepared according to Examples 3, 6, 9 and 12 above was placed on an XRPD silicon sample holder and exposed to the above defined accelerated ICH conditions in a suitable climatic chamber.

[0443] The samples were periodically analyzed by XRPD analysis (as described under Example 2.1 above) to observe potential crystalline conversion or amorphization.

[0444] The cocrystalline compound comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (S)-SLS and gentisic acid as prepared according to Example 3 as well as the cocrystalline compound comprising (S)-6-Chloro-2,3,4,9-tetrahydro-IH-carbazole-l-carboxamide (S)-SLS and nicotinamide as prepared according to Example 6 were stable under the accelerated ICH conditions for at least two months.

[0445] The cocrystalline compound comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (S)-SLS and oxalic acid as prepared according to Example 9 was stable under the accelerated ICH conditions for at least two days.

[0446] The cocrystalline compound comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide (S)-SLS and glycolic acid as prepared according to Example 12 was stable under the accelerated ICH conditions for at least seven days.Example 16: In-vitro determination of the inhibition of SIRT1 and SIRT2 by the cocrystalline compounds comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-1 -carboxamide ((S)-SLS) and a further pharmaceutically acceptable compound

[0447] The cocrystalline compounds of the present invention were tested for inhibition of sirtuins SIRT1 and SIRT2 according to the method as described in Michan, S. and Sinclair, D. (2007), Biochem. J.; 404: 1-13. The IC50values measured accordingly for the cocrystals of the present invention are summarized in Table 6 below:

[0448] Table 6:

[0449] Cocrystal IC50(SIRT1) [mol / L] IC50(SIRT2) [mol / L] (S)-SLS: gentisic acid 2.4* 10-71.4* 10-6

[0450] (S)-SLS: nicotinamide 2.1 * 10-78.6 * 10-7

[0451] (S)-SLS: oxalic acid 2.4* 10-71.3 * 10-6

[0452] (S)-SLS: glycolic acid 3.6* 10-71.2 * 10-6

[0453]

[0454] As a comparison, the corresponding ICso values were determined for pure (S)-SLS in the form of its polymorph X. In these experiments an IC50(SIRT1) of 1.7 * 10-7mol / L and an IC50(SIRT2) of 1.2 * 10-6mol / L were measured.

[0455] Example 17: In-vivo investigation of the metabolic profile of (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((SJ-SLS))

[0456] Solutions of (S)-SLS in an aqueous solvent mixture consisting of Tween 80 (5 % (v / v)), dimethylsulfoxide (DMSO, 5 % (v / v)), PEG-400 (40 % (v / v)) and water (50 % (v / v)) with (S)-SLS concentrations of 5 mg / mL and 2 mg / mL, respectively, were prepared by mixing DMSO and PEG-400, rapidly adding Tween 80, vortexing for 10 s and adding water to the resulting mixture.In an animal study approved by the competent Animal Experiment Board under Directive 2010 / 63 / EU, enantiomerically pure (S)-6-Chloro-2,3,4,9-tetrahydro-IH-carbazole-l-carboxamide ((S)-SLS) was administered to a total of 21 naive male Sprague Dawley rats (Charles River Laboratories, Germany) intravenously (i.v.) or orally (p.o.) by gavage in a dose of 10.0 mg / kg (regarding the weight of the corresponding animal). In the case of i.v. administration the dose was administered at a volume of 2 mL / kg. In the case of p.o. administration the dose was administered at a volume of 5 mL / kg.

[0457] After administration, blood samples were taken at 0.25, 0.5, 1, 2, 4, 6 and 8 h after dosing. Additional blood samples were taken at 0.083 h after i.v. dosing and at 24 h after p.o. dosing. Within 30 min following the sampling, the blood was centrifuged for plasma separation (room temperature; 10 min; 2700 G). The plasma samples were transferred into plastic tubes, frozen and stored at -20 °C until analysis. Cerebrospinal fluid (CSF) -samples were collected into plastic tubes under terminal isoflurane anaesthesia after the last plasma sampling time point at 8 h (i.v.) and 24 h (p.o.) after dosing (n = 3 per group). The CSF-samples were frozen and stored at -20°C.

[0458] The plasma samples were prepared for analysis by mixing 50 μL of plasma sample with 500 μL of internal standard solution (50 ng / ml of repaglinide in acetonitrile with 1% formic acid) and mixed. The samples were transferred to Waters Ostro 96-well plate and drawn through the plate by applying 15 inHg (inch of mercury) vacuum for 10 min. Samples were then dried under nitrogen flow, reconstituted into 100 μl of 1:1 (v:v) acetonitrile in water and submitted to LC-MS analysis.

[0459] Standard plasma samples were prepared by spiking blank rat plasma to obtain concentrations from 1 to 10000 ng / mL of racemic SLS in plasma by using one volume of spiking solution and nine volumes of plasma, thus S- and 7?-enantiomers concentrations were half of racemic. These samples were then prepared for analysis similarly as the samples and similarly, quality control samples were prepared for concentrations at 6, 30, 300 and 3000 ng / mL for racemic SLS and 3, 15, 150 and 1500 ng / ml for S- and 7?-enantiomers. Liquid chromatography-mass spectrometry wasperformed using a Thermo Vanquish UHPLC + Thermo TSQ Quantis triple quadrupole MS instrument with a Phenomenex Lux Cellulose-1 (3 μm, 150 x 2 mm) column plus precolumn.

[0460] The pharmacokinetic parameters were calculated using Phoenix 64 (Build 6.4.0.768) WinNonlin (version 6.4) software, using non-compartmental methods (NCA). Nominal doses were used for all animals. The terminal phase half-life (T1 / 2) was calculated by least-squares regression analysis of the terminal linear part of the log concentration-time curve. The area under the plasma concentration-time curve (AUC) was determined with the linear trapezoidal rule for increasing values and log trapezoidal rule for decreasing values up to the last measurable concentration (AUCo-iast), and extrapolation of the terminal elimination phase to infinity was used when possible; the following criteria were used:

[0461] • Minimum of 3 points (not including Cmax) used to calculate lambda (with R2adjusted >0.85)

[0462] • T1 / 2 shorter than the time-span used to calculate lambda

[0463] • AUCinf_Extrap % < 20%

[0464] The maximum plasma concentration (Cmax) and the time to reach Cmax (tmax) were derived directly from the plasma concentration data.

[0465] After i.v. administration of (S)-SLS (10.0 mg / kg), plasma concentrations of the 7?-enantiomer were quantified up to 4-6 hours post-dose. Plasma concentrations of (S)-SLS peaked between 0.083 h and 0.50 h post-dose with a mean Cmax of 4740 ng / mL (Standard Deviation (SD): 1230). The mean AUCo-inf of 74.9 h*ng / mL (SD: 5.22) and the mean half-life (T1 / 2) of 1.56 h (SD: 0.18) were observed for (7?)-SLS (the R-enantiomer of SLS) and a mean AUCo-inf of 7670 h*ng / mL (SD: 1110) and a mean half-life of 0.56 h (SD: 0.09) were observed for (S)-SLS. The mean steady state volume of distribution (Vss) estimate for (S)-SLS was 1810 mL / kg (SD: 218) and the mean clearance (CL) was 1320 mL / h / kg(SD: 183), corresponding approximately to 39.9% of rat hepatic blood flow (13.8 ml / min / 0.25kg; Davies B. and Morris T. Physiological Parameters in Laboratory Animals and Humans, Pharm. Res. 10:71093-95, 1993).

[0466] After p.o. administration of (S)-SLS (10.0 mg / kg), plasma concentrations of both enantiomers peaked at 2 hours post-dose with the mean Cmax of 12.7 ng / mL (SD:1.72) for (7?)-SLS and 1550 ng / mL (SD: 242) for (S)-SLS, respectively. The mean T1 / 2 for (S)-SLS was 0.58 (SD: 0.07). The mean AUCiast of 49.4 h*ng / mL (SD: 10.5) and 4260 h*ng / mL (SD: 519) were observed for (7?)-SLS and (S)-SLS, respectively, corresponding to mean apparent oral bioavailability (BA) of 55.5 % (SD: 6.67) for fS)-SLS.

[0467] Example 18: In-vivo investigation of the metabolic profiles of the cocrystalline compounds comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((S)-SLS) and a further pharmaceutically acceptable compound Example 17 as described above was exactly repeated using solutions of the cocrystals of the present invention (instead of (S)-SLS alone) which were administered intravenously (i.v.) and orally (p.o.) in the same animal model.

[0468] The pharmacokinetic data (mean values) determined accordingly for (S)-SLS after administration of the cocrystals comprising (S)-SLS and at least one further pharmaceutically acceptable compound is selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid is summarized in Table 7 below (Standard Deviations (SD) given as values in brackets):

[0469] Table 7:

[0470] (SJ-SLS: (SJ-SLS: (SJ-SLS: (S)-SLS: gentisic acid nicotinamide oxalic acid glycolic acid After i.v.

[0471] administration

[0472] Cmax [ng / mL] 3430 (1660) 5330 (699) 2490 (1320) 3890 (295) T1 / 2 [h] 0.511 (0.01) 0.613 (0.105) 0.775 (0.332) 0.548 (0.085) AUCo-inf 6950 (1360) 9640 (1060) 4730 (924) 7130 (1300) [h*ng / mL]

[0473] Vss [L / kg] 2.4 (0.789) 1.71 (0.088) 3.88 (1.77) 2.16 (0.201)

[0474]

[0475] CL 24.6 (4.76) 17.4 (1.99) 36.0 (6.33) 23.9 (4.08) [mL / min / kg]

[0476] After p.o.

[0477] administration

[0478] T1 / 2[h] 0.851 (0.148) 1.04 (0.185) 0.951 (0.223) 1 (0.506) AUCo-inf 4800 (1000) 5700 (671) 4860 (352) 5100 (1760) [h*ng / mL]

[0479] BA [%] 84.7 (17.7) 59.7 (7.0) 102.7 (7.5) 71.6 (24.8)

[0480]

Claims

Claims1. A composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l- carboxamide ((S)-SLS) of formula (S-l)and a further pharmaceutically acceptable compound,wherein the composition is in the form of a cocrystal, andwherein the further pharmaceutically acceptable compound is selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid.

2. The composition according to claim 1, wherein the further pharmaceutically acceptable compound is selected from the group consisting of gentisic acid, nicotinamide and glycolic acid, or wherein the further pharmaceutically acceptable compound is selected from the group consisting of gentisic acid and nicotinamide.

3. The composition according to claim 1 or 2, wherein the further pharmaceutically acceptable compound is gentisic acid.

4. The composition according to claim 3, wherein the cocrystalline composition has an X-ray powder diffraction pattern comprising 2-theta angle values (with a deviation of + / - 0.3 degree) of at least one of 6.3, 15.4 and 16.9 degrees, or of at least one of 6.3, 11.3, 15.4 and 16.9 degrees.

5. The composition according to any one of claims 1 to 3, wherein the further pharmaceutically acceptable compound is nicotinamide.

6. The composition according to claim 5, wherein the cocrystalline composition has an X-ray powder diffraction pattern comprising 2-theta angle values (with a deviation of + / - 0.3 degree) of at least one of 9.8, 16.9 and 24.1 degrees, or of at least one of 9.8, 13.2, 16.9, 23.6 and 24.1 degrees.

7. The composition according to any one of the preceding claims, wherein the composition comprises (5)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l- carboxamide ((5)-SLS) of formula (S-l) and the further pharmaceutically acceptable compound in a molar ratio selected within the range of from about 0.9: 1 to about 1.1: 1, preferably in a molar ratio of about 1: 1.

8. The composition according to any one of the preceding claims, wherein the composition is solvent- free and / or non-hygroscopic.

9. The composition according to any one of claims 2 to 8, wherein the composition 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 2 months.

10. The composition according to any one of the preceding claims, wherein the cocrystalline composition of (S)-SLS has an improved inhibition of SIRT, particularly SIRT1 and SIRT2, and / or increased systemic exposure than a Selisistat racemate.

11. A pharmaceutical composition comprising the composition comprising (5)-6- Chloro-2,3,4,9-tetrahydro-lH-carbazole-l-carboxamide ((Sj-SLS) and a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid in the form of a cocrystal according to any one of claims 1 to 10 and at least one pharmaceutically acceptable excipient.

12. The pharmaceutical composition according to claim 11, wherein the pharmaceutical composition is a solid dosage form for oral administration, preferably a tablet, a capsule or an oral film.

13. The composition comprising S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole-l- carboxamide ((5)-SLS) and a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid in the form of a cocrystal according to any one of claims 1 to 10 or the pharmaceutical composition according to claims 11 to 12 for use as a medicament.

14. The composition for use according to claim 13, for use in the prevention or treatment of a disease or condition associated with a sirtuin, preferably wherein the sirtuin is selected from SIRT1, SIRT2, SIRT3 and SIRT7, especially from SIRT1 and SIRT2.

15. The composition for use according to claim 13 or 14, for use in the prevention or treatment of cancer, metabolic diseases such as metabolic syndrome, type 1 diabetes or type II diabetes, obesity, dislipidemia, hyperlipidemia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, neurodegenerative conditions that are 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 1 (SCA1), spinocerebellar ataxia 2 (SCA2), Machado-Joseph disease (MJD; SCA3), spinocerebellar ataxia 6 (SCA6), spinocerebellar ataxia 7 (SCA7), and spinocerebellar ataxia 12 (SCA12).

16. A method for the preparation of a composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) of formula (S-I)Cl(S-l)and a further pharmaceutically acceptable compound,wherein the composition is in the form of a cocrystal, andwherein the further pharmaceutically acceptable compound is selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid according to any one of claims 1 to 10, the method comprising the steps of: a) Providing (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) in solid form, preferably in crystalline form; bj Providing a further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid; andc) Contacting (S)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) in solid form, preferably in crystalline form, as provided in step a) and the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid as provided in step b) in the presence of an organic solvent to form a mixture comprising the composition comprising (S)-6-Chloro-2,3,4,9-tetrahydro-lH-carbazole- 1-carboxamide ((S)-SLS) of formula (S-I) and the further pharmaceutically acceptable compound selected from the group consisting of gentisic acid, nicotinamide, oxalic acid and glycolic acid in the form of a cocrystal.

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