PATENT DOCUMENT

Abstract:
The invention relates to besylate salts of the compound of formula (I): 
     
       
                 
         
             
             
         
       
     
     Methods of preparing the salts, and their use as medicaments, in particular for sedative or hypnotic, anxiolytic, muscle relaxant, or anticonvulsant purposes is also described.

Full Description:
CROSS-REFERENCES TO RELATED APPLICATIONS 
       [0001]    This application is a continuation of currently pending U.S. application Ser. No. 14/948,889, filed Nov. 23, 2015 which is a continuation of U.S. Pat. No. 9,193,730 issued Nov. 24, 2015 (U.S. application Ser. No. 12/373,472, filed Nov. 2, 20091, which is the U.S. National Stage of International Application No. PCT/GB2007/002565, filed Jul. 10, 2007, which designated the United States and has been published as International Publication No. WO 2008/007071 and which claims the priority of Great Britain Patent Applications, Serial Nos.: 0613694.9 and 0613692.3 of Jul. 10, 2006, pursuant to 35 U.S.C. 119(a)-(d). The contents of the aforementioned applications are hereby incorporated herein by reference. 
     
    
     BACKGROUND OF THE INVENTION 
       [0002]    This invention relates to salts of a short acting benzodiazepine, and to use of the salts as medicaments, in particular for sedative or hypnotic, anxiolytic, muscle relaxant, or anticonvulsant purposes. 
         [0003]    European Patent No. 1,183,243 describes short-acting benzodiazepines that include a carboxylic acid ester moiety and are inactivated by non-specific tissue esterases. An organ-independent elimination mechanism is predicted to be characteristic of these benzodiazepines, providing a more predictable and reproducible pharmacodynamic profile. The compounds are suitable for therapeutic purposes, including sedative-hypnotic, anxiolytic, muscle relaxant and anticonvulsant purposes. The compounds are short-acting CNS depressants that are useful to be administered intravenously in the following clinical settings: preoperative sedation, anxiolysis, and amnestic use for perioperative events; conscious sedation during short diagnostic, operative or endoscopic procedures; as a component for the induction and maintenance of general anesthesia, prior and/or concomitant to the administration of other anaesthetic or analgesic agents; ICU sedation. 
         [0004]    One of the compounds disclosed in EP 1,183,243 (in Example Ic-8, page 36) is Methyl 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazol [1,2-a] [1,4]benzodiazepin-4-yl] propanoate, as shown in formula (I) below: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0005]    Whilst the free base of formula (I) is stable when stored at 5° C., samples stored at 40° C./75% relative humidity (open) are observed to deliquesce, become yellow to orange in colour, and show notable decreases in content relative to initial (see Example 1 below). 
         [0006]    It has now surprisingly been found that the compound of formula (I) forms highly crystalline mono (benzenesulfonic acid) besylate salts that are easily isolated from a range of pharmaceutically acceptable solvents and show good thermal stability, low hygroscopicity and high aqueous solubility. 
       SUMMARY OF THE INVENTION 
       [0007]    According to the invention there is provided a besylate salt of a compound of formula (I). Preferably the salt is a crystalline salt. Preferably the crystalline salt has a stoichiometry of 1:1 compound of formula (I):besylate. Preparation and characterisation of polymorphic forms of besylate salts is described in the Examples below. 
         [0008]    According to the invention there is provided a crystalline polymorph of a besylate salt of a compound of formula (I) (herein designated besylate Form 1), that exhibits an X-ray powder diffraction (XRPD) pattern which comprises a characteristic peak at about 7.3, 7.8, 9.4, 12.1, 14.1, 14.4, 14.7, or 15.6 degrees two-theta. 
         [0009]    Preferably the besylate Form 1 crystalline polymorph exhibits an XRPD pattern which comprises characteristic peaks at about 7.3, 7.8, 9.4, 12.1, 14.1, 14.4, 14.7, and 15.6 degrees two-theta. 
         [0010]    More preferably the besylate Form 1 crystalline polymorph exhibits an XRPD pattern which comprises characteristic peaks at: 7.25 (10.60), 7.84 (72.60), 9.36 (12.10), 12.13 (32.50), 14.06 (48.50), 14.41 (74.30), 14.70 (50.70), 15.60 (26.90) [angle two-theta degrees (percentage relative intensity)]. 
         [0011]    Preferably the besylate Form 1 crystalline polymorph has a differential scanning calorimetry (DSC) onset melting temperature in the range 187-204° C., preferably about 191-192° C. 
         [0012]    A crystal structure of Form 1 has been resolved at 190K (R factor of 6.3). Form I has a stoichiometry of 1:1 compound:besylate. Its crystallographic asymmetric unit contains two independent compound molecules and two besylate molecules. The two independent compound molecules are singly protonated on the imidazole ring. The crystal structure has unit cell dimensions of a=7.6868 Å, b=29.2607 Å, c=12.3756 Å, α=90°, β=97.7880°, γ=90°, and a space group of P2 1 . The crystal structure is described in more detail in Example 9, and crystallographic coordinates are given in Table 17. Bond lengths and angles for Form 1 are given in Tables 19 and 20, respectively. 
         [0013]    According to the invention there is provided a besylate salt of a compound of formula (I) which is a crystalline polymorph comprising a crystal with unit cell dimensions of a=7.6868 Å, b=29.2607 Å, c=12.3756 Å, α=90°, β=97.7880°, γ=90°. 
         [0014]    There is also provided according to the invention a besylate salt of a compound of formula (I) which is a crystalline polymorph having a crystal structure defined by the structural coordinates as shown in Table 17. 
         [0015]    There is further provided according to the invention a besylate salt of a compound of formula (I) with bond lengths and angles as shown in Tables 19 and 20, respectively. 
         [0016]    There is further provided according to the invention a crystalline polymorph of a besylate salt of a compound of formula (I) (herein designated besylate Form 2), that exhibits an XRPD pattern which comprises a characteristic peak at about 8.6, 10.5, 12.0, 13.1, 14.4, or 15.9 degrees two-theta. 
         [0017]    Preferably the besylate Form 2 crystalline polymorph exhibits an XRPD pattern which comprises characteristic peaks at about 8.6, 10.5, 12.0, 13.1, 14.4, and 15.9 degrees two-theta. 
         [0018]    More preferably the besylate Form 2 crystalline polymorph exhibits an XRPD pattern which comprises characteristic peaks at: 8.64 (17.60), 10.46 (21.00), 12.03 (22.80), 13.14 (27.70), 14.42 (11.20), 15.91 (100.00) [angle two-theta degrees (percentage relative intensity)]. 
         [0019]    Preferably the besylate Form 2 crystalline polymorph has a differential scanning calorimetry (DSC) onset melting temperature in the range 170-200° C., preferably about 180° C. 
         [0020]    A crystal structure of Form 2 has been resolved at 190K (R factor of 3.8). Form 2 has stoichiometry of 1:1 compound:besylate. Its crystallographic asymmetric unit contains one compound molecule and one besylate molecule. The compound molecule is singly protonated on the imidazole ring. The crystal structure has unit cell dimensions of a=8.92130 Å, b=11.1536 Å, c=25.8345 Å, α=90°, β=90°, γ=90°, and a space group of P2 1 2 1 2 1 . The crystal structure is described in more detail in Example 10, and crystallographic coordinates are given in Table 18. Bond lengths and angles for Form 2 are given in Tables 21 and 22, respectively. 
         [0021]    According to the invention there is provided a besylate salt of a compound of formula (I) which is a crystalline polymorph comprising a crystal with unit cell dimensions of a=8.92130 Å, b=11.1536 Å, c=25.8345 Å, α=90°, β=90°, γ=90°. 
         [0022]    There is also provided according to the invention a besylate salt of a compound of formula (I) which is a crystalline polymorph having a crystal structure defined by the structural coordinates as shown in Table 18. 
         [0023]    There is further provided according to the invention a besylate salt of a compound of formula (I) with bond lengths and angles as shown in Tables 21 and 22, respectively. 
         [0024]    There is further provided according to the invention a crystalline polymorph of a besylate salt of a compound of formula (I) (herein designated besylate Form 3), that exhibits an X-ray powder diffraction (XRPD) pattern which comprises a characteristic peak at about 7.6, 11.2, 12.4, 14.6, 15.2, 16.4, or 17.7 degrees two-theta. 
         [0025]    Preferably the besylate Form 3 crystalline polymorph exhibits an XRPD pattern which comprises characteristic peaks at about: 7.6, 11.2, 12.4, 14.6, 15.2, 16.4, and 17.7 degrees two-theta. 
         [0026]    More preferably the besylate Form 3 crystalline polymorph exhibits an XRPD pattern which comprises characteristic peaks at: 7.61 (65.70), 11.19 (33.20), 12.38 (48.70), 14.63 (30.60), 15.18 (33.20), 16.40 (29.60), 17.68 (51.30) [angle 2θ° (percentage relative intensity)]. 
         [0027]    Preferably the besylate Form 3 crystalline polymorph has a differential scanning calorimetry (DSC) onset melting temperature in the range 195-205° C., preferably about 200-201° C. 
         [0028]    There is further provided according to the invention a crystalline polymorph of a besylate salt of a compound of formula (I) (herein designated besylate Form 4), that exhibits an XRPD pattern which comprises a characteristic peak at about 7.6, 10.8, 15.2, 15.9, or 22.0 degrees two-theta. 
         [0029]    Preferably the besylate Form 4 crystalline polymorph exhibits an XRPD pattern which comprises characteristic peaks at about: 7.6, 10.8, 15.2, 15.9, and 22.0 degrees two-theta. 
         [0030]    Preferably the besylate Form 4 crystalline polymorph exhibits an XRPD pattern which comprises characteristic peaks at: 7.62 (83.50), 10.75 (14.70), 15.17 (37.80), 15.85 (28.70), 22.03 (100) [angle 2θ° (percentage relative intensity)]. 
         [0031]    Preferably the besylate Form 4 crystalline polymorph has a differential scanning calorimetry (DSC) onset melting temperature in the range 180-185° C., preferably about 182° C. 
         [0032]    A preferred salt is the besylate Form 1 based on the robustness of formation, yield, purity and chemical and solid form stability. 
         [0033]    There is also provided according to the invention a method of making a besylate salt of a compound of formula (I), which comprises reacting a free base of a compound of formula (I) with benzene sulfonic acid. 
         [0034]    Also according to the invention there is provided a method of making a salt of the invention, which comprises contacting a free base of a compound of formula (I) with benzene sulfonic acid in solution to cause formation of a precipitate of the besylate salt. Preferably the method further comprises isolating the precipitate. 
         [0035]    Preferably the free base is dissolved in toluene, ethanol, ethyl acetate, MtBE, dichloromethane (DCM), isopropyl acetate, ethyl formate, methanol, or acetone. More preferably the free base is dissolved in toluene or ethyl acetate. Preferably the benzene sulfonic acid is dissolved in ethanol. 
         [0036]    The besylate Form 1 may be prepared by contacting a solution of a free base of a compound of formula (I) in toluene, ethyl acetate, acetone, isopropyl acetate, or ethyl formate with a solution of benzene sulfonic acid in ethanol to cause formation of a precipitate of the salt. 
         [0037]    There is also provided according to the invention a besylate salt of a compound of formula (I) which is obtainable by the above method. 
         [0038]    The besylate Form 2 may be prepared by contacting a solution of a free base of a compound of formula (I) in methanol with a solution of benzene sulfonic acid in ethanol to cause formation of a precipitate of the salt. Preferably the mixture is cooled below ambient temperature (for example 4° C.). 
         [0039]    There is also provided according to the invention a besylate salt of a compound of formula (I) which is obtainable by the above method. 
         [0040]    The besylate Form 3 may be prepared by seeding liquor resulting from crystallisation of Form 1 from ethyl acetate/ethanol with Form 1. Preferably the liquor is cooled below ambient temperature (for example 4° C.). 
         [0041]    In one embodiment the besylate Form 3 may be prepared by seeding, with a besylate Form 1 crystalline salt of a compound of formula (I), a filtrate solution separated from the precipitate formed by contacting a solution of a compound of formula (I) in ethyl acetate with a solution of benzene sulfonic acid in ethanol, to produce the besylate Form 3 crystalline polymorph. 
         [0042]    There is also provided according to the invention a besylate salt of a compound of formula (I) which is obtainable by any of the above methods. 
         [0043]    The besylate Form 4 may be prepared by re-crystallising besylate Form 1 from isopropyl acetate/ethanol, preferably 40% isopropyl acetate/ethanol. 
         [0044]    There is also provided according to the invention a besylate salt of a compound of formula (I) which is obtainable by the above method. 
         [0045]    Salts of the invention may also be prepared by crystallising compound of formula (I) besylate from a suitable solvent, or from a suitable solvent/anti-solvent or solvent/co-solvent mixture. The solution or mixture may be cooled and/or evaporated to achieve crystallisation if appropriate. 
         [0046]    We have found that crystallisation of Form 2 is observed in conditions where there are extremes of either polarity (for example acetonitrile:water) or lipophilicity (n-nonane), or both (dimethyl sulfoxide:1,2-dichlorobenzene). 
         [0047]    Examples of solvents for crystallisation of Form 2 are: nonane; methanol. 
         [0048]    Examples of solvent/anti-solvent mixtures for crystallisation of Form 1 are: di methylacetamide/methyl isobutyl ketone; dimethylacetamide/tetrachloroethylene; acetonitrile/3-methylbutan-1-ol; acetonitrile/1,2-dichlorobenzene; acetonitrile/pentylacetate; methanol/3-methylbutan-1-ol; methanol/methyl isobutyl ketone; 2,2,2-trifluoroethanol/1,4-dimethylbenzene; ethanol/methyl isobutyl ketone; ethanol/1,4-dimethylbenzene; propan-1-ol/1,2-dichlorobenzene; propan-1-ol/tetrachloroethylene; propan-2-ol/1,2-dichlorobenzene; propan-2-ol/n-nonane; 2-methoxy ethanol/water; 2-methoxy ethanol/pentyl acetate; 2-methoxy ethanol/1,4-dimethylbenzene; tetrahydrofuran/water; tetrahydrofuran/3-methylbutan-1-ol; tetrahydrofuran/1,2-dichlorobenzene; tetrahydrofuran/ethyl acetate; tetrahydrofuran/1,3-dimethylbenzene. 
         [0049]    Examples of solvent/anti-solvent mixtures for crystallisation of Form 2 are: ethanol/ethyl acetate; ethanol/methyl isobutyl ketone; ethanol/p-cymene; dimethylsulfoxide/1,2-dichlorobenzene; acetonitrile/water; ethano/1,2-dichlorobenzene; ethanol/tetrachloroethylene; tetrahydrofuran/1,2-dichlorobenzene; tetrahydrofuran/ethyl acetate. 
         [0050]    According to a preferred embodiment, Form 1 is crystallised from 2-methoxyethanol/pentyl acetate. 
         [0051]    According to a preferred embodiment, Form 2 is crystallised from ethanol/ethyl acetate. 
         [0052]    According to a preferred embodiment, Form 2 is crystallised from methanol/ethanol (preferably by cooling a solution of compound of formula (I) besylate in methanol/ethanol below ambient temperature, for example 4° C.). 
         [0053]    According to a preferred embodiment, Form 3 is crystallised from ethanol/ethyl acetate (suitably by cooling the mixture below ambient temperature, for example 4° C.). 
         [0054]    According to a preferred embodiment, Form 4 is crystallised from isopropyl acetate/ethanol (preferably by cooling a solution of compound of formula (I) besylate in isopropyl acetate/ethanol to ambient temperature). 
         [0055]    There is also provided according to the invention a besylate salt of a compound of formula (I) obtainable by any of the above methods. 
         [0056]    Methods of preparing salts of the invention are described in detail in the Examples below. 
         [0057]    A salt of the invention may be used as a medicament, in particular for sedative or hypnotic, anxiolytic, muscle relaxant, or anticonvulsant purposes. 
         [0058]    While it is possible for a salt of the invention to be administered as a bulk active chemical, it is preferably provided with a pharmaceutically acceptable carrier, excipient, or diluent in the form a pharmaceutical composition. The carrier, excipient, or diluent must, of course, be acceptable in the sense of being compatible with the other ingredients of the composition and must not be deleterious to the recipient. 
         [0059]    Accordingly, the present invention provides a pharmaceutical composition comprising a salt of the invention and a pharmaceutically acceptable carrier, excipient, or diluent. 
         [0060]    Pharmaceutical compositions of the invention include those suitable for oral, rectal, topical, buccal (e.g. sub-lingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration. 
         [0061]    Preferably a salt of the invention is provided in the form of a pharmaceutical composition for parenteral administration, for example, by intravenous or intramuscular injection of a solution. Where the pharmaceutical composition is for parenteral administration, the composition may be an aqueous or non-aqueous solution or a mixture of liquids, which may include bacteriostatic agents, antioxidants, buffers or other pharmaceutically acceptable additives. 
         [0062]    A preferred formulation of a salt of the invention is in an aqueous acidic medium of pH 2-4 or in an aqueous solution of a cyclodextrin (CD). Cyclodextrins that can be used for these formulations are either the anionically charged sulfobutylether (SBE) derivatives of β-CD, specifically SBE7-β-CD, marketed under the tradename Captisol by CyDex, Inc. (Critical Reviews in Therapeutic Drug Carrier Systems, 14 (1), 1-104 (1997)), or the hydroxypropyl CD&#39;s. 
         [0063]    A further preferred formulation of a salt of the invention is a lyophilised formulation comprising, in addition to the salt, at least one of the following agents: ascorbic acid, citric acid, maleic acid, phosphoric acid, glycine, glycine hydrochloride, succinic acid or tartaric acid. These agents are believed to be useful as buffering, caking or vizualisation agents. In some cases it may be beneficial to include sodium chloride, mannitol, polyvinylpyrrolidone, or other ingredients in the formulation. 
         [0064]    The preferred method of formulation (i.e., acid buffer or CD-based) may depend on the physicochemical properties (e.g., aqueous solubility, pKa, etc.) of a particular salt. Alternatively the salt may be presented as a lyophilized solid for reconstitution with water (for injection) or a dextrose or saline solution. Such formulations are normally presented in unit dosage forms such as ampoules or disposable injection devices. They may also be presented in multi-dose forms such as a bottle from which the appropriate dose may be withdrawn. All such formulations should be sterile. 
         [0065]    According to the invention there is provided a method for producing sedation or hypnosis in a subject, which comprises administering an effective sedative or hypnotic amount of a salt of the invention to the subject. 
         [0066]    There is also provided according to the invention a method for inducing anxiolysis in a subject, which comprises administering an effective anxiolytic amount of a salt of the invention to the subject. 
         [0067]    There is further provided according to the invention a method for inducing muscle relaxation in a subject, which comprises administering an effective muscle relaxant amount of a salt of the invention to the subject. 
         [0068]    There is further provided according to the invention a method for treating convulsions in a subject, which comprises administering an effective anticonvulsant amount of a salt of the invention to the subject. 
         [0069]    According to the invention there is also provided use of a sedative or hypnotic amount of a salt of the invention in the manufacture of a medicament for producing sedation or hypnosis in a subject. 
         [0070]    According to the invention there is also provided a salt of the invention for producing sedation or hypnosis in a subject. 
         [0071]    There is also provided according to the invention use of an anxiolytic amount of a salt of the invention in the manufacture of a medicament for producing anxiolysis in a subject. 
         [0072]    There is also provided according to the invention a salt of the invention for producing anxiolysis in a subject. 
         [0073]    There is further provided according to the invention use of a muscle relaxant amount of a salt of the invention in the manufacture of a medicament for producing muscle relaxation in a subject. 
         [0074]    There is further provided according to the invention a salt of the invention for producing muscle relaxation in a subject. 
         [0075]    There is further provided according to the invention use of an anticonvulsant amount of a salt of the invention in the manufacture of a medicament for treating convulsions in a subject. 
         [0076]    There is further provided according to the invention a salt of the invention for treating convulsions in a subject. 
         [0077]    The subject is suitably a mammal, preferably a human. 
         [0078]    A suitable pharmaceutical parenteral preparation for administration to humans will preferably contain 0.1 to 20 mg/ml of a salt of the invention in solution or multiples thereof for multi-dose vials. 
         [0079]    Intravenous administration can take the form of bolus injection or, more appropriately, continuous infusion. The dosage for each subject may vary, however, a suitable intravenous amount or dosage of a salt of the invention to obtain sedation or hypnosis in a mammal would be 0.01 to 5.0 mg/kg of body weight, and more particularly, 0.02 to 0.5 mg/kg of body weight, the above being based on the weight of the salt which is the active ingredient. A suitable intravenous amount or dosage of a salt of the invention to obtain anxiolysis in a mammal would be 0.01 to 5.0 mg/kg of body weight, and more particularly, 0.02 to 0.5 mg/kg of body weight, the above being based on the weight of the salt which is the active ingredient. A suitable intravenous amount or dosage of a salt of the invention to obtain muscle relaxation in a mammal would be 0.01 to 5.0 mg/kg of body weight, and more particularly, 0.02 to 0.5 mg/kg of body weight, the above being based on the weight of the salt which is the active ingredient. A suitable intravenous amount or dosage of a salt of the invention to treat convulsions in a mammal would be 0.01 to 5.0 mg/kg of body weight, and more particularly, 0.02 to 0.5 mg/kg of body weight, the above being based on the weight of the salt which is the active ingredient. 
         [0080]    Salts of the invention are short-acting CNS depressants that are useful to be administered intravenously in the following clinical settings: preoperative sedation, anxiolysis, and amnestic use for perioperative events; conscious sedation during short diagnostic, operative or endoscopic procedures; as a component for the induction and maintenance of general anaesthesia, prior and/or concomitant to the administration of other anaesthetic or analgesic agents; ICU sedation. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0081]    Preferred embodiments of the invention are described in the following Examples with reference to the accompanying drawings in which: 
           [0082]      FIG. 1  shows a graph of compound of formula (I) content (% relative to initial) vs storage temperature; 
           [0083]      FIG. 2  shows Differential Scanning calorimetry (DSC) of LJC-039-081-1; 
           [0084]      FIG. 3  shows DSC of LJC-039-081-1 (solid) overlaid with LJC-039-081-2 (dotted); 
           [0085]      FIG. 4  shows DSC of besylate forms (Form 1 solid, Form 2 dashed); 
           [0086]      FIG. 5  shows DSC of besylate forms (Form 1 solid, Form 3 dotted and dashed); 
           [0087]      FIG. 6A  and  FIG. 6B  shows chromatographs of LJC-039-037-1 at T 0  and T 4  (and relate to the results in Table 10); 
           [0088]      FIG. 7  shows XRPD comparing LJC-039-037-1 (besylate salt) pre and post 4 week stability study; 
           [0089]      FIG. 8A  shows an XRPD comparison of besylate Form 1 and 2; 
           [0090]      FIG. 8B  shows Differential Scanning calorimetry (DSC) overlays of Form 1 and 2; 
           [0091]      FIG. 9A  shows an XRPD comparison of besylate Form 1 and 3, and  FIG. 9B  shows overlays of Form 1 and 3; 
           [0092]      FIG. 10  shows DSC of LJC-039-086-1 (besylate Form 4); 
           [0093]      FIGS. 11A-11I  show results for besylate Form 1:  FIG. 11A ) XRPD for 100 mg batch LJC-039-037-1;  FIG. 11B ) DSC for 100 mg batch LJC-039-037-1;  FIG. 11C ) TGA for 100 mg batch LJC-039-037-1;  FIG. 11D ) 1H NMR for 100 mg batch LJC-039-037-1;  FIG. 11E ) GVS for 100 mg batch LJC-039-037-1;  FIG. 11F ) XRPD post GVS for 100 mg batch LJC-039-037-1;  FIG. 11G ) XRPD post stability at 40° C./75% RH for 100 mg batch LJC-039-037-1;  FIG. 11H ) VT XRPD for 100 mg batch LJC-039-037-1;  FIG. 11I ) light polarised microscopy for 100 mg batch LJC-039-037-1; 
           [0094]      FIGS. 12A-12D  show results for besylate Form 2:  FIG. 12A ) XRPD for 100 mg batch LJC-039-067-8;  FIG. 12B ) DSC for 100 mg batch LJC-039-067-8;  FIG. 12C ) DSC with ramp rate of 2° C./min;  FIG. 12D )  1 H NMR for LJC-039-067-8; 
           [0095]      FIGS. 13A-13G  show results for besylate Form 3:  FIG. 13A ) XRPD for LJC-039-081-2 (2 nd  crop from liquors of LJC-039-081-1);  FIG. 13B ) DSC for LJC-039-081-2;  FIG. 13C ) DSC for LJC-039-081-2 (2° C./min ramp rate);  FIG. 13D ) TGA for LJC-039-081-2;  FIG. 13E ) 1 H NMR for LJC-039-081-2;  FIG. 13F ) GVS for LJC-039-081-2;  FIG. 13G ) XRPD post GVS for LJC-039-081-2; 
           [0096]      FIGS. 14A-14C  show results for besylate Form 4:  FIG. 14A ) XRPD for LJC-039-086-1;  FIG. 14B ) DSC for LJC-039-086-1;  FIG. 14C )  1 H NMR for LJC-039-086-1; 
           [0097]      FIGS. 15A and 15B  show HPLC chromatographs for release batch of besylate salts, followed by  FIGS. 15C and 15D  showing Agilent ChemStation reports detailing results; 
           [0098]      FIGS. 16A-16D  show chiral chromatography for LJC-039-081-1, and LJC-039-083-1; 
           [0099]      FIG. 17  shows exemplar images (ca. 4-8 mm diameter field of view) of the solid forms observed in crystallisations of compound of formula (I) besylate; 
           [0100]      FIG. 18  shows content of the asymmetric unit in Form 1; 
           [0101]      FIG. 19  shows molecular structure as determined by single-crystal X-ray diffraction of a crystal of compound of formula (I) besylate, Form 1, grown from a 2-methoxyethanol:pentyl acetate solution with atoms represented by thermal ellipsoids. Only hydrogens specifically located in the crystal structure are depicted; 
           [0102]      FIG. 20  shows conformation adopted by the two independent molecules in Form 1; 
           [0103]      FIG. 21  shows comparison of the conformation adopted by one independent molecule in Form 1 (top) and the conformation in Form 2 (bottom); 
           [0104]      FIG. 22  shows comparison of the conformation adopted by the two independent besylates in Form 1, view along two different directions; 
           [0105]      FIG. 23  shows comparison of the conformation adopted by one independent besylate in Form 1 (top) and the conformation in Form 2 (bottom); 
           [0106]      FIG. 24A-24C  show crystal structure, determined by single-crystal X-ray diffraction of a crystal of compound of formula (I) besylate grown from 2-methoxyethanol:pentyl acetate solution, viewed along the crystallographic a axis ( FIG. 24A ), b axis ( FIG. 24B ), and c axis ( FIG. 24C ); 
           [0107]      FIG. 25  shows short contact C—O&lt;3.6 Å, C—C&lt;3.6 Å, and N—O&lt;3.5 Å for Form 1; 
           [0108]      FIG. 26  shows calculated powder pattern diffraction from single crystal X-ray diffraction data for Form 1; 
           [0109]      FIG. 27  shows plate form crystals observed for compound of formula (I) besylate Form 2; 
           [0110]      FIG. 28  shows content of the asymmetric unit in Form 2; 
           [0111]      FIG. 29  shows molecular structure as determined by single-crystal X-ray diffraction of a crystal of compound of formula (I) besylate Form 2 with atoms represented by thermal ellipsoids. Only Hydrogens specifically located in the crystal structure are depicted; 
           [0112]      FIG. 30  shows conformation adopted by the independent molecule in Form 2; 
           [0113]      FIG. 31  shows conformation adopted by the independent besylate in Form 2, viewed along two different directions; 
           [0114]      FIGS. 32A-32C  show a crystal structure, determined by single-crystal X-ray diffraction of a crystal of compound of formula (I) besylate Form 2, viewed along the crystallographic a axis ( FIG. 32A ), b axis ( FIG. 32B ), and c axis ( FIG. 32C ); 
           [0115]      FIG. 33  shows short contact C—O&lt;3.6 Å, C—C&lt;3.6 Å and N—O&lt;3.5 Å for Form 2; 
           [0116]      FIG. 34  shows calculated powder pattern diffraction from single crystal X-ray diffraction data for Form 2; 
           [0117]      FIG. 35  shows labelling of atomic centres for Compound of formula (I) besylate Form 1; and 
           [0118]      FIG. 36  shows labelling of atomic centres for Compound of formula (I) besylate Form 2. 
       
    
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
     Example 1 
     Solid-State Stability Study of Compound of Formula (I) 
       [0119]    Method/Technique. 
         [0120]    2 mg samples of compound of formula (I), accurately weighed, were placed in 4-mL clear glass screw-cap vials. Samples were tested at initial and after 34 days stored at 5° C./Ambient Relative Humidity (AMRH) Closed, 30° C./60% RH Closed, 40° C./75% RH Open and 60° C./AMRH Closed. 
         [0000]    
       
         
               
             
               
               
             
               
               
               
               
             
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                 HPLC Method Condition 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Column: 
                   
               
               
                 Phase = 
                 Phenomenex Luna C18(2) 
               
               
                 Length × i.d = 
                 100 × 4.6 mm 
               
               
                 Particle size = 
                 3 μm 
               
               
                 Mobile phase: 
                 A = 1000:1 Water/Trifluoroacetic Acid 
               
               
                   
                 B = 1000:0.5 Acetonitrile/Trifluoroacetic Acid 
               
               
                 Flow rate: 
                 1.0 mL/min 
               
               
                 Column Temperature: 
                 40° C. 
               
               
                   
               
             
          
           
               
                 Gradient 
                 Time (min) 
                 % A 
                 % B 
               
               
                   
               
               
                   
                 0.0 
                 80 
                 20 
               
               
                   
                 20.0 
                 20 
                 60 
               
               
                   
                 25.0 
                 20 
                 60 
               
               
                   
                 25.1 
                 80 
                 20 
               
               
                   
                 30.0 
                 80 
                 20 
               
             
          
           
               
                 Detection Wavelength: 
                 230 mm 
               
               
                 Sample Mass Injected 
                 μg, typically 1 μL injection of 1.0 mg 
               
               
                   
                 compound of formula (I)/mL in 60:40 
               
               
                   
                 Water/Acetonitrile 
               
               
                 Retention Times 
                 Compound of formula (I) elutes at 
               
               
                   
                 approximately 7.64 min 
               
               
                   
               
             
          
         
       
     
       Results 
       [0121]    Appearance. 
         [0122]    Table 2 lists the appearance results. 
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Summary of Compound of Formula (I) Appearance Data 
               
             
          
           
               
                 Storage Condition 
                 Timepoint days 
                 Appearance 
               
               
                   
               
               
                 RT 
                 initial 
                 Cream to light yellow powder 
               
               
                 5 C./AMRH Closed 
                 34 
                 Cream to light yellow powder 
               
               
                 30 C./60% RH Closed 
                 34 
                 Cream to light yellow powder 
               
               
                 40 C./75% RH Open 
                 34 
                 Deliquesced yellow mass on 
               
               
                   
                   
                 bottom of vial 
               
               
                 60 C./AMRH Closed 
                 34 
                 Deliquesced dark yellow to 
               
               
                   
                   
                 orange mass on bottom of vial 
               
               
                   
               
             
          
         
       
     
         [0123]    Compound of Formula (I) Content (% w/w). 
         [0124]    The % w/w content values (see Table 3) show too much variability to detect differences between the initial value and those measured after 34 days at 5° C./AMRH Closed, 30° C./60% RH Closed or 40° C./75% RH Open. The average % w/w measured for the samples stored 34 days at 60° C./AMRH Closed show a 10% w/w decrease from the initial value. 
         [0125]    Compound of Formula (I) Content (% Area). 
         [0126]    The compound of formula (I) % area content (see Table 3 and  FIG. 1 ) shows no significant change after 34 days stored at 5° C./AMRH Closed, but decreases steadily with increasing storage temperature for samples at 30° C./60% RH Closed, 40° C./75% RH Open or 60° C./AMRH Closed. Major degradation peaks are observed at RRT 0.68, 0.87 and RRT 0.90, but the chromatograms, which are relatively complex even at initial (23 peaks), also show many new small degradent peaks (e.g. 7 peaks at 30° C./60% RH Closed; 13-20 peaks at 60° C./AMRH Closed). These observations suggest multiple degradation pathways. The degradent at RRT 0.68 is tentatively identified as the ester hydrolysis product (the free acid of compound of formula (I)). It is most prevalent in the 40° C./75% RH Open samples, as would be expected for a hydrolysis product. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 Summary of Compound of Formula (I) HPLC Data 
               
             
          
           
               
                   
                   
                 Compound of Formula 
                 % Relative to 
               
               
                   
                 Timepoint 
                 (I) Content 
                 Avg. Initial % 
               
             
          
           
               
                 Storage Condition 
                 Days 
                 % w/w 
                 % area 
                 area 
               
               
                   
               
             
          
           
               
                 RT 
                 initial 
                 100.5 
                 95.14 
                 Avg = 94.81 
               
               
                 RT 
                 initial 
                 104.1 
                 94.47 
               
               
                 5 C./AMRH 
                 34 
                 102.6 
                 95.30 
                 100.52 
               
               
                 Closed#1 1   
               
               
                 30 C./60% RH 
                 34 
                 94.7 
                 94.20 
                 99.36 
               
               
                 Closed #1 1   
               
               
                 40 C./75% RH 
                 34 
                 105.4 
                 93.45 
                 98.57 
               
               
                 Open #1 
               
               
                 40 C./75% RH 
                 34 
                 100.3 
                 93.39 
                 98.50 
               
               
                 Open #2 
               
               
                 60 C./AMRH 
                 34 
                 93.4 
                 87.77 
                 92.57 
               
               
                 Closed #1 
               
               
                 60 C./AMRH 
                 34 
                 91.1 
                 87.77 
                 92.57 
               
               
                 Closed #2 
               
               
                   
               
               
                 Notes 
               
               
                 Only one sample was tested due to an autosampler sequencer error. 
               
             
          
         
       
     
       Conclusions 
       [0127]    Compound of formula (I) is stable with respect to appearance and content for at least 34 days stored at 5° C./AMRH Closed. No change in appearance was noted at 30° C./60% RH Closed, but an approximately 0.6% drop in compound of formula (I) content relative to the initial % area was observed. Samples stored at 40° C./75% RH Open or 60° C./AMRH Closed deliquesced, became yellow to orange in colour and showed notable decreases (1.5 to 8%) in compound of formula (I) content relative to initial. Major degradation peaks at RRT 0.68, 0.87 and RRT 0.90 are observed along with numerous smaller peaks, suggesting multiple degradation pathways. The degradent at RRT 0.68 is tentatively identified as the ester hydrolysis product. These results indicate that compound of formula (I) should be stored refrigerated for long term storage. 
       Example 2 
       [0128]    The solubility of the compound of formula (I) was determined in a wide range of organic solvents. The solubility data is shown in Table 4 below. 
         [0000]    
       
         
               
               
               
             
           
               
                   
                 TABLE 4 
               
               
                   
                   
               
               
                   
                 Solvent 
                 Min solvent required/mg/ml 
               
               
                   
                   
               
             
             
               
                   
                 Methanol 
                 446 
               
               
                   
                 Ethanol 
                 324 
               
               
                   
                 Propan-2-ol 
                 454 
               
               
                   
                 Acetone 
                 214 
               
               
                   
                 Toluene 
                 460 
               
               
                   
                 Ethyl acetate 
                 218 
               
               
                   
                 Tetrahydrofuran 
                 311 
               
               
                   
                 Acetonitrile 
                 362 
               
               
                   
                   
               
             
          
         
       
     
         [0129]    The data clearly shows that the compound of formula (I) has high solubility in common organic solvents. The preferred solvents are ethanol and toluene. 
         [0130]    Two basic centres of the free base of the compound were measured for pKa. However, the basic centre of the pyridine ring had a pKa of 1.99. The pKa of the basic centre of the imidazole ring was measured to be 4.53. 
         [0131]    Benzene sulfonic acid was used to produce a besylate salt of the compound of formula (I). Experiments were conducted on a 20 mg scale using 6 volumes of solvent. All reactions were carried out at ambient temperature with acids charged as stock solutions in ethanol (1M) or as solids depending on solubility. 
         [0132]    Solids isolated showed significant peak shifts in  1 H NMR to confirm salt formation. X-Ray Powder Diffraction (XRPD) showed that the salt had crystalline indication. Table 5 summarises the isolated salt form. 
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 5 
               
               
                   
               
               
                 Entry 
                 Salt 
                 Solvent 
                 ID 
               
               
                   
               
             
             
               
                 1 
                 besylate 
                 toluene 
                 LJC-039-009-7 
               
               
                   
               
             
          
         
       
     
         [0133]    The salt was subsequently stored at 40° C./75% RH for two weeks then re-analysed by XRPD and HPLC for chemical purity to assess stability of the materials. The salt retained the same powder pattern after exposure to the humidity conditions, and also retained high chemical purity supporting improved stability. 
         [0134]    It can be seen from the T 1  purity results of the isolated salt (Table 6 below) that the besylate salt from toluene showed high purity values before and after the stability study. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                 Summary of purity before and after 40° C./75% RH for 1 week 
               
             
          
           
               
                 Entry 
                 Salt 
                 ID 
                 Purity T 0 /% 
                 Purity T 1 /% 
               
               
                   
               
               
                 1 
                 besylate 
                 LJC-039-009-7 
                 95.9 
                 95.9 
               
               
                   
               
             
          
         
       
     
         [0135]    The results above show that the besylate salt form showed high purity and favourable stability results. 
       Example 3 
       [0136]    Scale up of the besylate salt to 100 mg was performed based on data in Example 2. Toluene was found to be the preferred solvent for isolating besylate salts. 
       Besylate Salt of Compound of Formula (I) 
       [0137]    A scale up to 50 mg of input material was carried out in order to confirm whether or not the process would scale up, and to confirm that the material isolated was of the same crystalline form (Form 1) seen from the previous smaller scale experiment. Once the analysis confirmed the salt to be Form 1 and that the properties were in keeping with what was expected, another scale up was carried out with 100 mg of input material in order to carry out full characterisation and submit the sample for a 4 week stability study at 40° C./75% RH. Both the scaled up reactions were carried out in toluene with benzene sulfonic acid added as a solution in ethanol (1M). 
       Besylate Experimental Procedure 
       [0138]    Compound of formula (I) free base (100 mg, batch 704-17) was charged to a vial and toluene (600 μl) was added at ambient temperature. To the solution benzene sulfonic acid (250 μl, 1M in ethanol) was added and the reaction mixture stirred for fifteen minutes, after which time a solid had precipitated from the solution which was filtered, washed with toluene and oven dried at 40° C. under vacuum. Analysis by XRPD showed the solid to be of identical powder pattern as other besylates generated, and the  1 H NMR confirmed salt formation due to significant peak shifts. 
         [0000]    
       
         
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 7 
               
               
                   
               
               
                   
                   
                   
                   
                 Onset 
                 TGA 
                   
                   
                 Chiral 
               
               
                   
                   
                   
                 GVS 
                 melt/ 
                 weight 
                 Solubility 
                 Chemical 
                 purity/% 
               
               
                 Entry 
                 ID 
                 salt 
                 uptake/% 
                 ° C. 
                 loss/% 
                 mg/ml 
                 purity/% 
                 e.e 
               
               
                   
               
             
             
               
                 1 
                 LJC- 
                 besylate 
                 2.0 
                 201.3 
                 4.9 
                 8.3 
                 97.1 
                 94.4 
               
               
                   
                 039- 
               
               
                   
                 037-1 
               
               
                   
               
             
          
         
       
     
         [0139]    The enantiomeric excess for LJC-039-037-1 was only 94.4 therefore the result was compared to another batch of besylate (LJC-039-081-1) that was isolated under identical conditions. The enantiomeric excess of this batch was 99.1%. 
       Process Optimisation 
       [0140]    To improve further yields of besylate salt (Form 1) four solvents were screened (isopropyl acetate, ethyl formate, methanol and acetone). In total eight 100 mg scale reactions were conducted in these solvents with the relevant acid added as stock solution in ethanol for comparison to previous experiments. 
         [0141]    Compound of formula (I) (batch 704-38, 100 mg) dissolved in solvent (600 μl) at ambient. Acid (250 μl, 1M stock solution in ethanol) added and all reaction mixtures stood for 48 hours at ambient. The results are summarised in Table 8. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 8 
               
             
             
               
                   
               
               
                 Results of process optimisation experiments 
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 Purity post 
               
               
                   
                   
                   
                   
                   
                   
                   
                 40° C./75% RH 
               
               
                 Table 
                 Lab book 
                   
                   
                   
                   
                 Purity/ 
                 for 4 
               
               
                 entry 
                 reference 
                 Salt 
                 Solvent 
                 XRPD 
                 Yield/% 
                 % area 
                 weeks 
               
               
                   
               
               
                 1 
                 LJC-039- 
                 besylate 
                 acetone 
                 Form 1 
                 38 
                 98.4 
                 98.1 
               
               
                   
                 067-2 
               
               
                 2 
                 LJC-039- 
                 besylate 
                 iPrOAc 
                 Form 1 
                 79 
                 97.7 
                 95.9 
               
               
                   
                 067-4 
               
               
                 3 
                 LJC-039- 
                 besylate 
                 Ethyl 
                 Form 1 
                 40 
                 98.6 
                 98.3 
               
               
                   
                 067-6 
                   
                 formate 
               
               
                 4 
                 LJC-039- 
                 besylate 
                 MeOH 
                 Single 
                 Not 
                 98.1 
                 Not 
               
               
                   
                 067-8 
                   
                   
                 crystals, 
                 recorded 
                   
                 recorded 
               
               
                   
                   
                   
                   
                 Form 2 
               
               
                   
               
             
          
         
       
     
         [0142]    All reactions except that of besylate formation in methanol showed Form 1. The methanol reaction was stored at 4° C. The data obtained confirmed anhydrous besylate 1:1, and a powder pattern of the material confirmed the existence of a new form (Form 2). 
         [0143]    It was concluded from the study that solvents such as isopropyl acetate increased the purity of the salts, however reduced the recovery. Because the previous choice of solvent (ethyl acetate) gave high yielding salts with high purity values, it was decided to use ethyl acetate for the final scale up experiments. 
       Besylate (Form 1) 1 g Scale-Up 
       [0144]    A 1 g formation of the besylate salt was carried out. This successfully produced 950 mg (70% yield) of Form 1. The liquors were highly coloured (yellow) and therefore seeded with a small amount of Form 1, to assist recovery. The liquors were stored at 4° C. for 16 hours. The solid obtained displayed a new powder pattern (Form 3). The solid was analysed by thermal analysis and variable temperature XRPD to confirm whether or not it was a true polymorph or a solvate. Interpretation of the analysis concluded it not to be a solvate from the  1 H NMR evidence, and the DSC showed two endothermic events confirmed by hostage microscopy ( FIG. 3 ). It was interpreted that the seeds of Form 1 melted at 187° C., with Form 3 melting at 200° C. The reason that Form 1 was not identified by XRPD is that this is a less sensitive technique than microscopy. 
         [0145]    Form 3 precipitates at a lower temperature to Form 1. 
         [0146]    Characterisation was carried out on the polymorphs to propose the relationship between them. 
         [0000]                                          TABLE 9                   Thermal data of besylate forms            Entry   ID   Form   Onset of Melt/° C.   ΔH/Jg −1                 1   LJC-039-081-1   1   201   56       2   LJC-039-067-8   2   180   73       3   LJC-039-081-2   1, 3   187, 200   7.6, 37                    
The lower melting point of the small amount of Form 1 present in LJC-039-081-2 can be potentially attributed to lower purity (97.2% compared with 97.9% in LJC-039-081-1).
 
         [0147]      FIG. 4  shows the DSC of besylate forms 1 (solid) and 2 (dashed). 
         [0148]      FIG. 5  shows the DSC of besylate forms 1 (solid) and 3 (dotted and dashed). 
       Example 4 
     Salt Stability Studies 
       [0149]      
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 10 
               
             
             
               
                   
               
               
                 Summary Table of salt purities after 4 week stability study 
               
             
          
           
               
                 Sample ID 
                 salt 
                 T 0   
                 T 1   
                 T 2   
                 T 3   
                 T 4   
               
               
                   
               
               
                 LJC-039-037-1 
                 besylate 
                 97.1 
                 97.3 
                 97.4 
                 96.7 
                 96.7 
               
               
                   
               
             
          
         
       
     
         [0150]    Crystalline samples of besylate were stored at 40° C./75% RH for a total of four weeks and samples were taken for HPLC every seven days. The besylate hplc purity remained consistent up until T 3  when it reached 96.7%. This value did however remain consistent to T 4 . 
         [0151]    The hplc chromatographs for the besylate salt form are shown in  FIG. 6  for time points week zero and week four. 
         [0152]    It is suspected that the dominant peak prior to that of the parent is from contamination as the λ max  does not match the λ max  of the parent peak. It is also absent from the impurity profile of T 1 , T 2 , T 3  and T 4 . 
         [0153]    It can be seen from the powder patterns of the salts pre and post humidity studies that there are no changes in form. 
         [0154]      FIG. 7  shows XRPD comparing LJC-039-037-1 (besylate salt) pre and post 4 week stability study. 
       Example 5 
     Polymorphism Investigation 
       [0155]    In order to determine the propensity of besylate salts to exhibit polymorphism, a maturation experiment was set up using thirty solvents (fifteen neat plus their 2.5% aqueous counterparts). The solid was slurried in various solvents (see Table 11) for one week on a heat/cool cycle from ambient to 60° C. After one week the slurries were evaporated and the solids analysed by XRPD and HPLC. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 11 
               
             
             
               
                   
               
               
                 Results of polymorphism investigation for besylate (LJC-039-058-2) 
               
               
                 starting hplc purity 97.7% 
               
             
          
           
               
                 Entry 
                 solvent 
                 XRPD post 1 week 
                 HPLC purity/% area 
               
               
                   
               
             
          
           
               
                 1 
                 acetone 
                 Form 1 
                 97.5 
               
               
                 2 
                 THF 
                 Form 1 
                 97.6 
               
               
                 3 
                 IPA 
                 amorphous 
                 97.1 
               
               
                 4 
                 MtBE 
                 Form 1 
                 97.7 
               
               
                 5 
                 DCM 
                 amorphous 
                 97.4 
               
               
                 6 
                 EtOH 
                 oil 
                 not analysed 
               
               
                 7 
                 MEK 
                 Form 1 
                 97.2 
               
               
                 8 
                 1,4-Dioxane 
                 Form 1 
                 97.2 
               
               
                 9 
                 iPrOAc 
                 Form 1 
                 97.5 
               
               
                 10 
                 DMF 
                 oil 
                 not analysed 
               
               
                 11 
                 MeCN 
                 Form 1 
                 94.3 
               
               
                 12 
                 nBuOH 
                 oil 
                 not analysed 
               
               
                 13 
                 nPrOH 
                 oil 
                 not analysed 
               
               
                 14 
                 MIBK 
                 Form 1 
                 97.7 
               
               
                 15 
                 MeOH 
                 oil 
                 not analysed 
               
               
                 16 
                 2.5% aq acetone 
                 Form 1 
                 96.8 
               
               
                 17 
                 2.5% aq THF 
                 amorphous 
                 93.3 
               
               
                 18 
                 2.5% aq IPA 
                 Form 1 
                 76.1 
               
               
                 19 
                 2.5% aq MtBE 
                 oil 
                 not analysed 
               
               
                 20 
                 2.5% aq DCM 
                 Form 1 
                 97.4 
               
               
                 21 
                 2.5% aq EtOH 
                 oil 
                 not analysed 
               
               
                 22 
                 2.5% aq MEK 
                 Form 1 
                 93.9 
               
               
                 23 
                 2.5% aq 1,4-Dioxane 
                 Form 1 
                 86 
               
               
                 24 
                 2.5% aq iPrOAc 
                 oil 
                 not analysed 
               
               
                 25 
                 2.5% aq DMF 
                 oil 
                 not analysed 
               
               
                 26 
                 2.5% aq MeCN 
                 Form 1 
                 93.3 
               
               
                 27 
                 2.5% aq nBuOH 
                 oil 
                 not analysed 
               
               
                 28 
                 2.5% aq nPrOH 
                 oil 
                 not analysed 
               
               
                 29 
                 2.5% aq MIBK 
                 Form 1 
                 97.3 
               
               
                 30 
                 2.5% aq MeOH 
                 oil 
                 not analysed 
               
               
                   
               
             
          
         
       
     
         [0156]    The maturation study using the besylate salt revealed no new forms. The purity results post maturation show that those slurried in acetonitrile, aqueous THF, aqueous IPA aqueous MEK, aqueous dioxane and aqueous acetonitrile degraded. This suggests that the besylate salt (Form 1) has good solution stability in neat organic solvents at high temperature. 
       Investigating New Forms of Besylate 
       [0157]    Although no new forms of the besylate salt were seen from the maturation study, a new form was seen when crystals were grown in methanol. The single crystals obtained from methanol were ground in order to obtain a powder pattern. This pattern turned out to be different from Form 1. A repeat experiment was carried out in order to obtain a further supply of Form 2. It was only possible to isolate Form 2 from precipitation over 16 hours from the liquors, opposed to allowing the solvent to evaporate, this gave Form 1. Interestingly two habits were present; needles and blocks. Both showed the same powder pattern as the needle habit that was used for single crystal structure determination. 
         [0158]    Full analysis was carried out on Form 2. It had been concluded that it was a true polymorph as the single crystal data confirmed anhydrous besylate 1:1. 
         [0159]      FIG. 8A  shows an XRPD comparison of besylate Form 1 and 2. There is an obvious difference between Form 1 (trace 1) and Form 2 (trace 2). As can be seen from the two powder patterns, both forms are very different. Thermal analysis was carried out to compare the melting points of the two forms and also thermodynamic solubility measurements recorded. 
         [0160]      FIG. 8B  shows overlays of Form 1 and 2. Form 1 and 2 show one endothermic event (melting). 
         [0161]    Form 3 was identified when a second crop was isolated from the liquors of LJC-039-081-1 (the 1 g scale-up reaction). Analysis was carried out in order to determine whether or not it was a solvate and how the forms interconvert. 
         [0162]      FIG. 9A  shows an XRPD comparison of besylate Form 1 and 3.  FIG. 9B  shows overlays of Form 1, and 3. 
         [0163]    Form 1 shows one endothermic event (melting), whereas Form 3 shows two events. Hostage microscopy on Form 3 clearly shows two melts within 20° C. of each other. It is postulated that a small amount of the lower melting polymorph is present as it was not picked up in variable temperature XRPD, which is a less sensitive technique. It is quite possible that the first endothermic event represents Form 1 as it was used to seed the liquors that Form 3 was isolated from. 
         [0164]    The solubility data shows that all three forms have very similar aqueous solubilities of 7.8 to 8.3 mg/ml at pH 3. 
       Besylate Salt Form 4 
       [0165]    The release batch of besylate salt Form 1 (LJC-039-083-1) was of high purity (97.6%), but contained a small amount of impurity carried through from the free base (0.78%, 11.9 min RT). This impurity was observed in the DSC experiment showing an endothermic transition (onset at 130° C.). The peak was confirmed as having an unrelated λmax to that of the parent peak. 
         [0166]    A 100 mg sample was taken for a re-crystallisation attempt from 40% isopropyl acetate/ethanol. The re-crystallisation was carried out traditionally by dissolving the salt in the minimum amount of hot solvent, then cooling slowly to ambient to yield a precipitate. The dried solid was analysed by XRPD which indicated a new form, and with thermal analysis and  1 H NMR it was confirmed to be a polymorph and not a solvate.  FIG. 10  shows DSC of LJC-039-086-1. 
         [0167]    The salt screen investigations have shown that compound of formula (I) forms many salts within the appropriate pKa range, and that they are easily isolated from a range of solvents. From full characterisation of the salts, it has been determined that the besylate salts have good stability with respect to humidity. It has been concluded that there are two polymorphic forms of besylate. Form 3 came from the second crop of LJC-039-081-1 liquors after seeding with Form 1. Form 4 has been observed after a re-crystallisation of Form 1 was carried out from 40% isopropyl acetate/ethanol. 
         [0168]    Full analytical data is shown in  FIGS. 11-14  below. 
       Experimental Methods for Examples 2-5 
     Example 2 
       [0169]    Compound of formula (I) (5 mg/well) was dissolved in solvent (ethanol, toluene, and acetonitrile) (30 μl) in HPLC vials. To the solutions, benzene sulfonic acid (11.4 μl, 1M in ethanol) was added and the reaction mixtures stood overnight at ambient. Those vials that contained solid were dried at 40° C. under vacuum, and those that remained as solutions were concentrated by evaporation and then treated with heptane. Those that precipitated were dried as mentioned, and those that oiled were stored at 4° C. 
       Besylate Form 1 Scale Up 
       [0170]    Compound of formula (I) (100 mg) dissolved in ethyl acetate (600 μl) and benzene sulfonic acid (250 μl, 1M in ethanol) added. Precipitation occurred instantly and the reaction mixture was stirred for 24 hours at ambient. The solid was filtered, washed with ethyl acetate and oven dried at 40° C. under vacuum for 16 hours. 
       Analysis Methods 
     Differential Scanning Calorimetry (DSC) 
       [0171]    DSC data was collected on a TA instrument Q1000 equipped with a 50 position autosampler. The energy and temperature calibration standard was indium. Samples were heated at a rate of 10° C./min between 25 and 350° C. A nitrogen purge at 30 ml/min was maintained over the sample. 
         [0172]    Between 0.5 and 3 mg of sample was used, unless otherwise stated, and all samples ran in a pin holed aluminium pan. 
       Thermogravimetric Analysis (TGA) 
       [0173]    TGA data was collected on a TA Instrument Q500 TGA, calibrated with Alumel and running at scan rates of 10° C./minute. A nitrogen purge at 60 ml/min was maintained over the sample. 
         [0174]    Typically 5-10 mg of sample was loaded onto a pre-tared platinum crucible unless otherwise stated. 
       NMR 
       [0175]    All spectra were collected on a Bruker 400 MHz equipped with autosampler. Samples were prepared in d6-DMSO, unless otherwise stated. 
       XRPD (X-Ray Powder Diffraction) 
     Bruker AXS C2 GADDS Diffractometer 
       [0176]    X-ray powder diffraction patterns for the samples were acquired on a Bruker AXS C2 GADDS diffractometer using Cu Kα radiation (40 kV, 40 mA), automated XYZ stage, laser video microscope for auto-sample positioning and a HiStar 2-dimensional area detector. X-ray optics consists of a single Göbel multilayer mirror coupled with a pinhole collimator of 0.3 mm. 
         [0177]    Beam divergence, i.e. the effective size of the X-ray beam on the sample, was approximately 4 mm. A θ-θ continuous scan mode was employed with a sample to detector distance of 20 cm which gives an effective 2θ range of 3.2-29.8°. A typical exposure time of a sample would be 120 s. 
         [0178]    Samples run under ambient conditions were prepared as flat plate specimens using powder as received without grinding. Approximately 1-2 mg of the sample was lightly pressed on a glass slide to obtain a flat surface. Samples run under non-ambient conditions were mounted on a silicon wafer with heat conducting compound. The sample was then heated to the appropriate temperature at ca. 20° C./minute and subsequently held isothermally for ca 1 minute before data collection was initiated. 
         [0179]    Purity Analysis: 
       Chemical Method 
       [0180]    Purity analysis was performed on a HP1100 Agilent: 
       Method: Gradient, Reverse Phase 
     Method Duration/min: 34 
       [0181]    Column: Phenomenex Gemini C18 5 μm (2.0×50 mm) (Guard cartridge Phenomenex Gemini C18 guard cartridge 2×4 mm) 
       Column Temperature/° C.: 40 
     Injection/μl: 5 
       [0182]    Flow Rate ml/min: 0.8 
       Detection: UV 
       [0183]    Wavelength/nm: 255 (bandwidth of 90 nm), 240 (bandwidth of 80 nm), 254 (bandwidth of 8 nm)
 
Phase A: 2 mmol NH 4 HCO 3  (adjusted to pH10 with NH 3  solution)
 
Phase B: acetonitrile
 
       Timetable: 
       [0184]      
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
               
               
                 Time/Min 
                 % A 
                 % B 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 0 
                 90 
                 10 
               
               
                 25 
                 10 
                 90 
               
               
                 28.8 
                 10 
                 90 
               
               
                 29 
                 90 
                 10 
               
               
                 34 
                 90 
                 10 
               
               
                   
               
             
          
         
       
     
         [0185]    Chiral Method 
         [0000]    Purity analysis was performed on a Gilson HPLC system: 
       Method: Isocratic, Normal Phase 
     Method Duration/min: 50 
       [0186]    Column: Diacel Chiralcel OJ-H (5 μm) 4.6×250 mm (Guard cartridge Diacel Chiralcel
 
OJ-H analytical guard cartridge 5 μm 4.0×10 mm)
 
       Column Temperature/° C.: 40 
     Injection/μl: 10 
       [0187]    Flow Rate ml/min: 1.0 
       Detection: UV 
       [0188]    Wavelength/nm: 225 (single wavelength detector)
 
Phase A: hexane
 
Phase B: ethanol
 
       Timetable: 
       [0189]      
         [0000]    
       
         
               
               
               
             
           
               
                   
               
               
                 Time/Min 
                 % A 
                 % B 
               
               
                   
               
             
             
               
                 0 
                 93 
                 7 
               
               
                   
               
             
          
         
       
     
       Gravimetric Vapour Sorption (GVS) Studies 
       [0190]    All samples were run on a Hiden IGASorp moisture sorption analyser running CFRSorp software. Sample sizes were typically 10 mg. A moisture adsorption desorption isotherm was performed as outlined below (2 scans giving 1 complete cycle). All samples were loaded/unloaded at typical room humidity and temperature (40% RH, 25° C.). All samples were analysed by XRPD post GVS analysis. The standard isotherm was performed at 25° C. at 10% RH intervals over a 0-90% RH range unless otherwise stated. 
         [0000]    
       
         
               
               
               
             
               
               
               
             
               
               
               
             
           
               
                   
               
               
                 Scan1 
                 Scan2 
                   
               
             
          
           
               
                 Adsorption 
                 Desorption 
                 Adsorption 
               
               
                   
               
             
          
           
               
                 40 
                 85 
                 10 
               
               
                 50 
                 75 
                 20 
               
               
                 60 
                 65 
                 30 
               
               
                 70 
                 45 
                 40 
               
               
                 80 
                 35 
                   
               
               
                 90 
                 25 
                   
               
               
                   
                 15 
                   
               
               
                   
                 5 
                   
               
               
                   
                 0 
               
               
                   
               
             
          
         
       
     
       Solubility 
       [0191]    This was measured by suspending sufficient compound in 0.25 ml of solvent (water) to give a maximum final concentration of 10 mg/ml of the parent free form of the compound. The suspension was equilibrated at 25° C. for 24 hrs followed by a pH check and filtration through a glass fibre C 96 well plate. The filtrate is then diluted down 101×. Quantitation was by HPLC with reference to a standard dissolved in DMSO at approx 0.1 mg/ml. Different volumes of the standard, diluted and undiluted tests were injected. The solubility was calculated by integration of the peak area found at the same retention time as the peak maximum in the standard injection. If there is sufficient solid in the filter plate the XRPD is normally checked for phase changes, hydrate formation, amorphization, crystallization etc. 
       Timetable: 
       [0192]      
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
               
               
                 Time/min 
                 % Phase A 
                 % Phase B 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 0.0 
                 95 
                 5 
               
               
                 1.0 
                 80 
                 20 
               
               
                 2.3 
                 5 
                 95 
               
               
                 3.3 
                 5 
                 95 
               
               
                 3.5 
                 95 
                 5 
               
               
                 4.4 
                 95 
                 5 
               
               
                   
               
             
          
         
       
     
       pKa Determination 
       [0193]    pKa determination was performed on a Sirius GlpKa instrument with D-PAS attachment. Measurements were made by potentiometric titration in MeOH:H2O mixtures at 25° C. The titration media was ionic strength adjusted with 0.15M KCl. The values found in the MeOH:H 2 O mixtures were extrapolated to 0% co-solvent via a Yasuda-Shedlovsky extrapolation. 
       Hot Stage Microscopy 
       [0194]    Hot stage microscopy was studied using a Leica LM/DM polarised microscope combined with a Mettler-Toledo MTFP82HT hot-stage in the temperature range 25-350° C. with typical heating rates in the range 10-20° C./min. A small amount of sample was dispersed onto a glass slide with individual particles separated as well as possible. Samples were viewed under normal or cross-polarised light (coupled to a λ false-colour filter) with a ×20 objective lens. 
         [0195]    Chiral Purity Method 
       System Setup 
       [0196]    Pump: Gilson 322 binary pump 
       Detector: Gilson 152 UV/Vis 
       [0197]    Autosampler: Gilson 233XL rack+Gilson 402 dual syringe pump
 
Column oven: Phenomenex Thermasphere TS-130
 
Software: Gilson Unipoint LC software
 
       Column: Daicel Chiralcel OJ-H, 5 μm, 4.6×250 mm 
       [0198]    Guard column: Daicel Chiralcel OJ-H analytical guard cartridge, 5 μm, 4.6×10 mm 
       HPLC Conditions 
     Channel A: Hexane (93%) 
     Channel B: Ethanol (7%) 
       [0199]    Flow rate: 1.0 ml/min
 
Detector wavelength 225 nm
 
       Column Temperature: 40° C. 
       [0200]    Run time: 50.0 mins 
       Sample Conditions 
       [0201]    Approximately 0.2 mg of sample was dissolved in the appropriate volume of Hexane:Ethanol 1:1 v/v to give a 0.2 mg/ml solution. This was capped and placed on a vortex mixer at high speed for a duration of ˜15 seconds. If solid remained at this point, then the sample vial was sonicated for approximately 10 seconds followed by a further 10 to 15 seconds on the vortex mixer. 10 μl was injected onto the HPLC system. Samples were injected in duplicate following an initial duplicate injection of Hexane:Ethanol 1:1 v/v as a blank. 
       Example 5 
     Pharmacological Test Example 
       [0202]    The anaesthetic and sedative effects of the besylate salt Form 1 of the present invention was evaluated. The besylate (benzenesulfonic acid) salt was dissolved in physiological saline for administration of the test composition to the animal. The test composition was administered to mice, placed in individual Plexiglas cages (20×10×10 cm). Mice were injected with either vehicle or test substance by the intravenous route. The latency to sleep and the duration of anaesthesia (maximum: 90 minutes after test-substance administration) were recorded. Anaesthesia is indicated by loss of the righting reflex (LRR). The righting reflex test was performed as soon as the animals appear sedated, approximately every 20-30 seconds. Once the righting reflex is absent, duration of loss of righting reflex was measured by testing for the return of the righting reflex approximately every 20-30 seconds thereafter. Eight mice were studied per group and the test was performed blind. Results from the study are given in the table below. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                   
                 NUMBER 
                 LATENCY 
                   
               
               
                 TREATMENT 
                 OF MICE 
                 TO LRR (min) 
                 LRR DURATION (##) 
               
               
                 (mg/kg) 
                 WITH 
                 mean ± s.e.m. 
                 (min) 
               
             
          
           
               
                 i.v. 
                 LRR 
                 (#) 
                 mean ± s.e.m. (#) 
                 p value 
               
               
                   
               
               
                 Vehicle 
                 0 
                 — 
                 0.0 ± 0.0 
                 — 
               
               
                 CNS 7056X 
                 2 
                 — 
                 1.7 ± 1.3 NS 
                 0.1441 
               
               
                 besylate (20.4) 
                   
                   
                   
                   
               
               
                 CNS 7056X 
                 5+ 
                 3.0 ± 0.2 
                 4.9 ± 1.6* 
                 0.0106 
               
               
                 besylate (27.2) 
                   
                   
                   
                   
               
               
                 CNS 7056X 
                 6++ 
                 1.8 ± 0.2 
                 6.0 ± 1.9** 
                 0.0038 
               
               
                 besylate (34) 
                   
                   
                   
                   
               
               
                 CNS 7056X 
                 6++ 
                 1.6 ± 0.5 
                 7.3 ± 2.5** 
                 0.0038 
               
               
                 besylate (40.8) 
               
               
                   
               
               
                 Mann-Whitney U test: NS = Not Significant; *= p &lt; 0.05; **= p &lt; 0.01 
               
               
                 Fisher&#39;s Exact test (number of mice with LRR): no indication = not significant; += p &lt; 0.05; ++= p &lt; 0.01 
               
               
                 (#): not calculated if n &lt; 3 
               
               
                 (##): maximum = 90 minutes after injection 
               
             
          
         
       
     
         [0203]    The results in the above table show that the besylate salt Form 1 has a short latency to loss of righting reflex and therefore a short induction time to anaesthesia in the animals. Additionally the mice recover rapidly from anaesthesia as indicated by the short duration of loss of righting reflex. Thus, this compound can provide rapid induction and recovery from anaesthesia. 
       Example 6 
     Additional Conditions for Crystallisation of Forms 2, 3, and 4 
       [0204]    Additional conditions were tested in an attempt to reproduce the previously reported crystallisations of Forms 2, 3 and 4. However, the reported scales were substantially reduced and the methodology modified accordingly, as described below. 
       Form 2 
       [0205]    5 mg of solid was dissolved in 25 ul of methanol and 10 ul of ethanol added; the solution was then chilled at 4° C. for 3 days. 
       Form 3 
       [0206]    Three variants were attempted: 
         [0207]    5 mg of solid was dissolved in 50 ul of ethanol and 120 ul of ethyl acetate added; the solution was then chilled at 4° C. for 3 days. 
         [0208]    10.1 mg of solid was dissolved in 300 ul of ethanol and 120 ul of ethyl acetate added; the solution was then chilled at 4° C. for 3 days. 
         [0209]    2.5 mg of solid was dissolved in 50 ul of ethanol in a silanized vial and 100 ul of ethyl acetate added; the solution was then chilled at 4° C. for 3 days. 
       Form 4 
       [0210]    Three variants were attempted: 
         [0211]    A warmed (70° C.) mixture isopropyl acetate:ethanol (40%:60% v/v) was added to 5 mg of warmed solid in 20 ul aliquots until the solid dissolved (60 ul of solvent mixture in total); the solution was then allowed to cool slowly to ambient in a thermostated waterbath initially at 70° C. over a period of hours. 
         [0212]    5 mg of solid was dissolved in 180 ul of warmed (50° C.) isopropyl acetate:ethanol (40%:60% v/v) solvent and the solution allowed to cool slowly to ambient in a thermostated waterbath (initially at 50° C.) over a period of hours. 
         [0213]    5 mg portion of solid was dissolved in 100 ul of warmed (50° C.) isopropyl acetate:ethanol (40%:60% v/v) solvent in a silanized vial and the solution allowed to cool slowly to ambient in a thermostated waterbath (initially at 50° C.) over a period of hours. 
         [0214]    Each of the crystallisations yielded solid material with blade and plate-like habits, with the Form 4 crystallisations also yielding needle-like material. 
       Example 7 
     Characterisation of Compound of Formula (I) Besylate 
       [0215]    Compound of formula (I) besylate is chiral and assumed to be of the single enantiomeric form below, i.e. the S enantiomer (consistent with the subsequently determined crystal structures): 
         [0000]    
       
                 
         
             
             
         
       
     
         [0216]    The heterocyclic structure contains a basic Nitrogen in the imidazole ring (pKa of ca. 5), and a weaker basic Nitrogen in the pyridyl ring (pKa of ca. 2). The imidazole-Nitrogen will typically be protonated in the presence of the strongly acidic besylate (pKa ca. −0.6) in aqueous solution, with the pyridyl-Nitrogen also potentially being protonated under conditions of excess besylate. 
         [0217]    The neutral free base form (i.e. unprotonated) of the compound is expected to be somewhat lipophilic (log P octanol:water  ca. 4.0) and thus would prefer some lipophilic environments over aqueous ones. Moreover, it is likely to retain a degree of lipophillicity even when monoprotonated (log D octanol:water  ca. 2 at pH3), although the effect of the besylate counter-ion is likely to ameliorate this tendency through its inherent hydrophilicity. The degree of lipophilicity further diminishes for the diprotonated form (log D octanol:water  ca. 0.6 at pH0). 
         [0218]    The compound also has an excess of Hydrogen bond acceptors and therefore will be suitably partnered by Hydrogen bond donating solvents. It is thus expected that the compound will prefer solubilisation in a range of polar organic solvents such as the alcohols, particularly those which provide a partially lipophilic, Hydrogen bond donating environment. This has been borne out by experimental evidence (details of solvents used are given in Example 8): 
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
               
               
                   
                   
                 Observed solubility 
               
               
                   
                 Solvent 
                 (mg/ml) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Formamide 
                 350 
               
               
                   
                 Water 
                 2 
               
               
                   
                 Dimethyl sulfoxide 
                 500 
               
               
                   
                 Dimethylacetamide 
                 200 
               
               
                   
                 1,2-ethanediol 
                 60 
               
               
                   
                 Dimethylformamide 
                 300 
               
               
                   
                 Acetonitrile 
                 &gt;20 
               
               
                   
                 Methanol 
                 400 
               
               
                   
                 2-ethoxyethanol 
                 20 
               
               
                   
                 2,2,2-trifluoroethanol 
                 1000 
               
               
                   
                 Ethanol 
                 100 
               
               
                   
                 Acetone 
                 2 
               
               
                   
                 Propan-1-ol 
                 15 
               
               
                   
                 Propan-2-ol 
                 4.8 
               
               
                   
                 2-methoxyethanol 
                 167 
               
               
                   
                 Hexafluoropropan-2-ol 
                 &gt;700 
               
               
                   
                 Dichloromethane 
                 &lt;&lt;0.3 
               
               
                   
                 Tetrahydrofuran 
                 2.5 
               
               
                   
                 Methylbenzoate 
                 2 
               
               
                   
                 Ethyl acetate 
                 0.2 
               
               
                   
                 Chloroform 
                 &lt;&lt;0.4 
               
               
                   
                 1,4-dioxan 
                 1 
               
               
                   
               
               
                 Soluble (&gt;5 mg/ml), partially soluble (2.5-5 mg/ml), partially insoluble (0.5-2.5 mg/ml, insoluble (&lt;0.5 mg/ml). 
               
               
                 Values quoted are approximate, but experimentally confirmed. 
               
             
          
         
       
     
         [0219]    These results highlight the good solubility of the compound in a wide variety of polar organic solvents. In particular, 2,2,2-trifluoroethanol and hexafluoropropan-2-ol are both identified as extremely good solvents for this compound. This is consistent with the considerations discussed above, both solvents being strong Hydrogen bond donors. Likewise, the more substantially lipophilic solvents are identified as poor solvents and thence potential anti-solvents for crystallisations. 
       Example 8 
     Compound of Formula (I) Besylate Crystallisations 
       [0220]    Various conditions conducive to obtaining crystalline material of compound of formula (I) besylate Forms 1 and 2 are described. Crystallisation conditions which include alcohols or acetonitrile solvents as components, with their respectively compatible anti-solvents or co-solvents, are believed to provide the most promising conditions to yield useful crystalline material. Crystallisation using solvent/anti-solvent binary mixtures was primarily used. Crystallisations were performed by retarded evaporation from sub-saturated solutions of the compound in solvent/anti-solvent mixtures, at ambient and reduced (4° C.) temperature. Crystallisation was typically observed within 3-5 days of preparation. 
         [0221]    Where sample quantity allowed, all crystallisation conditions were performed in duplicate in a glass 96-wellplate format; one half of each wellplate being used to duplicate the conditions in the other half of the wellplate. Cross-contamination between wells is minimised by design. All of the conditions tested behaved reproducibly in at least duplicate, most yielding solid material suitable for further analysis. 
         [0222]    In all cases, equipment coming into contact with samples and crystallisation media were scrupulously cleaned with a variety of solvents and reagents before being bathed in ethanol and blown dry using copious evaporated nitrogen. 
         [0223]    High quality solvents from commercial suppliers were employed, as described in Table 12. 
         [0000]    
       
         
               
               
               
               
               
               
             
           
               
                 TABLE 12 
               
               
                   
               
               
                   
                   
                 Cat. 
                   
                   
                   
               
               
                 Solvent 
                 Supplier 
                 No. 
                 Batch No. 
                 Grade 
                 Purity 
               
               
                   
               
             
             
               
                 1,2-dichlorobenzene 
                 Romil 
                 H177 
                 E558470 
                 SpS 
                 &gt;99.8% 
               
               
                 1,4- 
                 Fluka 
                 95682 
                 429739/1 
                 puriss p.a. 
                   &gt;99% 
               
               
                 dimethylbenzene 
                   
                   
                   
                   
                   
               
               
                 1,4-dioxan 
                 Romil 
                 H297 
                 H540480 
                 SpS 
                 &gt;99.9% 
               
               
                 2,2,2- 
                 Romil 
                 H860 
                 M538412 
                 SpS 
                 &gt;99.9% 
               
               
                 trifluoroethanol 
                   
                   
                   
                   
                   
               
               
                 acetonitrile 
                 Romil 
                 H049 
                 D531490 
                 SpS 
                 &gt;99.9% 
               
               
                 dimethylacetamide 
                 Romil 
                 H249 
                 B540480 
                 SpS 
                 &gt;99.9% 
               
               
                 dimethylsulfoxide 
                 Romil 
                 H280 
                 W530480 
                 SpS 
                 &gt;99.9% 
               
               
                 ethanol 
                 Romil 
                 H314 
                 O533480 
                 SpS 
                 &gt;99.8% 
               
               
                 ethyl acetate 
                 Romil 
                 H346 
                 T533480 
                 SpS 
                 &gt;99.9% 
               
               
                 methyl iso-butyl 
                 Romil 
                 H446 
                 M539430 
                 SpS 
                 &gt;99.9% 
               
               
                 ketone 
                   
                   
                   
                   
                   
               
               
                 n-nonane 
                 Romil 
                 H568 
                 O558450 
                 SpS 
                 &gt;99.9% 
               
               
                 pentylacetate 
                 Fluka 
                 46022 
                 13248/1 
                 puriss p.a. 
                 &gt;98.5% 
               
               
                 propan-1-ol 
                 Romil 
                 H624 
                 G531460 
                 SpS 
                 &gt;99.9% 
               
               
                 propan-2-ol 
                 Romil 
                 H625 
                 O530480 
                 SpS 
                 &gt;99.9% 
               
               
                 tetrachloroethylene 
                 Romil 
                 H702 
                 W536450 
                 SpS 
                 &gt;99.9% 
               
               
                 tetrahydrofuran 
                 Romil 
                 H718 
                 B532470 
                 SpS 
                 &gt;99.9% 
               
               
                 Acetone 
                 Romil 
                 H031 
                 E559470 
                 SpS 
                 &gt;99.9% 
               
               
                 Chloroform 
                 Romil 
                 H135 
                 B554470 
                 SpS 
                 &gt;99.9% 
               
               
                 Dichloromethane 
                 Romil 
                 H202 
                 O554460 
                 SpS 
                 &gt;99.9% 
               
               
                 Dimethylformamide 
                 Romil 
                 H253 
                 T546460 
                 SpS 
                 &gt;99.9% 
               
               
                 Formamide 
                 Romil 
                 H351 
                 Q537480 
                 BioPure 
                 &gt;99.9% 
               
               
                 Hexafluoropropan- 
                 Romil 
                 H359 
                 H559470 
                 SpS 
                 &gt;99.9% 
               
               
                 2-ol 
                   
                   
                   
                   
                   
               
               
                 Methylbenzoate 
                 Fluka 
                 12460 
                 417868/1 
                 purum 
                   &gt;98% 
               
               
                 water 
                 Romil 
                 H950 
                 D537480 
                 SpS 
                 &gt;99.9% 
               
               
                   
               
             
          
         
       
     
         [0224]    Visual analysis of the resulting crystalline morphologies was achieved using a binocular microscope (ca. 10×-40× magnification) with digital camera attached, employing both transmitted and reflected lighting as appropriate. 
         [0225]    Visual characterisation of the solid material is summarised in Table 14 below. A predominance of blade or tabular/plate morphologies, either as unique crystals or as spherulites, was observed. Over all, there was little morphological difference between the crystallisations performed at ambient temperatures and those at 4° C., with the exception of those with ethanol as solvent where the tendency for spherulite and interface type growth diminished with lowered temperature. It is notable that the use of anti-solvent can improve the quality of the crystalline material substantially. 
         [0226]    Example images of the crystalline material observed are presented in  FIG. 17 . As illustrated in this Figure, acetonitrile has a tendency to produce spherulite growth, typically seen as a consequence of poor nucleation and thence growth from poor quality crystal surfaces. In contrast, 2-methoxyethanol has a tendency to produce unique crystals of blade/needle-like morphology. 
         [0227]    There appears to be a general preference for Form 1 to crystallise from many of the conditions. However, it is notable that Form 2 has also been observed from several crystallisation conditions, including the scaled-down analogues for obtaining Forms 3 and 4 (described in Example 6). Form 2 is observed in conditions where there are extremes of either polarity (acetonitrile:water) or lipophilicity (n-nonane) or both (dimethyl sulfoxide:1,2-dichlorobenzene). In general, the crystals of Form 2 were notable in their superior quality and distinctive well-formed plate/tabular habit. 
       Single Crystal X-Ray Diffraction Cell Determinations 
       [0228]    To provide corroborative evidence of the crystalline forms generated, the cell parameters of a number of crystals of suitable quality were determined using single crystal X-ray diffraction. Crystal unit cell parameters were determined using a Kappa CCD diffractometer with Mo radiation, the crystals mounted on a glass fibre with oil and held at 260K. The parameters for Form 1 and Form 2 have been determined as summarised in Table 13. 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 13 
               
             
             
               
                   
               
               
                 Cell parameters determined for crystals of compound of formula (I) 
               
               
                 besylate. 
               
             
          
           
               
                   
                 Form 1 
                 Form 2 
               
               
                   
               
             
          
           
               
                   
                 Crystal State 
                   
                   
               
               
                   
                 Solvent 
                 2-methoxyethanol 
                 ethanol 
               
               
                   
                 Anti-solvent/Co- 
                 pentyl acetate 
                 ethyl acetate 
               
               
                   
                 solvent 
                   
                   
               
               
                   
                 Crystal Morphology 
                 needle 
                 plate 
               
               
                   
                 Crystal Size (mm) 
                 0.8 × 0.04 × 0.02 
                 0.7 × 0.3 × 0.25 
               
               
                   
                 Colour 
                 colourless 
                 colourless 
               
               
                   
                 Crystal Structure 
                   
                   
               
               
                   
                 System 
                 monoclinic 
                 orthorhombic 
               
               
                   
                 Unit Cell a (Å) 
                  7.6868 (1) 
                  8.92130 (10) 
               
               
                   
                 b (Å) 
                 29.2607 (5) 
                 11.1536 (2) 
               
               
                   
                 c (Å) 
                 12.3756 (3) 
                 25.8345 (4) 
               
               
                   
                 α (°) 
                 90 
                 90 
               
               
                   
                 β (°) 
                 97.7880 (8) 
                 90 
               
               
                   
                 γ (°) 
                 90 
                 90 
               
               
                   
                 Volume (Å 3 ) 
                 2757.86 (9) 
                 2570.65 (7) 
               
               
                   
               
             
          
         
       
     
         [0229]    The crystallisation results from solvent/co-solvent and solvent/anti-solvent conditions for compound of formula (I) besylate with single crystal X-ray diffraction unit cell results are tabulated in Table 14. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 14 
               
             
             
               
                   
               
               
                 Experimental crystallisation results from solvent/co-solvent and 
               
               
                 solvent/anti-solvent conditions for compound of formula (I) besylate, with single 
               
               
                 crystal X-ray diffraction unit cell results (X-ray results for ambient crystallisations 
               
               
                 unless otherwise stated). 
               
             
          
           
               
                   
                   
                   
                 X-ray 
               
               
                   
                   
                 Observed 
                 Form 
               
               
                   
                 Co/Anti-solvent 
                 Crystallisations 
                 (No &amp; habit 
               
               
                 Solvent 
                 (&amp; conditions) 
                 Habit 
                 of crystals) 
               
               
                   
               
               
                 methanol 
                 ethanol (at 4° C., 3 
                 blades &amp; plates 
                 2 (hex, blade) 
               
               
                   
                 days) 
                   
                   
               
               
                 ethanol 
                 ethyl acetate (at 
                 blades &amp; plates 
                 2 (4 plates) 
               
               
                   
                 4° C., 3 days) 
                   
                   
               
               
                 ethanol 
                 ethyl acetate 
                 blades &amp; plates 
                 2 (6 plates) 
               
               
                 isopropyl acetate 
                 ethanol (70° C. → 
                 blades, plates &amp; 
                 2 (2 plates) 
               
               
                   
                 20° C.) 
                 needles 
                   
               
               
                 isopropyl acetate 
                 ethanol (50° C. → 
                 blades &amp; plates 
                 2 (2 hex 
               
               
                   
                 20° C.) 
                   
                 plates, 2 
               
               
                   
                   
                   
                 plates, 2 
               
               
                   
                   
                   
                 blades) 
               
               
                 ethanol 
                 methyl isobutyl 
                 tabular plates 
                 2 (3 plates) 
               
               
                   
                 ketone (at 4° C., 3 
                   
                   
               
               
                   
                 days, silanized vial) 
                   
                   
               
               
                 ethanol 
                 p-cymene (at 4° C., 3 
                 plate &amp; tabular 
                 2 (2 tabular) 
               
               
                   
                 days, silanized vial) 
                   
                   
               
               
                 nonane 
                 none (silanized vial) 
                 blades &amp; plates 
                 2 (plate) 
               
               
                 dimethylsulfoxide 
                 1,2- 
                 intergrown blades 
                 2 (tabular) 
               
               
                   
                 dichlorobenzene 
                 dendrite, one huge 
                   
               
               
                   
                   
                 tabular 
                   
               
               
                 dimethylacetamide 
                 methyl isobutyl 
                 plate-like 
                 1 (blade) 
               
               
                   
                 ketone 
                 fragments 
                   
               
               
                 dimethylacetamide 
                 tetrachloroethylene 
                 intergrown blades 
                 1 (2 blades) 
               
               
                 acetonitrile 
                 water 
                 interface 
                 2 (2 tabular) 
               
               
                 acetonitrile 
                 3-methylbutan-1-ol 
                 triangular plates, 
                 1 (blade) 
               
               
                   
                   
                 fragments &amp; 
                   
               
               
                   
                   
                 dendrite 
                   
               
               
                 acetonitrile 
                 1,2- 
                 spherulite blades 
                 1 (2 blades) 
               
               
                   
                 dichlorobenzene 
                   
                   
               
               
                 acetonitrile 
                 pentyl acetate 
                 spherulite blades 
                 1 (blade) 
               
               
                 methanol 
                 none 
                 interface plates 
                 2 (plate) 
               
               
                 methanol 
                 3-methylbutan-1-ol 
                 triangular plates &amp; 
                 1 (2 blades) 
               
               
                   
                   
                 fragments 
                   
               
               
                 methanol 
                 methyl isobutyl 
                 fragments &amp; blade 
                 1 (blade) 
               
               
                   
                 ketone 
                   
                   
               
               
                 2,2,2- 
                 1,2- 
                 interface &amp; blade 
                 1 (trans, 
               
               
                 trifluoroethanol 
                 dichlorobenzene 
                 opaque &amp; 
                 blade) 
               
               
                   
                   
                 translucent blades 
                   
               
               
                 2,2,2- 
                 1,4- 
                 plate-like 
                 1 (sph, plate) 
               
               
                 trifluoroethanol 
                 dimethylbenzene 
                 fragments 
                   
               
               
                 ethanol 
                 methyl isobutyl 
                 interface plates 
                 1 (interface), 
               
               
                   
                 ketone 
                 (5° C.: tabular &amp; 
                 2 (tabular) 
               
               
                   
                   
                 plate) 
                   
               
               
                 ethanol 
                 1,2- 
                 interface plates, 
                 2 (plate) 
               
               
                   
                 dichlorobenzene 
                 (5° C.: needles) 
                   
               
               
                 ethanol 
                 tetrachloroethylene 
                 interface (5° C.: 
                 2 (blade 4° C.) 
               
               
                   
                   
                 hexagonal tabular) 
                   
               
               
                 ethanol 
                 1,4- 
                 interface blades 
                 1 (blade) 
               
               
                   
                 dimethylbenzene 
                   
                   
               
               
                 propan-1-ol 
                 none 
                 plate-like 
                 1 (plate) 
               
               
                   
                   
                 fragments 
                   
               
               
                 propan-1-ol 
                 1,2- 
                 interface 
                 1 (blade) 
               
               
                   
                 dichlorobenzene 
                   
                   
               
               
                 propan-1-ol 
                 tetrachloroethylene 
                 plate-like 
                 1 (blade) 
               
               
                   
                   
                 fragments &amp; 
                   
               
               
                   
                   
                 interface 
                   
               
               
                 propan-2-ol 
                 1,2- 
                 fan needles &amp; 
                 1 (blade) 
               
               
                   
                 dichlorobenzene 
                 dendrite 
                   
               
               
                 propan-2-ol 
                 n-nonane 
                 blades, needles &amp; 
                 1 (needle) 
               
               
                   
                   
                 spherulite needles 
                   
               
               
                 2-methoxy 
                 water 
                 blade 
                 1 (2 blades) 
               
               
                 ethanol 
                   
                   
                   
               
               
                 2-methoxy 
                 pentyl acetate 
                 needles 
                 1 (blade) 
               
               
                 ethanol 
                   
                   
                   
               
               
                 2-methoxy 
                 1,4- 
                 blades &amp; needles 
                 1 (blade) 
               
               
                 ethanol 
                 dimethylbenzene 
                   
                   
               
               
                 2-methoxy 
                 n-nonane 
                 blades &amp; dendrite 
                 1 (blade) 
               
               
                 ethanol 
                   
                   
                   
               
               
                 tetrahydrofuran 
                 water 
                 plate 
                 1 (plate) 
               
               
                 tetrahydrofuran 
                 3-methylbutan-1-ol 
                 intergrown blades 
                 1 (plate) 
               
               
                 tetrahydrofuran 
                 1,2- 
                 prismatic tabular, 
                 2 (3 tabular) 
               
               
                   
                 dichlorobenzene 
                 fragments, powder 
                   
               
               
                 tetrahydrofuran 
                 ethyl acetate 
                 dendrite, interface 
                 2 (plate 4° C.) 
               
               
                 tetrahydrofuran 
                 isopropyl acetate 
                 intergrown plates 
                 1 (plate) 
               
               
                   
                   
                 &amp; intergrown 
                   
               
               
                   
                   
                 blades 
                   
               
               
                 tetrahydrofuran 
                 1,3- 
                 intergrown blades 
                 1 (blade) 
               
               
                   
                 dimethylbenzene 
                   
                   
               
               
                 1,4-dioxane 
                 pentyl acetate 
                 triangular plates, 
                 1 (2 tri plate) 
               
               
                   
                   
                 some part of 
                   
               
               
                   
                   
                 spherulite 
                   
               
               
                 1,4-dioxane 
                 1,4- 
                 blade 
                 1 (blade) 
               
               
                   
                 dimethylbenzene 
               
               
                   
               
             
          
         
       
     
         [0230]    A variety of crystals of suitable quality for full single crystal X-ray diffraction crystal structure determination were achieved and the full structure obtained for Forms 1 and 2. These crystal structures are reported in Examples 9 and 10. 
       Example 9 
     Crystal Structure of Form 1 
       [0231]    Crystals of compound of formula (I) besylate grown from a 2-methoxyethanol:pentyl acetate solution which have a needle habit, are imaged in  FIG. 17 . 
         [0232]    A single needle habit crystal (ca. 0.8×0.04×0.02 mm in size) was selected and its cell parameters determined at 260K and then at 190K. No transition was observed on lowering the temperature between 260-190K. The structure analysed here is for the data at 190K; parameters of the crystal and the X-ray diffraction refinement are given in Table 15. 
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 15 
               
               
                   
               
               
                 Data of the 2-methoxyethanol:pentyl acetate grown crystal of compound 
               
               
                 of formula (I) besylate, Form 1. 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Crystal State 
                   
               
               
                   
                 Code 
                 CNS7056 besylate 
               
               
                   
                 Solvent 
                 2-methoxyethanol 
               
               
                   
                 Anti-solvent/Co-solvent 
                 pentyl acetate 
               
               
                   
                 Crystal Morphology 
                 needle 
               
               
                   
                 Crystal Size (mm) 
                 0.8 × 0.04 × 0.02 
               
               
                   
                 Colour 
                 colourless 
               
               
                   
                 Crystal Structure 
                   
               
               
                   
                 Formula 
                 C 54 H 50 Br 2 N 8 O 10 S 2   
               
               
                   
                 Formula Weight 
                 1194.98 
               
               
                   
                 System 
                 monoclinic 
               
               
                   
                 Space Group 
                 P 2 1   
               
               
                   
                 Unit Cell a (Å) 
                  7.6868 (1) 
               
               
                   
                 b (Å) 
                 29.2607 (5) 
               
               
                   
                 c (Å) 
                 12.3756 (3) 
               
               
                   
                 α (°) 
                 90 
               
               
                   
                 β (°) 
                 97.7880 (8) 
               
               
                   
                 γ (°) 
                 90 
               
               
                   
                 Volume (Å 3 ) 
                 2757.86 (9) 
               
               
                   
                 Z (No. molecules in unit) 
                 2 
               
               
                   
                 Z′ (No. molecules in asymmetric 
                 2 
               
               
                   
                 unit) 
                   
               
               
                   
                 Density (g cm 3 ) 
                 1.439 
               
               
                   
                 Absorption μ [MoKα] (mm −1 ) 
                 1.610 
               
               
                   
                 F(000) 
                 1224 
               
               
                   
                 Data Collection 
                   
               
               
                   
                 Temperature, (K) 
                 190 
               
               
                   
                 Instrument 
                 Kappa CCD diffractometer 
               
               
                   
                 Scan Type 
                 ω 
               
               
                   
                 Absorption Correction Type 
                 multi-scan 
               
               
                   
                 No. of Measured Reflections 
                 9868 
               
               
                   
                 No. of Independent Reflections 
                 9848 
               
               
                   
                 θ min/max (°) 
                  1.80/27.49 
               
               
                   
                 h min/max 
                 −9/9 
               
               
                   
                 k min/max 
                 −37/36 
               
               
                   
                 l min/max 
                 −15/15 
               
               
                   
                 Refinement 
                   
               
               
                   
                 Refinement On 
                 F 
               
               
                   
                 I/σ(I) Cut-off 
                 3 
               
               
                   
                 No. of Used Reflections 
                 6821 
               
               
                   
                 No. of Parameters 
                 686 
               
               
                   
                 R factor (%) 
                 6.34 
               
               
                   
                 Rw factor (%) 
                 6.39 
               
               
                   
                 S 
                 1.00 
               
               
                   
                 Δρ(min) Å −3   
                 −0.8 
               
               
                   
                 Δρ(max) Å −3   
                 0.8 
               
               
                   
                 Max Shift/Error 
                 0.0005 
               
               
                   
                 Flack Parameter 
                   0.027 (11) 
               
               
                   
               
             
          
         
       
     
         [0233]    The content of the asymmetric unit is displayed in  FIG. 18 . It consists of two independent molecules of the compound and two independent besylate counter ions. Each compound has the imidazole-Nitrogen protonated. 
         [0234]    The Flack “Enantiopole” parameter was determined as 0.03(1) and thus the stereochemistry of the structures depicted here are well established and are consistent with the purported stereochemistry for the compound: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0235]    Crystallographic co-ordinates and other relevant data are tabulated in the form of a SHELX file in Table 17. 
         [0236]    The conformational disorder can be represented (in first approximation) by the “thermal ellipsoids” of the atomic positions, as presented on  FIG. 19 . It can be seen that the major regions of disorder lie in the methyl groups and in the besylate. 
         [0237]    The difference between the two independent molecules comes mainly from the ester chains as seen in  FIG. 20 . One molecule has the ester chain being coplanar with the imidazole ring, whereas the other molecule has the ester chain being orthogonal. 
         [0238]    The conformation of the ester chains are different to that adopted in Form 2 ( FIG. 21 ). The orthogonal conformation observed in Form 1 bears the greatest similarity to that found in Form 2. 
         [0239]    The two independent besylates have staggered conformations ( FIG. 22 ). No substantial differences in bond lengths are apparent. 
         [0240]    One besylate adopts the conformation observed for the besylate in Form 2 ( FIG. 23 ). 
         [0241]    The resolved crystal structure, viewed along the crystallographic a, b and c axes, is illustrated in  FIG. 24 a, b  and  c    respectively.  FIG. 25  summarises the shortest contacts observed in the crystal packing. 
         [0242]    Each compound interacts with the two independent besylates. In particular, a short distance (hydrogen-bond type) is established between one oxygen atom of one besylate and the protonated nitrogen of the imidazole ring of the compound. The second independent compound interacts similarly, but with the second independent besylate. 
         [0243]    Other close contacts (C—O, H—O) are observed between the compounds and the besylates mainly in the vicinity of the imidazole and pyridyl ring. Some close contacts are also observed between the two compounds themselves (Br—N, C—C, O—H) and the two besylate themselves (O—H contacts) but to a lesser extent for the latter. 
         [0244]    Using the crystal structure determined experimentally, a powder diffraction pattern for Form 1 has been calculated using CrystalDiffract® (CrystalDiffract is a registered TradeMark of CrystalMaker Ltd) and is depicted in  FIG. 26 . This powder pattern matches the experimental powder pattern reported for Form 1. 
       Example 10 
     Crystal Structure of Form 2 
       [0245]    A crystal of compound of formula (I) besylate Form 2, which has a plate habit, is imaged in  FIG. 27 . 
         [0246]    A single plate habit crystal (ca. 0.7×0.30×0.25 mm in size) was selected and its cell parameters determined at 260K then at 190K. No transition was observed on lowering the temperature between 260-190K. The structure analysed here is for the data at 190K; parameters of the crystal and the X-ray diffraction refinement are given in Table 16. 
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 16 
               
               
                   
               
               
                 Data of the ethanol:ethyl acetate grown crystal of compound of formula 
               
               
                 (I) besylate, Form 2. 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Crystal State 
                   
               
               
                   
                 Code 
                 CNS7056 besylate 
               
               
                   
                 Solvent 
                 ethanol 
               
               
                   
                 Anti-solvent/Co-solvent 
                 ethyl acetate 
               
               
                   
                 Crystal Morphology 
                 plate 
               
               
                   
                 Crystal Size (mm) 
                 0.7 × 0.30 × 0.25 
               
               
                   
                 Colour 
                 colourless 
               
               
                   
                 Crystal Structure 
                   
               
               
                   
                 Formula 
                 C 27 H 25 Br 1 N 4 O 5 S 1   
               
               
                   
                 Formula Weight 
                 597.49 
               
               
                   
                 System 
                 Orthorhombic 
               
               
                   
                 Space Group 
                 P 2 1 2 1 2 1   
               
               
                   
                 Unit Cell a (Å) 
                  8.92130 (10) 
               
               
                   
                 b (Å) 
                 11.1526 (2) 
               
               
                   
                 c (Å) 
                 25.8345 (4) 
               
               
                   
                 α (°) 
                 90 
               
               
                   
                 β (°) 
                 90 
               
               
                   
                 γ (°) 
                 90 
               
               
                   
                 Volume (Å 3 ) 
                 2570.65 (7) 
               
               
                   
                 Z (No. molecules in unit) 
                 4 
               
               
                   
                 Z′ (No. molecules in asymmetric 
                 1 
               
               
                   
                 unit) 
                   
               
               
                   
                 Density (g cm 3 ) 
                 1.544 
               
               
                   
                 Absorption μ [MoKα] (mm −1 ) 
                 1.727 
               
               
                   
                 F(000) 
                 1224 
               
               
                   
                 Data Collection 
                   
               
               
                   
                 Temperature, (K) 
                 190 
               
               
                   
                 Instrument 
                 Kappa CCD diffractometer 
               
               
                   
                 Scan Type 
                 ω 
               
               
                   
                 Absorption Correction Type 
                 multi-scan 
               
               
                   
                 No. of Measured Reflections 
                 5750 
               
               
                   
                 No. of Independent Reflections 
                 5727 
               
               
                   
                 θ min/max (°) 
                  5.15/27.48 
               
               
                   
                 h min/max 
                 −11/11 
               
               
                   
                 k min/max 
                 −14/14 
               
               
                   
                 l min/max 
                 −33/33 
               
               
                   
                 Refinement 
                   
               
               
                   
                 Refinement On 
                 F 
               
               
                   
                 I/σ(I) Cut-off 
                 3 
               
               
                   
                 No. of Used Reflections 
                 4067 
               
               
                   
                 No. of Parameters 
                 344 
               
               
                   
                 R factor (%) 
                 3.85 
               
               
                   
                 Rw factor (%) 
                 3.66 
               
               
                   
                 S 
                 1.12 
               
               
                   
                 Δρ(min) Å −3   
                 −0.6 
               
               
                   
                 Δρ(max) Å −3   
                 0.5 
               
               
                   
                 Max Shift/Error 
                 0.0003 
               
               
                   
                 Flack Parameter 
                  0.011 (9) 
               
               
                   
               
             
          
         
       
     
         [0247]    The content of the asymmetric unit is displayed in  FIG. 28 . It consists of one independent molecule of the compound and one independent besylate. The compound has the imidazole-Nitrogen protonated. 
         [0248]    The Flack “Enantiopole” parameter was determined as 0.011(9) and thus the stereochemistry of the structures depicted here are well established and are consistent with the purported stereochemistry for the compound. Crystallographic co-ordinates and other relevant data are tabulated in the form of a SHELX file in Table 18. 
         [0249]    The conformational disorder can be represented (in first approximation) by the “thermal ellipsoids” of the atomic positions, as presented on  FIG. 29 . It can be seen that the major regions of disorder lie in the besylate. 
         [0250]    As discussed above, the conformation of the ester chain in Form 2, depicted in  FIG. 30 , is different to that adopted in Form 1. 
         [0251]    However, the conformation of the besylate is similar to the one observed for one of the besylate in Form 1 ( FIG. 31 ). 
         [0252]    The resolved crystal structure, viewed along the crystallographic a, b and c axes, is illustrated in  FIG. 32 a, b  and  c    respectively with  FIG. 33  summarising the shortest contacts observed in the crystal packing. The compound establishes a short contact (hydrogen-bond type) with one oxygen atom of the besylate through its protonated nitrogen of the imidazole ring. Other short contacts (C—C, C—O, H—O) are observed between the compound and the besylate through the imidazole ring. 
         [0253]    Some close contacts are also observed between the two compounds themselves (Br—C, C—C, O—C, O—H), most of which are via the ester chain. There are no close contacts between the besylate themselves. 
         [0254]    Using the crystal structure determined experimentally, a powder diffraction pattern for Form 2 has been calculated using CrystalDiffract® ( FIG. 34 ). This powder pattern matches the experimental powder pattern reported for Form 2. 
         [0000]    
       
         
               
             
               
               
             
           
               
                 TABLE 17 
               
               
                   
               
               
                 Crystallographic co-ordinates and other relevant data tabulated in the 
               
               
                 form of a SHELX File for Compound of formula (I) besylate Form 1. 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 TITL 12161316 Compound CNS7056 Form 1 
               
               
                   
                 CELL 0.71073 7.687 29.261 12.376 90.000 97.788 90.000 
               
               
                   
                 ZERR 2 0.0001 0.0005 0.0003 0.0000 0.0008 0.0000 
               
               
                   
                 LATT −1 
               
               
                   
                 SYMM −X, Y + 0.500, −Z 
               
               
                   
                 SFAC C 2.3100 20.8439 1.0200 10.2075 1.5886 0.5687 0.8650 = 
               
               
                   
                 51.6512 0.2156 0.0033 0.0016 1.15 0.7700 12.0110 
               
               
                   
                 SFAC H 0.4930 10.5109 0.3229 26.1257 0.1402 3.1424 0.0408 = 
               
               
                   
                 57.7998 0.0030 0.0000 0.0000 0.06 0.3200 1.0079 
               
               
                   
                 SFAC O 3.0485 13.2771 2.2868 5.7011 1.5463 0.3239 0.8670 = 
               
               
                   
                 32.9089 0.2508 0.0106 0.0060 3.25 0.7700 15.9994 
               
               
                   
                 SFAC BR 17.1789 2.1723 5.2358 16.5796 5.6377 0.2609 3.9851 = 
               
               
                   
                 41.4328 2.9557 −0.2901 2.4595 1000.00 1.1000 79.9040 
               
               
                   
                 SFAC N 12.2126 0.0057 3.1322 9.8933 2.0125 28.9975 1.1663 = 
               
               
                   
                 0.5826 −11.5290 0.0061 0.0033 1.96 0.7700 14.0067 
               
               
                   
                 SFAC S 6.9053 1.4679 5.2034 22.2151 1.4379 0.2536 1.5863 = 
               
               
                   
                 56.1720 0.8669 0.1246 0.1234 53.20 1.1100 32.0660 
               
               
                   
                 UNIT 108. 100. 20. 4. 16. 4. 
               
               
                   
                 S80 6 0.23964 0.43139 0.09908 11.00000 0.04634 0.03299 = 
               
               
                   
                 0.04052 0.00002 0.01880 −0.00340 
               
               
                   
                 O81 3 0.16028 0.39374 0.15143 11.00000 0.06864 0.04111 = 
               
               
                   
                 0.05255 −0.00210 0.02801 0.00002 
               
               
                   
                 O82 3 0.14598 0.47435 0.11207 11.00000 0.08099 0.03603 = 
               
               
                   
                 0.04614 0.00545 0.03373 −0.00236 
               
               
                   
                 O83 3 0.42589 0.43401 0.12925 11.00000 0.05754 0.08564 = 
               
               
                   
                 0.05198 −0.01536 0.01792 −0.00644 
               
               
                   
                 C84 1 0.20581 0.41866 −0.04324 11.00000 0.05949 0.04444 = 
               
               
                   
                 0.02903 0.00359 0.01728 0.00704 
               
               
                   
                 C85 1 0.03624 0.41100 −0.09142 11.00000 0.06649 0.10092 = 
               
               
                   
                 0.05586 0.01088 0.01751 0.00507 
               
               
                   
                 C86 1 0.00323 0.39810 −0.20187 11.00000 0.08670 0.14765 = 
               
               
                   
                 −0.02096 −0.03160 −0.00004 
               
               
                   
                 C87 1 0.14311 0.39209 −0.25693 11.00000 0.07916 0.11651 = 
               
               
                   
                 0.06238 −0.01696 0.00195 0.02481 
               
               
                   
                 C88 1 0.30473 0.39806 −0.20987 11.00000 0.09246 0.09710 = 
               
               
                   
                 0.04155 0.00157 0.01795 0.02685 
               
               
                   
                 C89 1 0.33456 0.41126 −0.10133 11.00000 0.05999 0.09817 = 
               
               
                   
                 0.07178 −0.01451 0.00886 0.02173 
               
               
                   
                 S90 6 0.68868 0.81145 0.51625 11.00000 0.04072 0.02869 = 
               
               
                   
                 0.05437 0.00158 0.00214 0.00223 
               
               
                   
                 O91 3 0.79129 0.77464 0.57315 11.00000 0.08025 0.03751 = 
               
               
                   
                 0.04867 −0.00213 −0.00954 0.01626 
               
               
                   
                 O92 3 0.52601 0.81933 0.56122 11.00000 0.04778 0.05360 = 
               
               
                   
                 0.06934 −0.00642 0.01702 0.00039 
               
               
                   
                 O93 3 0.78935 0.85213 0.50763 11.00000 0.07515 0.04369 = 
               
               
                   
                 0.05025 −0.01354 0.01764 −0.01547 
               
               
                   
                 C94 1 0.62446 0.78970 0.38130 11.00000 0.04232 0.04028 = 
               
               
                   
                 0.05049 0.00898 0.00929 0.00525 
               
               
                   
                 C95 1 0.74659 0.76959 0.32396 11.00000 0.06194 0.06998 = 
               
               
                   
                 0.03238 0.00341 −0.00103 0.00990 
               
               
                   
                 C96 1 0.69911 0.75023 0.22476 11.00000 0.12417 0.10337 = 
               
               
                   
                 0.03441 0.01537 0.02421 0.03314 
               
               
                   
                 C97 1 0.51941 0.75295 0.17732 11.00000 0.11897 0.11939 = 
               
               
                   
                 −0.01324 −0.00963 −0.00586 
               
               
                   
                 C98 1 0.40301 0.77268 0.23169 11.00000 0.06106 0.10242 = 
               
               
                   
                 0.00570 −0.01263 −0.00283 
               
               
                   
                 C99 1 0.45446 0.79193 0.33547 11.00000 0.05307 0.07089 = 
               
               
                   
                 0.00728 −0.00426 −0.01944 
               
               
                   
                 BR1 4 0.06011 0.52462 0.55140 11.00000 0.04153 0.05204 = 
               
               
                   
                 0.07369 −0.00524 0.02434 0.00670 
               
               
                   
                 C2 1 0.25757 0.50395 0.49005 11.00000 0.02832 0.04536 = 
               
               
                   
                 0.03350 −0.00752 0.01511 0.00763 
               
               
                   
                 C3 1 0.28921 0.45781 0.47911 11.00000 0.03135 0.03107 = 
               
               
                   
                 0.04579 0.00145 0.00221 −0.00479 
               
               
                   
                 C4 1 0.42954 0.44393 0.43174 11.00000 0.03767 0.03461 = 
               
               
                   
                 −0.00320 −0.00151 −0.00125 
               
               
                   
                 C5 1 0.54674 0.47556 0.39943 11.00000 0.03535 0.02939 = 
               
               
                   
                 0.03479 −0.00390 0.00647 0.00183 
               
               
                   
                 C6 1 0.51907 0.52242 0.41134 11.00000 0.04226 0.03479 = 
               
               
                   
                 0.04333 −0.00172 0.00236 0.00188 
               
               
                   
                 C7 1 0.37213 0.53602 0.45794 11.00000 0.03598 0.02793 = 
               
               
                   
                 0.04586 −0.00044 0.01652 0.00336 
               
               
                   
                 C8 1 0.64321 0.55824 0.38118 11.00000 0.03964 0.02453 = 
               
               
                   
                 0.02719 0.00516 0.00457 0.00373 
               
               
                   
                 C9 1 0.68998 0.59645 0.46059 11.00000 0.03743 0.03694 = 
               
               
                   
                 0.04454 −0.00375 0.01588 0.00649 
               
               
                   
                 N10 5 0.69097 0.58514 0.56581 11.00000 0.06070 0.03116 = 
               
               
                   
                 0.04918 −0.00640 0.02020 −0.00054 
               
               
                   
                 C11 1 0.74090 0.61847 0.63822 11.00000 0.06804 0.05787 = 
               
               
                   
                 0.04752 −0.00600 0.01695 −0.00669 
               
               
                   
                 C12 1 0.78515 0.66221 0.61053 11.00000 0.05480 0.04458 = 
               
               
                   
                 0.05526 −0.02125 0.01554 −0.00787 
               
               
                   
                 C13 1 0.77550 0.67229 0.50132 11.00000 0.04463 0.03102 = 
               
               
                   
                 0.05452 0.00407 0.01432 −0.00038 
               
               
                   
                 C14 1 0.73186 0.63955 0.42553 11.00000 0.04272 0.03021 = 
               
               
                   
                 0.04282 −0.00243 0.01499 0.00270 
               
               
                   
                 N15 5 0.71451 0.55972 0.29408 11.00000 0.04979 0.02502 = 
               
               
                   
                 0.03692 0.00975 0.01748 0.00775 
               
               
                   
                 C16 1 0.67500 0.52204 0.21324 11.00000 0.04463 0.02346 = 
               
               
                   
                 0.04948 −0.00464 0.01738 0.00561 
               
               
                   
                 C17 1 0.75857 0.47996 0.26673 11.00000 0.04549 0.02673 = 
               
               
                   
                 0.01954 −0.00693 0.00506 −0.00121 
               
               
                   
                 N18 5 0.70009 0.45973 0.35317 11.00000 0.03293 0.02806 = 
               
               
                   
                 0.02597 −0.00088 0.00321 0.00207 
               
               
                   
                 C19 1 0.81334 0.42409 0.39181 11.00000 0.03678 0.02848 = 
               
               
                   
                 0.03351 −0.00426 0.00585 0.00488 
               
               
                   
                 C20 1 0.93968 0.42402 0.32661 11.00000 0.03371 0.02802 = 
               
               
                   
                 0.03711 0.00202 0.00106 0.00680 
               
               
                   
                 N21 5 0.90585 0.45925 0.25315 11.00000 0.04775 0.03416 = 
               
               
                   
                 0.02231 −0.01051 0.01052 −0.00308 
               
               
                   
                 C22 1 0.79597 0.39511 0.48941 11.00000 0.03997 0.03711 = 
               
               
                   
                 0.04548 0.01039 0.00508 0.00197 
               
               
                   
                 C23 1 0.74788 0.53407 0.10940 11.00000 0.05650 0.04712 = 
               
               
                   
                 0.03514 0.00836 0.00449 0.00605 
               
               
                   
                 C24 1 0.68780 0.50047 0.01647 11.00000 0.08242 0.04077 = 
               
               
                   
                 0.03001 −0.00046 0.01385 0.00523 
               
               
                   
                 C25 1 0.71419 0.51690 −0.09234 11.00000 0.06429 0.06543 = 
               
               
                   
                 0.03392 0.00018 0.00559 −0.00499 
               
               
                   
                 O26 3 0.76261 0.55440 −0.11450 11.00000 0.12347 0.08282 = 
               
               
                   
                 0.04188 0.01501 0.01658 −0.04001 
               
               
                   
                 O27 3 0.65910 0.48459 −0.16756 11.00000 0.10340 0.06919 = 
               
               
                   
                 0.03191 0.00253 0.01824 −0.00449 
               
               
                   
                 C28 1 0.66642 0.49760 −0.27953 11.00000 0.19131 0.12699 = 
               
               
                   
                 0.01390 −0.01417 0.02134 −0.05279 
               
               
                   
                 BR51 4 1.06737 0.71057 0.98743 11.00000 0.03812 0.08781 = 
               
               
                   
                 0.06774 0.00566 −0.00531 0.00447 
               
               
                   
                 C52 1 0.84276 0.73306 0.93243 11.00000 0.03132 0.05952 = 
               
               
                   
                 0.03819 0.00358 0.00226 −0.00263 
               
               
                   
                 C53 1 0.81293 0.77906 0.93249 11.00000 0.04627 0.06820 = 
               
               
                   
                 0.03723 −0.00581 0.00481 −0.00474 
               
               
                   
                 C54 1 0.65043 0.79579 0.88269 11.00000 0.04551 0.03939 = 
               
               
                   
                 0.04858 −0.00084 0.00376 −0.01071 
               
               
                   
                 C55 1 0.51946 0.76552 0.84226 11.00000 0.04294 0.03573 = 
               
               
                   
                 0.03413 0.00062 0.00952 −0.00208 
               
               
                   
                 C56 1 0.54512 0.71765 0.84581 11.00000 0.02688 0.03659 = 
               
               
                   
                 0.04586 −0.00025 0.00561 0.00047 
               
               
                   
                 C57 1 0.71139 0.70186 0.88914 11.00000 0.03105 0.04840 = 
               
               
                   
                 0.04447 −0.00668 −0.00429 0.00504 
               
               
                   
                 C58 1 0.40956 0.68443 0.79765 11.00000 0.03348 0.02893 = 
               
               
                   
                 0.04334 0.00070 0.00351 0.00421 
               
               
                   
                 C59 1 0.38048 0.64253 0.86694 11.00000 0.03165 0.03488 = 
               
               
                   
                 0.04951 0.00002 0.00425 0.00528 
               
               
                   
                 N60 5 0.42879 0.64650 0.97247 11.00000 0.03542 0.05694 = 
               
               
                   
                 0.03178 0.00872 0.00154 0.00467 
               
               
                   
                 C61 1 0.38962 0.61026 1.03529 11.00000 0.04457 0.06338 = 
               
               
                   
                 0.05765 0.01416 0.00707 0.00171 
               
               
                   
                 C62 1 0.30187 0.57202 0.98967 11.00000 0.06548 0.04957 = 
               
               
                   
                 0.11303 0.03456 0.03582 0.00696 
               
               
                   
                 C63 1 0.25733 0.56863 0.88018 11.00000 0.07395 0.04664 = 
               
               
                   
                 0.09803 0.00115 0.01240 −0.01007 
               
               
                   
                 C64 1 0.29561 0.60475 0.81590 11.00000 0.08355 0.04152 = 
               
               
                   
                 0.05459 −0.00010 0.00128 −0.02308 
               
               
                   
                 N65 5 0.31344 0.68797 0.70771 11.00000 0.03846 0.03072 = 
               
               
                   
                 0.04952 −0.00160 0.00032 0.00597 
               
               
                   
                 C66 1 0.33129 0.72953 0.64125 11.00000 0.03574 0.02676 = 
               
               
                   
                 0.05519 0.00406 0.00580 0.00330 
               
               
                   
                 C67 1 0.26347 0.76733 0.70231 11.00000 0.03803 0.03316 = 
               
               
                   
                 0.04166 0.01528 0.00868 0.00029 
               
               
                   
                 N68 5 0.35122 0.78274 0.79764 11.00000 0.03387 0.03259 = 
               
               
                   
                 0.05055 0.00549 0.00427 0.00218 
               
               
                   
                 C69 1 0.24763 0.81583 0.84108 11.00000 0.05345 0.03305 = 
               
               
                   
                 0.04570 0.00005 0.02067 −0.00546 
               
               
                   
                 C70 1 0.09873 0.81841 0.77077 11.00000 0.04465 0.03799 = 
               
               
                   
                 0.06107 0.00794 0.01464 0.00936 
               
               
                   
                 N71 5 0.10819 0.78841 0.68720 11.00000 0.03892 0.03266 = 
               
               
                   
                 0.05306 0.00974 0.01063 0.00803 
               
               
                   
                 C72 1 0.30218 0.84064 0.94469 11.00000 0.08091 0.04934 = 
               
               
                   
                 0.08052 −0.01505 0.02392 −0.00661 
               
               
                   
                 C73 1 0.22541 0.72388 0.52948 11.00000 0.04039 0.05583 = 
               
               
                   
                 0.03295 0.00047 0.00724 −0.00165 
               
               
                   
                 C74 1 0.30154 0.68566 0.46508 11.00000 0.05896 0.05343 = 
               
               
                   
                 0.05504 −0.00576 0.00667 0.02016 
               
               
                   
                 C75 1 0.18003 0.67204 0.36587 11.00000 0.05296 0.05447 = 
               
               
                   
                 0.04241 0.00546 0.01355 0.00171 
               
               
                   
                 O76 3 0.06782 0.69497 0.31818 11.00000 0.05552 0.07543 = 
               
               
                   
                 0.05719 −0.00702 −0.00194 0.02108 
               
               
                   
                 O77 3 0.22119 0.62976 0.33149 11.00000 0.08466 0.04267 = 
               
               
                   
                 0.04376 −0.00714 0.00726 0.00488 
               
               
                   
                 C78 1 0.10717 0.61220 0.23887 11.00000 0.06302 0.09312 = 
               
               
                   
                 0.07465 −0.02449 0.02418 −0.00980 
               
               
                   
                 H611 2 10.42342 10.61111 11.10933 11.00000 0.06582 
               
               
                   
                 H621 2 10.27371 10.54835 11.03412 11.00000 0.09086 
               
               
                   
                 H631 2 10.20282 10.54235 10.84949 11.00000 0.08585 
               
               
                   
                 H641 2 10.26600 10.60396 10.74163 11.00000 0.07058 
               
               
                   
                 H661 2 10.45616 10.73494 10.63683 11.00000 0.04658 
               
               
                   
                 H701 2 10.00528 10.83765 10.77749 11.00000 0.05724 
               
               
                   
                 H721 2 10.20390 10.85662 10.96784 11.00000 0.10482 
               
               
                   
                 H722 2 10.39143 10.86250 10.93477 11.00000 0.10500 
               
               
                   
                 H723 2 10.34863 10.81975 11.00178 11.00000 0.10479 
               
               
                   
                 H731 2 10.22647 10.75279 10.49048 11.00000 0.05050 
               
               
                   
                 H732 2 10.10462 10.71635 10.53573 11.00000 0.05107 
               
               
                   
                 H741 2 10.41143 10.69632 10.44327 11.00000 0.06599 
               
               
                   
                 H742 2 10.32279 10.65905 10.51273 11.00000 0.06616 
               
               
                   
                 H571 2 10.73613 10.67093 10.88928 11.00000 0.04893 
               
               
                   
                 H531 2 10.89874 10.79871 10.96543 11.00000 0.05990 
               
               
                   
                 H541 2 10.63029 10.82681 10.87790 11.00000 0.05285 
               
               
                   
                 H161 2 10.54702 10.51731 10.19609 11.00000 0.04687 
               
               
                   
                 H201 2 11.03302 10.40374 10.33036 11.00000 0.03977 
               
               
                   
                 H221 2 10.90306 10.37871 10.51025 11.00000 0.06107 
               
               
                   
                 H222 2 10.77354 10.41394 10.54853 11.00000 0.06102 
               
               
                   
                 H223 2 10.70245 10.37370 10.47387 11.00000 0.06087 
               
               
                   
                 H231 2 10.71028 10.56434 10.08666 11.00000 0.05487 
               
               
                   
                 H232 2 10.87494 10.53365 10.12431 11.00000 0.05471 
               
               
                   
                 H241 2 10.56546 10.49241 10.01723 11.00000 0.06095 
               
               
                   
                 H242 2 10.75795 10.47323 10.02815 11.00000 0.06099 
               
               
                   
                 H111 2 10.74728 10.61186 10.71244 11.00000 0.06882 
               
               
                   
                 H121 2 10.81997 10.68398 10.66349 11.00000 0.06182 
               
               
                   
                 H131 2 10.79812 10.70154 10.48020 11.00000 0.05215 
               
               
                   
                 H141 2 10.72939 10.64544 10.35226 11.00000 0.04595 
               
               
                   
                 H71 2 10.35042 10.56684 10.46668 11.00000 0.04408 
               
               
                   
                 H31 2 10.21444 10.43638 10.50355 11.00000 0.04223 
               
               
                   
                 H41 2 10.44931 10.41280 10.42055 11.00000 0.04056 
               
               
                   
                 H891 2 10.44977 10.41481 9.93226 11.00000 0.09285 
               
               
                   
                 H881 2 10.39917 10.39332 9.75106 11.00000 0.09266 
               
               
                   
                 H871 2 10.12372 10.38356 9.66972 11.00000 0.10194 
               
               
                   
                 H861 2 9.88808 10.39388 9.76390 11.00000 0.11607 
               
               
                   
                 H851 2 9.94416 10.41466 9.94909 11.00000 0.08904 
               
               
                   
                 H951 2 10.86472 10.76918 10.35546 11.00000 0.06580 
               
               
                   
                 H961 2 10.78321 10.73544 10.18942 11.00000 0.10497 
               
               
                   
                 H971 2 10.48493 10.74055 10.10914 11.00000 0.10604 
               
               
                   
                 H981 2 10.28646 10.77378 10.20054 11.00000 0.08719 
               
               
                   
                 H991 2 10.37377 10.80653 10.37249 11.00000 0.07037 
               
               
                   
                 H781 2 10.14480 10.58182 10.22240 11.00000 0.11588 
               
               
                   
                 H782 2 10.11102 10.63197 10.17669 11.00000 0.11581 
               
               
                   
                 H783 2 9.98883 10.61082 10.25546 11.00000 0.11600 
               
               
                   
                 H711 2 10.01359 10.78308 10.62464 11.00000 0.05205 
               
               
                   
                 H211 2 10.98261 10.46785 10.19729 11.00000 0.04161 
               
               
                   
                 H281 2 10.62358 10.47180 9.67092 11.00000 0.11566 
               
               
                   
                 H282 2 10.59036 10.52501 9.70225 11.00000 0.11566 
               
               
                   
                 H283 2 10.79029 10.50514 9.71088 11.00000 0.11566 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
             
           
               
                 TABLE 18 
               
               
                   
               
               
                 Crystallographic co-ordinates and other relevant data tabulated in the 
               
               
                 form of a SHELX File for Compound of formula (I) besylate Form 2. 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 TITL 1142055 Compound CNS7056 form 2 
               
               
                   
                 CELL 0.71073 8.921 11.154 25.834 90.000 90.000 90.000 
               
               
                   
                 ZERR 4 0.0001 0.0002 0.0004 0.0000 0.0000 0.0000 
               
               
                   
                 LATT −1 
               
               
                   
                 SYMM X + 0.500, −Y + 0.500, −Z 
               
               
                   
                 SYMM −X, Y + 0.500, −Z + 0.500 
               
               
                   
                 SYMM −X + 0.500, −Y, Z + 0.500 
               
               
                   
                 SFAC C 2.3100 20.8439 1.0200 10.2075 1.5886 0.5687 0.8650 = 
               
               
                   
                 51.6512 0.2156 0.0033 0.0016 1.15 0.7700 12.0110 
               
               
                   
                 SFAC H 0.4930 10.5109 0.3229 26.1257 0.1402 3.1424 0.0408 = 
               
               
                   
                 57.7998 0.0030 0.0000 0.0000 0.06 0.3200 1.0079 
               
               
                   
                 SFAC BR 17.1789 2.1723 5.2358 16.5796 5.6377 0.2609 3.9851 = 
               
               
                   
                 41.4328 2.9557 −0.2901 2.4595 1000.00 1.1000 79.9040 
               
               
                   
                 SFAC N 12.2126 0.0057 3.1322 9.8933 2.0125 28.9975 1.1663 = 
               
               
                   
                 0.5826 −11.5290 0.0061 0.0033 1.96 0.7700 14.0067 
               
               
                   
                 SFAC O 3.0485 13.2771 2.2868 5.7011 1.5463 0.3239 0.8670 = 
               
               
                   
                 32.9089 0.2508 0.0106 0.0060 3.25 0.7700 15.9994 
               
               
                   
                 SFAC S 6.9053 1.4679 5.2034 22.2151 1.4379 0.2536 1.5863 = 
               
               
                   
                 56.1720 0.8669 0.1246 0.1234 53.20 1.1100 32.0660 
               
               
                   
                 UNIT 108. 100. 4. 16. 20. 4. 
               
               
                   
                 BR1 3 −0.04819 −0.10880 −0.27710 11.00000 0.07032 0.03277 = 
               
               
                   
                 0.00144 −0.01238 −0.02224 
               
               
                   
                 C2 1 −0.15018 −0.21830 −0.32054 11.00000 0.02777 0.02177 = 
               
               
                   
                 −0.00009 −0.00209 −0.00471 
               
               
                   
                 C3 1 −0.17401 −0.18875 −0.37205 11.00000 0.02963 0.01861 = 
               
               
                   
                 0.02702 0.00623 0.00188 −0.00107 
               
               
                   
                 C4 1 −0.24491 −0.26965 −0.40362 11.00000 0.02825 0.02442 = 
               
               
                   
                 0.01718 0.00327 0.00106 −0.00145 
               
               
                   
                 C5 1 −0.29275 −0.37943 −0.38401 11.00000 0.02223 0.01822 = 
               
               
                   
                 0.01875 −0.00067 0.00141 0.00066 
               
               
                   
                 C6 1 −0.27139 −0.40894 −0.33163 11.00000 0.02028 0.01967 = 
               
               
                   
                 0.01926 0.00182 0.00105 −0.00153 
               
               
                   
                 C7 1 −0.20042 −0.32532 −0.29979 11.00000 0.02809 0.02763 = 
               
               
                   
                 0.01685 0.00206 0.00190 −0.00055 
               
               
                   
                 C8 1 −0.32197 −0.52600 −0.30927 11.00000 0.01670 0.02233 = 
               
               
                   
                 0.00135 −0.00476 −0.00144 
               
               
                   
                 C9 1 −0.39853 −0.52353 −0.25770 11.00000 0.01623 0.02317 = 
               
               
                   
                 0.00259 −0.00384 −0.00281 
               
               
                   
                 N10 4 −0.46099 −0.41943 −0.24363 11.00000 0.02251 0.02613 = 
               
               
                   
                 0.02353 −0.00189 0.00408 0.00155 
               
               
                   
                 C11 1 −0.52777 −0.41652 −0.19697 11.00000 0.02617 0.03441 = 
               
               
                   
                 0.02357 −0.00451 0.00365 0.00346 
               
               
                   
                 C12 1 −0.53610 −0.51390 −0.16425 11.00000 0.02740 0.04329 = 
               
               
                   
                 0.02040 −0.00335 0.00652 −0.00779 
               
               
                   
                 C13 1 −0.47518 −0.62062 −0.17997 11.00000 0.03584 0.03200 = 
               
               
                   
                 0.02405 0.00767 0.00645 −0.00687 
               
               
                   
                 C14 1 −0.40334 −0.62685 −0.22730 11.00000 0.02879 0.02223 = 
               
               
                   
                 0.02565 0.00090 0.00272 −0.00057 
               
               
                   
                 N15 4 −0.30040 −0.62781 −0.33049 11.00000 0.02151 0.02416 = 
               
               
                   
                 0.01713 0.00287 −0.00002 0.00182 
               
               
                   
                 C16 1 −0.21928 −0.62991 −0.38036 11.00000 0.02330 0.02286 = 
               
               
                   
                 0.01602 0.00057 0.00417 0.00450 
               
               
                   
                 C17 1 −0.32510 −0.57975 −0.41920 11.00000 0.02824 0.02308 = 
               
               
                   
                 0.01704 −0.00121 0.00336 −0.00285 
               
               
                   
                 N18 4 −0.36294 −0.46298 −0.41818 11.00000 0.02482 0.02037 = 
               
               
                   
                 0.01483 0.00150 −0.00070 0.00079 
               
               
                   
                 C19 1 −0.46920 −0.44117 −0.45641 11.00000 0.03022 0.02725 = 
               
               
                   
                 0.01634 0.00325 0.00039 −0.00224 
               
               
                   
                 C20 1 −0.49445 −0.54753 −0.47911 11.00000 0.03071 0.03401 = 
               
               
                   
                 0.00110 −0.00174 −0.00215 
               
               
                   
                 N21 4 −0.40440 −0.63226 −0.45591 11.00000 0.03619 0.02354 = 
               
               
                   
                 0.02146 −0.00463 0.00147 −0.00154 
               
               
                   
                 C22 1 −0.54310 −0.32298 −0.46595 11.00000 0.03636 0.03429 = 
               
               
                   
                 0.00778 −0.00982 −0.00011 
               
               
                   
                 C23 1 −0.15995 −0.75547 −0.39193 11.00000 0.03430 0.02640 = 
               
               
                   
                 0.01793 −0.00359 0.00177 0.00554 
               
               
                   
                 C24 1 −0.06166 −0.79435 −0.34621 11.00000 0.04707 0.03881 = 
               
               
                   
                 0.02350 0.00041 0.00034 0.01530 
               
               
                   
                 C25 1 0.06625 −0.87542 −0.35603 11.00000 0.03182 0.02650 = 
               
               
                   
                 0.00340 −0.00125 −0.00016 
               
               
                   
                 O26 5 0.17233 −0.88334 −0.32760 11.00000 0.03778 0.06570 = 
               
               
                   
                 0.03313 −0.01160 −0.01173 0.00417 
               
               
                   
                 O27 5 0.05245 −0.94265 −0.39885 11.00000 0.03130 0.03874 = 
               
               
                   
                 0.02467 −0.00799 −0.00330 0.01418 
               
               
                   
                 C28 1 0.17574 −1.02443 −0.40865 11.00000 0.05622 0.08123 = 
               
               
                   
                 0.03697 −0.01153 −0.00496 0.04396 
               
               
                   
                 S80 6 −0.94275 −0.52899 −0.49624 11.00000 0.03340 0.02679 = 
               
               
                   
                 0.02442 0.00000 0.00210 −0.00075 
               
               
                   
                 O81 5 −0.83867 −0.47114 −0.53020 11.00000 0.05118 0.08336 = 
               
               
                   
                 0.02297 −0.00622 −0.02476 
               
               
                   
                 O82 5 −1.08156 −0.46260 −0.49186 11.00000 0.04015 0.07788 = 
               
               
                   
                 0.05503 −0.01022 −0.00539 0.01721 
               
               
                   
                 O83 5 −0.97025 −0.65272 −0.50726 11.00000 0.13945 0.03230 = 
               
               
                   
                 0.06071 −0.01467 0.01447 −0.00725 
               
               
                   
                 C84 1 −0.86288 −0.52210 −0.43343 11.00000 0.02735 0.05893 = 
               
               
                   
                 0.02832 0.01509 0.00686 −0.00534 
               
               
                   
                 C85 1 −0.87781 −0.41462 −0.40588 11.00000 0.03763 0.08695 = 
               
               
                   
                 0.03855 −0.01799 0.00427 −0.00754 
               
               
                   
                 C86 1 −0.81420 −0.39965 −0.35764 11.00000 0.05438 0.16315 = 
               
               
                   
                 0.04455 −0.02905 0.00147 −0.02905 
               
               
                   
                 C87 1 −0.73766 −0.49241 −0.33773 11.00000 0.06202 0.20226 = 
               
               
                   
                 0.03510 −0.02105 −0.05062 
               
               
                   
                 C88 1 −0.71885 −0.60444 −0.36221 11.00000 0.04217 0.17120 = 
               
               
                   
                 0.11388 0.10762 −0.01320 −0.03729 
               
               
                   
                 C89 1 −0.78500 −0.61610 −0.41251 11.00000 0.03725 0.08786 = 
               
               
                   
                 0.05538 −0.00772 −0.01074 
               
               
                   
                 H891 2 9.22557 9.31210 9.56883 11.00000 0.08027 
               
               
                   
                 H881 2 9.33331 9.33306 9.65289 11.00000 0.13097 
               
               
                   
                 H851 2 9.06867 9.64846 9.57936 11.00000 0.06577 
               
               
                   
                 H861 2 9.17563 9.67239 9.66111 11.00000 0.10509 
               
               
                   
                 H161 2 9.86530 9.42517 9.62245 11.00000 0.02469 
               
               
                   
                 H111 2 9.42959 9.65626 9.81326 11.00000 0.03383 
               
               
                   
                 H121 2 9.41618 9.49292 9.86839 11.00000 0.03606 
               
               
                   
                 H131 2 9.51614 9.31066 9.84059 11.00000 0.03697 
               
               
                   
                 H141 2 9.64103 9.30191 9.76144 11.00000 0.03108 
               
               
                   
                 H231 2 9.89972 9.24922 9.57680 11.00000 0.03066 
               
               
                   
                 H232 2 9.75764 9.18723 9.60372 11.00000 0.03099 
               
               
                   
                 H241 2 9.87585 9.16237 9.67759 11.00000 0.04434 
               
               
                   
                 H242 2 9.97980 9.27746 9.67100 11.00000 0.04489 
               
               
                   
                 H281 2 10.15353 8.92912 9.56085 11.00000 0.08666 
               
               
                   
                 H282 2 10.18989 8.92278 9.62053 11.00000 0.08723 
               
               
                   
                 H283 2 10.26566 9.02166 9.58620 11.00000 0.08710 
               
               
                   
                 H201 2 9.44027 9.43682 9.49457 11.00000 0.03327 
               
               
                   
                 H221 2 9.36727 9.66624 9.51370 11.00000 0.05146 
               
               
                   
                 H222 2 9.52479 9.72860 9.51527 11.00000 0.05104 
               
               
                   
                 H223 2 9.43193 9.71611 9.56601 11.00000 0.05131 
               
               
                   
                 H41 2 9.73983 9.74902 9.56204 11.00000 0.02807 
               
               
                   
                 H31 2 9.85823 9.88568 9.61518 11.00000 0.03001 
               
               
                   
                 H71 2 9.81367 9.65791 9.73490 11.00000 0.02870 
               
               
                   
                 H871 2 9.30621 9.51762 9.69480 11.00000 0.13226 
               
               
                   
                 H211 2 9.59801 9.29339 9.53630 11.00000 0.03270 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 19 
               
               
                   
               
               
                 Bond lengths for Compound of formula (I) besylate Form 1. 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 S80 
                 O81 
                 1.454(5) 
                 Å 
                 S80 
                 O82 
                 1.468(5) 
                 Å 
               
               
                 S80 
                 O83 
                 1.432(6) 
                 Å 
                 S80 
                 C84 
                 1.784(7) 
                 Å 
               
               
                 C84 
                 C85 
                 1.376(12) 
                 Å 
                 C84 
                 C89 
                 1.318(12) 
                 Å 
               
               
                 C85 
                 C86 
                 1.408(14) 
                 Å 
                 C85 
                 H851 
                 0.927 
                 Å 
               
               
                 C86 
                 C87 
                 1.360(16) 
                 Å 
                 C86 
                 H861 
                 0.936 
                 Å 
               
               
                 C87 
                 C88 
                 1.310(15) 
                 Å 
                 C87 
                 H871 
                 0.934 
                 Å 
               
               
                 C88 
                 C89 
                 1.386(14) 
                 Å 
                 C88 
                 H881 
                 0.935 
                 Å 
               
               
                 C89 
                 H891 
                 0.932 
                 Å 
                 S90 
                 O91 
                 1.459(5) 
                 Å 
               
               
                 S90 
                 O92 
                 1.454(6) 
                 Å 
                 S90 
                 O93 
                 1.431(5) 
                 Å 
               
               
                 S90 
                 C94 
                 1.793(8) 
                 Å 
                 C94 
                 C95 
                 1.383(11) 
                 Å 
               
               
                 C94 
                 C99 
                 1.354(11) 
                 Å 
                 C95 
                 C96 
                 1.356(13) 
                 Å 
               
               
                 C95 
                 H951 
                 0.938 
                 Å 
                 C96 
                 C97 
                 1.428(17) 
                 Å 
               
               
                 C96 
                 H961 
                 0.934 
                 Å 
                 C97 
                 C98 
                 1.323(15) 
                 Å 
               
               
                 C97 
                 H971 
                 0.924 
                 Å 
                 C98 
                 C99 
                 1.409(13) 
                 Å 
               
               
                 C98 
                 H981 
                 0.927 
                 Å 
                 C99 
                 H991 
                 0.924 
                 Å 
               
               
                 Br1 
                 C2 
                 1.886(6) 
                 Å 
                 C2 
                 C3 
                 1.382(9) 
                 Å 
               
               
                 C2 
                 C7 
                 1.381(9) 
                 Å 
                 C3 
                 C4 
                 1.358(10) 
                 Å 
               
               
                 C3 
                 H31 
                 0.928 
                 Å 
                 C4 
                 C5 
                 1.388(9) 
                 Å 
               
               
                 C4 
                 H41 
                 0.937 
                 Å 
                 C5 
                 C6 
                 1.398(9) 
                 Å 
               
               
                 C5 
                 N18 
                 1.454(8) 
                 Å 
                 C6 
                 C7 
                 1.394(9) 
                 Å 
               
               
                 C6 
                 C8 
                 1.498(9) 
                 Å 
                 C7 
                 H71 
                 0.926 
                 Å 
               
               
                 C8 
                 C9 
                 1.500(9) 
                 Å 
                 C8 
                 N15 
                 1.274(8) 
                 Å 
               
               
                 C9 
                 N10 
                 1.343(9) 
                 Å 
                 C9 
                 C14 
                 1.386(9) 
                 Å 
               
               
                 N10 
                 C11 
                 1.345(10) 
                 Å 
                 C11 
                 C12 
                 1.379(11) 
                 Å 
               
               
                 C11 
                 H111 
                 0.933 
                 Å 
                 C12 
                 C13 
                 1.375(11) 
                 Å 
               
               
                 C12 
                 H121 
                 0.927 
                 Å 
                 C13 
                 C14 
                 1.351(10) 
                 Å 
               
               
                 C13 
                 H131 
                 0.918 
                 Å 
                 C14 
                 H141 
                 0.921 
                 Å 
               
               
                 N15 
                 C16 
                 1.492(9) 
                 Å 
                 C16 
                 C17 
                 1.500(9) 
                 Å 
               
               
                 C16 
                 C23 
                 1.511(9) 
                 Å 
                 C16 
                 H161 
                 0.988 
                 Å 
               
               
                 C17 
                 N18 
                 1.352(8) 
                 Å 
                 C17 
                 N21 
                 1.315(8) 
                 Å 
               
               
                 N18 
                 C19 
                 1.400(8) 
                 Å 
                 C19 
                 C20 
                 1.344(9) 
                 Å 
               
               
                 C19 
                 C22 
                 1.496(9) 
                 Å 
                 C20 
                 N21 
                 1.376(8) 
                 Å 
               
               
                 C20 
                 H201 
                 0.927 
                 Å 
                 N21 
                 H211 
                 1.000 
                 Å 
               
               
                 C22 
                 H221 
                 0.958 
                 Å 
                 C22 
                 H222 
                 0.950 
                 Å 
               
               
                 C22 
                 H223 
                 0.953 
                 Å 
                 C23 
                 C24 
                 1.536(11) 
                 Å 
               
               
                 C23 
                 H231 
                 0.962 
                 Å 
                 C23 
                 H232 
                 0.969 
                 Å 
               
               
                 C24 
                 C25 
                 1.470(11) 
                 Å 
                 C24 
                 H241 
                 0.971 
                 Å 
               
               
                 C24 
                 H242 
                 0.962 
                 Å 
                 C25 
                 O26 
                 1.202(10) 
                 Å 
               
               
                 C25 
                 O27 
                 1.354(10) 
                 Å 
                 O27 
                 C28 
                 1.445(10) 
                 Å 
               
               
                 C28 
                 H281 
                 1.000 
                 Å 
                 C28 
                 H282 
                 1.000 
                 Å 
               
               
                 C28 
                 H283 
                 1.000 
                 Å 
                 Br51 
                 C52 
                 1.886(7) 
                 Å 
               
               
                 C52 
                 C53 
                 1.366(11) 
                 Å 
                 C52 
                 C57 
                 1.412(10) 
                 Å 
               
               
                 C53 
                 C54 
                 1.404(11) 
                 Å 
                 C53 
                 H531 
                 0.927 
                 Å 
               
               
                 C54 
                 C55 
                 1.383(10) 
                 Å 
                 C54 
                 H541 
                 0.921 
                 Å 
               
               
                 C55 
                 C56 
                 1.414(9) 
                 Å 
                 C55 
                 N68 
                 1.427(9) 
                 Å 
               
               
                 C56 
                 C57 
                 1.396(9) 
                 Å 
                 C56 
                 C58 
                 1.489(9) 
                 Å 
               
               
                 C57 
                 H571 
                 0.925 
                 Å 
                 C58 
                 C59 
                 1.530(10) 
                 Å 
               
               
                 C58 
                 N65 
                 1.254(8) 
                 Å 
                 C59 
                 N60 
                 1.314(9) 
                 Å 
               
               
                 C59 
                 C64 
                 1.391(10) 
                 Å 
                 N60 
                 C61 
                 1.372(10) 
                 Å 
               
               
                 C61 
                 C62 
                 1.386(14) 
                 Å 
                 C61 
                 H611 
                 0.918 
                 Å 
               
               
                 C62 
                 C63 
                 1.355(15) 
                 Å 
                 C62 
                 H621 
                 0.928 
                 Å 
               
               
                 C63 
                 C64 
                 1.378(13) 
                 Å 
                 C63 
                 H631 
                 0.932 
                 Å 
               
               
                 C64 
                 H641 
                 0.917 
                 Å 
                 N65 
                 C66 
                 1.485(8) 
                 Å 
               
               
                 C66 
                 C67 
                 1.474(9) 
                 Å 
                 C66 
                 C73 
                 1.516(10) 
                 Å 
               
               
                 C66 
                 H661 
                 0.982 
                 Å 
                 C67 
                 N68 
                 1.354(9) 
                 Å 
               
               
                 C67 
                 N71 
                 1.334(8) 
                 Å 
                 N68 
                 C69 
                 1.406(9) 
                 Å 
               
               
                 C69 
                 C70 
                 1.343(11) 
                 Å 
                 C69 
                 C72 
                 1.484(12) 
                 Å 
               
               
                 C70 
                 N71 
                 1.366(10) 
                 Å 
                 C70 
                 H701 
                 0.925 
                 Å 
               
               
                 N71 
                 H711 
                 1.000 
                 Å 
                 C72 
                 H721 
                 0.964 
                 Å 
               
               
                 C72 
                 H722 
                 0.958 
                 Å 
                 C72 
                 H723 
                 0.965 
                 Å 
               
               
                 C73 
                 C74 
                 1.535(10) 
                 Å 
                 C73 
                 H731 
                 0.975 
                 Å 
               
               
                 C73 
                 H732 
                 0.967 
                 Å 
                 C74 
                 C75 
                 1.493(12) 
                 Å 
               
               
                 C74 
                 H741 
                 0.972 
                 Å 
                 C74 
                 H742 
                 0.977 
                 Å 
               
               
                 C75 
                 O76 
                 1.185(9) 
                 Å 
                 C75 
                 O77 
                 1.360(9) 
                 Å 
               
               
                 O77 
                 C78 
                 1.440(11) 
                 Å 
                 C78 
                 H781 
                 0.965 
                 Å 
               
               
                 C78 
                 H782 
                 0.966 
                 Å 
                 C78 
                 H783 
                 0.960 
                 Å 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 20 
               
               
                   
               
               
                 Angles for Compound of formula (I) besylate Form 1 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 O81 
                 S80 
                 O82 
                 111.0(3)° 
                 O81 
                 S80 
                 O83 
                 112.9(4)° 
               
               
                 O82 
                 S80 
                 O83 
                 114.4(4)° 
                 O81 
                 S80 
                 C84 
                 105.5(3)° 
               
               
                 O82 
                 S80 
                 C84 
                 106.2(3)° 
                 O83 
                 S80 
                 C84 
                 106.0(4)° 
               
               
                 S80 
                 C84 
                 C85 
                 117.7(6)° 
                 S80 
                 C84 
                 C89 
                 123.6(7)° 
               
               
                 C85 
                 C84 
                 C89 
                 118.3(8)° 
                 C84 
                 C85 
                 C86 
                 120.0(9)° 
               
               
                 C84 
                 C85 
                 H851 
                 119.626° 
                 C86 
                 C85 
                 H851 
                 120.377° 
               
               
                 C85 
                 C86 
                 C87 
                 118.1(10)° 
                 C85 
                 C86 
                 H861 
                 120.636° 
               
               
                 C87 
                 C86 
                 H861 
                 121.303° 
                 C86 
                 C87 
                 C88 
                 121.8(10)° 
               
               
                 C86 
                 C87 
                 H871 
                 119.251° 
                 C88 
                 C87 
                 H871 
                 118.984° 
               
               
                 C87 
                 C88 
                 C89 
                 119.3(10)° 
                 C87 
                 C88 
                 H881 
                 120.392° 
               
               
                 C89 
                 C88 
                 H881 
                 120.264° 
                 C84 
                 C89 
                 C88 
                 122.5(10)° 
               
               
                 C84 
                 C89 
                 H891 
                 118.485° 
                 C88 
                 C89 
                 H891 
                 119.061° 
               
               
                 O91 
                 S90 
                 O92 
                 111.7(3)° 
                 O91 
                 S90 
                 O93 
                 112.8(4)° 
               
               
                 O92 
                 S90 
                 O93 
                 113.5(3)° 
                 O91 
                 S90 
                 C94 
                 104.5(3)° 
               
               
                 O92 
                 S90 
                 C94 
                 105.7(3)° 
                 O93 
                 S90 
                 C94 
                 108.0(3)° 
               
               
                 S90 
                 C94 
                 C95 
                 120.6(6)° 
                 S90 
                 C94 
                 C99 
                 120.1(6)° 
               
               
                 C95 
                 C94 
                 C99 
                 119.3(8)° 
                 C94 
                 C95 
                 C96 
                 121.6(9)° 
               
               
                 C94 
                 C95 
                 H951 
                 118.566° 
                 C96 
                 C95 
                 H951 
                 119.820° 
               
               
                 C95 
                 C96 
                 C97 
                 118.4(10)° 
                 C95 
                 C96 
                 H961 
                 119.911° 
               
               
                 C97 
                 C96 
                 H961 
                 121.695° 
                 C96 
                 C97 
                 C98 
                 119.9(8)° 
               
               
                 C96 
                 C97 
                 H971 
                 119.699° 
                 C98 
                 C97 
                 H971 
                 120.397° 
               
               
                 C97 
                 C98 
                 C99 
                 120.8(9)° 
                 C97 
                 C98 
                 H981 
                 119.080° 
               
               
                 C99 
                 C98 
                 H981 
                 120.094° 
                 C94 
                 C99 
                 C98 
                 119.9(9)° 
               
               
                 C94 
                 C99 
                 H991 
                 119.276° 
                 C98 
                 C99 
                 H991 
                 120.819° 
               
               
                 Br1 
                 C2 
                 C3 
                 121.0(5)° 
                 Br1 
                 C2 
                 C7 
                 118.5(5)° 
               
               
                 C3 
                 C2 
                 C7 
                 120.5(5)° 
                 C2 
                 C3 
                 C4 
                 119.7(6)° 
               
               
                 C2 
                 C3 
                 H31 
                 120.203° 
                 C4 
                 C3 
                 H31 
                 120.109° 
               
               
                 C3 
                 C4 
                 C5 
                 120.6(6)° 
                 C3 
                 C4 
                 H41 
                 120.600° 
               
               
                 C5 
                 C4 
                 H41 
                 118.766° 
                 C4 
                 C5 
                 C6 
                 120.6(6)° 
               
               
                 C4 
                 C5 
                 N18 
                 119.6(5)° 
                 C6 
                 C5 
                 N18 
                 119.8(6)° 
               
               
                 C5 
                 C6 
                 C7 
                 117.8(6)° 
                 C5 
                 C6 
                 C8 
                 123.3(6)° 
               
               
                 C7 
                 C6 
                 C8 
                 118.8(6)° 
                 C2 
                 C7 
                 C6 
                 120.6(6)° 
               
               
                 C2 
                 C7 
                 H71 
                 119.721° 
                 C6 
                 C7 
                 H71 
                 119.679° 
               
               
                 C6 
                 C8 
                 C9 
                 117.5(5)° 
                 C6 
                 C8 
                 N15 
                 126.6(6)° 
               
               
                 C9 
                 C8 
                 N15 
                 115.9(6)° 
                 C8 
                 C9 
                 N10 
                 114.9(6)° 
               
               
                 C8 
                 C9 
                 C14 
                 121.2(6)° 
                 N10 
                 C9 
                 C14 
                 123.9(6)° 
               
               
                 C9 
                 N10 
                 C11 
                 115.5(6)° 
                 N10 
                 C11 
                 C12 
                 124.4(7)° 
               
               
                 N10 
                 C11 
                 H111 
                 118.526° 
                 C12 
                 C11 
                 H111 
                 117.061° 
               
               
                 C11 
                 C12 
                 C13 
                 117.4(7)° 
                 C11 
                 C12 
                 H121 
                 121.279° 
               
               
                 C13 
                 C12 
                 H121 
                 121.289° 
                 C12 
                 C13 
                 C14 
                 120.4(6)° 
               
               
                 C12 
                 C13 
                 H131 
                 119.499° 
                 C14 
                 C13 
                 H131 
                 120.125° 
               
               
                 C9 
                 C14 
                 C13 
                 118.3(6)° 
                 C9 
                 C14 
                 H141 
                 120.274° 
               
               
                 C13 
                 C14 
                 H141 
                 121.419° 
                 C8 
                 N15 
                 C16 
                 118.0(5)° 
               
               
                 N15 
                 C16 
                 C17 
                 105.9(5)° 
                 N15 
                 C16 
                 C23 
                 109.4(5)° 
               
               
                 C17 
                 C16 
                 C23 
                 112.4(5)° 
                 N15 
                 C16 
                 H161 
                 110.723° 
               
               
                 C17 
                 C16 
                 H161 
                 109.539° 
                 C23 
                 C16 
                 H161 
                 108.851° 
               
               
                 C16 
                 C17 
                 N18 
                 122.7(6)° 
                 C16 
                 C17 
                 N21 
                 130.3(6)° 
               
               
                 N18 
                 C17 
                 N21 
                 106.5(5)° 
                 C5 
                 N18 
                 C17 
                 123.1(5)° 
               
               
                 C5 
                 N18 
                 C19 
                 127.0(5)° 
                 C17 
                 N18 
                 C19 
                 109.8(5)° 
               
               
                 N18 
                 C19 
                 C20 
                 105.2(5)° 
                 N18 
                 C19 
                 C22 
                 125.3(6)° 
               
               
                 C20 
                 C19 
                 C22 
                 129.4(6)° 
                 C19 
                 C20 
                 N21 
                 108.0(5)° 
               
               
                 C19 
                 C20 
                 H201 
                 126.017° 
                 N21 
                 C20 
                 H201 
                 126.026° 
               
               
                 C17 
                 N21 
                 C20 
                 110.5(5)° 
                 C17 
                 N21 
                 H211 
                 124.840° 
               
               
                 C20 
                 N21 
                 H211 
                 124.681° 
                 C19 
                 C22 
                 H221 
                 109.508° 
               
               
                 C19 
                 C22 
                 H222 
                 109.778° 
                 H221 
                 C22 
                 H222 
                 108.808° 
               
               
                 C19 
                 C22 
                 H223 
                 110.905° 
                 H221 
                 C22 
                 H223 
                 108.786° 
               
               
                 H222 
                 C22 
                 H223 
                 109.018° 
                 C16 
                 C23 
                 C24 
                 112.3(6)° 
               
               
                 C16 
                 C23 
                 H231 
                 109.392° 
                 C24 
                 C23 
                 H231 
                 108.812° 
               
               
                 C16 
                 C23 
                 H232 
                 108.378° 
                 C24 
                 C23 
                 H232 
                 109.105° 
               
               
                 H231 
                 C23 
                 H232 
                 108.825° 
                 C23 
                 C24 
                 C25 
                 114.3(7)° 
               
               
                 C23 
                 C24 
                 H241 
                 109.968° 
                 C25 
                 C24 
                 H241 
                 110.030° 
               
               
                 C23 
                 C24 
                 H242 
                 108.195° 
                 C25 
                 C24 
                 H242 
                 105.346° 
               
               
                 H241 
                 C24 
                 H242 
                 108.752° 
                 C24 
                 C25 
                 O26 
                 126.4(7)° 
               
               
                 C24 
                 C25 
                 O27 
                 109.4(7)° 
                 O26 
                 C25 
                 O27 
                 123.9(7)° 
               
               
                 C25 
                 O27 
                 C28 
                 115.2(7)° 
                 O27 
                 C28 
                 H281 
                 109.674° 
               
               
                 O27 
                 C28 
                 H282 
                 109.261° 
                 H281 
                 C28 
                 H282 
                 109.475° 
               
               
                 O27 
                 C28 
                 H283 
                 109.465° 
                 H281 
                 C28 
                 H283 
                 109.476° 
               
               
                 H282 
                 C28 
                 H283 
                 109.476° 
                 Br51 
                 C52 
                 C53 
                 119.3(6)° 
               
               
                 Br51 
                 C52 
                 C57 
                 119.0(5)° 
                 C53 
                 C52 
                 C57 
                 121.7(7)° 
               
               
                 C52 
                 C53 
                 C54 
                 118.9(7)° 
                 C52 
                 C53 
                 H531 
                 120.141° 
               
               
                 C54 
                 C53 
                 H531 
                 120.985° 
                 C53 
                 C54 
                 C55 
                 119.8(7)° 
               
               
                 C53 
                 C54 
                 H541 
                 120.227° 
                 C55 
                 C54 
                 H541 
                 120.000° 
               
               
                 C54 
                 C55 
                 C56 
                 122.1(6)° 
                 C54 
                 C55 
                 N68 
                 119.4(6)° 
               
               
                 C56 
                 C55 
                 N68 
                 118.5(6)° 
                 C55 
                 C56 
                 C57 
                 117.2(6)° 
               
               
                 C55 
                 C56 
                 C58 
                 123.2(6)° 
                 C57 
                 C56 
                 C58 
                 119.5(6)° 
               
               
                 C52 
                 C57 
                 C56 
                 120.2(7)° 
                 C52 
                 C57 
                 H571 
                 119.709° 
               
               
                 C56 
                 C57 
                 H571 
                 120.138° 
                 C56 
                 C58 
                 C59 
                 116.5(6)° 
               
               
                 C56 
                 C58 
                 N65 
                 126.7(6)° 
                 C59 
                 C58 
                 N65 
                 116.8(6)° 
               
               
                 C58 
                 C59 
                 N60 
                 116.3(6)° 
                 C58 
                 C59 
                 C64 
                 118.5(7)° 
               
               
                 N60 
                 C59 
                 C64 
                 125.0(7)° 
                 C59 
                 N60 
                 C61 
                 116.1(7)° 
               
               
                 N60 
                 C61 
                 C62 
                 121.7(8)° 
                 N60 
                 C61 
                 H611 
                 119.342° 
               
               
                 C62 
                 C61 
                 H611 
                 118.993° 
                 C61 
                 C62 
                 C63 
                 120.6(8)° 
               
               
                 C61 
                 C62 
                 H621 
                 120.029° 
                 C63 
                 C62 
                 H621 
                 119.353° 
               
               
                 C62 
                 C63 
                 C64 
                 118.4(9)° 
                 C62 
                 C63 
                 H631 
                 120.452° 
               
               
                 C64 
                 C63 
                 H631 
                 121.124° 
                 C59 
                 C64 
                 C63 
                 118.1(8)° 
               
               
                 C59 
                 C64 
                 H641 
                 120.844° 
                 C63 
                 C64 
                 H641 
                 121.057° 
               
               
                 C58 
                 N65 
                 C66 
                 118.2(6)° 
                 N65 
                 C66 
                 C67 
                 105.4(5)° 
               
               
                 N65 
                 C66 
                 C73 
                 109.7(5)° 
                 C67 
                 C66 
                 C73 
                 111.5(6)° 
               
               
                 N65 
                 C66 
                 H661 
                 109.122° 
                 C67 
                 C66 
                 H661 
                 108.890° 
               
               
                 C73 
                 C66 
                 H661 
                 112.017° 
                 C66 
                 C67 
                 N68 
                 121.8(6)° 
               
               
                 C66 
                 C67 
                 N71 
                 130.3(7)° 
                 N68 
                 C67 
                 N71 
                 107.4(6)° 
               
               
                 C55 
                 N68 
                 C67 
                 122.5(6)° 
                 C55 
                 N68 
                 C69 
                 128.7(6)° 
               
               
                 C67 
                 N68 
                 C69 
                 108.7(6)° 
                 N68 
                 C69 
                 C70 
                 105.5(6)° 
               
               
                 N68 
                 C69 
                 C72 
                 124.0(7)° 
                 C70 
                 C69 
                 C72 
                 130.5(7)° 
               
               
                 C69 
                 C70 
                 N71 
                 109.1(6)° 
                 C69 
                 C70 
                 H701 
                 125.444° 
               
               
                 N71 
                 C70 
                 H701 
                 125.502° 
                 C67 
                 N71 
                 C70 
                 109.2(6)° 
               
               
                 C67 
                 N71 
                 H711 
                 125.400° 
                 C70 
                 N71 
                 H711 
                 125.366° 
               
               
                 C69 
                 C72 
                 H721 
                 110.667° 
                 C69 
                 C72 
                 H722 
                 109.838° 
               
               
                 H721 
                 C72 
                 H722 
                 108.539° 
                 C69 
                 C72 
                 H723 
                 110.831° 
               
               
                 H721 
                 C72 
                 H723 
                 108.455° 
                 H722 
                 C72 
                 H723 
                 108.445° 
               
               
                 C66 
                 C73 
                 C74 
                 111.0(6)° 
                 C66 
                 C73 
                 H731 
                 108.535° 
               
               
                 C74 
                 C73 
                 H731 
                 110.248° 
                 C66 
                 C73 
                 H732 
                 110.751° 
               
               
                 C74 
                 C73 
                 H732 
                 108.249° 
                 H731 
                 C73 
                 H732 
                 108.042° 
               
               
                 C73 
                 C74 
                 C75 
                 112.4(6)° 
                 C73 
                 C74 
                 H741 
                 108.496° 
               
               
                 C75 
                 C74 
                 H741 
                 109.125° 
                 C73 
                 C74 
                 H742 
                 108.155° 
               
               
                 C75 
                 C74 
                 H742 
                 108.578° 
                 H741 
                 C74 
                 H742 
                 110.035° 
               
               
                 C74 
                 C75 
                 O76 
                 126.2(7)° 
                 C74 
                 C75 
                 O77 
                 110.7(7)° 
               
               
                 O76 
                 C75 
                 O77 
                 123.0(7)° 
                 C75 
                 O77 
                 C78 
                 115.6(7)° 
               
               
                 O77 
                 C78 
                 H781 
                 109.214° 
                 O77 
                 C78 
                 H782 
                 109.848° 
               
               
                 H781 
                 C78 
                 H782 
                 109.923° 
                 O77 
                 C78 
                 H783 
                 109.687° 
               
               
                 H781 
                 C78 
                 H783 
                 109.026° 
                 H782 
                 C78 
                 H783 
                 109.127° 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 21 
               
               
                   
               
               
                 Bond Lengths for Compound of formula (I) besylate Form 2. 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Br1 
                 C2 
                 1.892(3) 
                 Å 
                 C2 
                 C3 
                 1.387(5) 
                 Å 
               
               
                 C2 
                 C7 
                 1.383(5) 
                 Å 
                 C3 
                 C4 
                 1.371(5) 
                 Å 
               
               
                 C3 
                 H31 
                 0.938 
                 Å 
                 C4 
                 C5 
                 1.392(5) 
                 Å 
               
               
                 C4 
                 H41 
                 0.921 
                 Å 
                 C5 
                 C6 
                 1.406(4) 
                 Å 
               
               
                 C5 
                 N18 
                 1.428(4) 
                 Å 
                 C6 
                 C7 
                 1.395(5) 
                 Å 
               
               
                 C6 
                 C8 
                 1.497(4) 
                 Å 
                 C7 
                 H71 
                 0.924 
                 Å 
               
               
                 C8 
                 C9 
                 1.497(4) 
                 Å 
                 C8 
                 N15 
                 1.276(4) 
                 Å 
               
               
                 C9 
                 N10 
                 1.338(4) 
                 Å 
                 C9 
                 C14 
                 1.395(5) 
                 Å 
               
               
                 N10 
                 C11 
                 1.345(4) 
                 Å 
                 C11 
                 C12 
                 1.378(5) 
                 Å 
               
               
                 C11 
                 H111 
                 0.935 
                 Å 
                 C12 
                 C13 
                 1.370(5) 
                 Å 
               
               
                 C12 
                 H121 
                 0.948 
                 Å 
                 C13 
                 C14 
                 1.382(5) 
                 Å 
               
               
                 C13 
                 H131 
                 0.936 
                 Å 
                 C14 
                 H141 
                 0.934 
                 Å 
               
               
                 N15 
                 C16 
                 1.478(4) 
                 Å 
                 C16 
                 C17 
                 1.487(5) 
                 Å 
               
               
                 C16 
                 C23 
                 1.527(5) 
                 Å 
                 C16 
                 H161 
                 0.976 
                 Å 
               
               
                 C17 
                 N18 
                 1.346(4) 
                 Å 
                 C17 
                 N21 
                 1.320(4) 
                 Å 
               
               
                 N18 
                 C19 
                 1.391(4) 
                 Å 
                 C19 
                 C20 
                 1.342(5) 
                 Å 
               
               
                 C19 
                 C22 
                 1.494(5) 
                 Å 
                 C20 
                 N21 
                 1.378(5) 
                 Å 
               
               
                 C20 
                 H201 
                 0.912 
                 Å 
                 N21 
                 H211 
                 0.854 
                 Å 
               
               
                 C22 
                 H221 
                 0.965 
                 Å 
                 C22 
                 H222 
                 0.966 
                 Å 
               
               
                 C22 
                 H223 
                 0.960 
                 Å 
                 C23 
                 C24 
                 1.534(5) 
                 Å 
               
               
                 C23 
                 H231 
                 0.969 
                 Å 
                 C23 
                 H232 
                 0.981 
                 Å 
               
               
                 C24 
                 C25 
                 1.478(5) 
                 Å 
                 C24 
                 H241 
                 0.960 
                 Å 
               
               
                 C24 
                 H242 
                 0.988 
                 Å 
                 C25 
                 O26 
                 1.201(4) 
                 Å 
               
               
                 C25 
                 O27 
                 1.342(4) 
                 Å 
                 O27 
                 C28 
                 1.451(5) 
                 Å 
               
               
                 C28 
                 H281 
                 0.964 
                 Å 
                 C28 
                 H282 
                 0.965 
                 Å 
               
               
                 C28 
                 H283 
                 0.962 
                 Å 
                 S80 
                 O81 
                 1.431(3) 
                 Å 
               
               
                 S80 
                 O82 
                 1.447(3) 
                 Å 
                 S80 
                 O83 
                 1.430(3) 
                 Å 
               
               
                 S80 
                 C84 
                 1.774(4) 
                 Å 
                 C84 
                 C85 
                 1.400(7) 
                 Å 
               
               
                 C84 
                 C89 
                 1.369(7) 
                 Å 
                 C85 
                 C86 
                 1.380(7) 
                 Å 
               
               
                 C85 
                 H851 
                 0.932 
                 Å 
                 C86 
                 C87 
                 1.342(13) 
                 Å 
               
               
                 C86 
                 H861 
                 0.943 
                 Å 
                 C87 
                 C88 
                 1.410(13) 
                 Å 
               
               
                 C87 
                 H871 
                 0.934 
                 Å 
                 C88 
                 C89 
                 1.433(10) 
                 Å 
               
               
                 C88 
                 H881 
                 0.925 
                 Å 
                 C89 
                 H891 
                 0.940 
                 Å 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 22 
               
               
                   
               
               
                 Angles for Compound of formula (I) besylate Form 2. 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Br1 
                 C2 
                 C3 
                 119.3(3)° 
                 Br1 
                 C2 
                 C7 
                 118.9(3)° 
               
               
                 C3 
                 C2 
                 C7 
                 121.8(3)° 
                 C2 
                 C3 
                 C4 
                 119.0(3)° 
               
               
                 C2 
                 C3 
                 H31 
                 120.033° 
                 C4 
                 C3 
                 H31 
                 120.959° 
               
               
                 C3 
                 C4 
                 C5 
                 120.3(3)° 
                 C3 
                 C4 
                 H41 
                 119.485° 
               
               
                 C5 
                 C4 
                 H41 
                 120.261° 
                 C4 
                 C5 
                 C6 
                 121.0(3)° 
               
               
                 C4 
                 C5 
                 N18 
                 118.9(3)° 
                 C6 
                 C5 
                 N18 
                 120.1(3)° 
               
               
                 C5 
                 C6 
                 C7 
                 118.2(3)° 
                 C5 
                 C6 
                 C8 
                 122.3(3)° 
               
               
                 C7 
                 C6 
                 C8 
                 119.5(3)° 
                 C2 
                 C7 
                 C6 
                 119.7(3)° 
               
               
                 C2 
                 C7 
                 H71 
                 120.432° 
                 C6 
                 C7 
                 H71 
                 119.874° 
               
               
                 C6 
                 C8 
                 C9 
                 117.7(3)° 
                 C6 
                 C8 
                 N15 
                 124.4(3)° 
               
               
                 C9 
                 C8 
                 N15 
                 117.9(3)° 
                 C8 
                 C9 
                 N10 
                 116.6(3)° 
               
               
                 C8 
                 C9 
                 C14 
                 120.0(3)° 
                 N10 
                 C9 
                 C14 
                 123.4(3)° 
               
               
                 C9 
                 N10 
                 C11 
                 116.7(3)° 
                 N10 
                 C11 
                 C12 
                 123.7(3)° 
               
               
                 N10 
                 C11 
                 H111 
                 117.041° 
                 C12 
                 C11 
                 H111 
                 119.278° 
               
               
                 C11 
                 C12 
                 C13 
                 118.8(3)° 
                 C11 
                 C12 
                 H121 
                 120.443° 
               
               
                 C13 
                 C12 
                 H121 
                 120.783° 
                 C12 
                 C13 
                 C14 
                 119.3(3)° 
               
               
                 C12 
                 C13 
                 H131 
                 120.694° 
                 C14 
                 C13 
                 H131 
                 119.952° 
               
               
                 C9 
                 C14 
                 C13 
                 118.1(3)° 
                 C9 
                 C14 
                 H141 
                 120.942° 
               
               
                 C13 
                 C14 
                 H141 
                 120.983° 
                 C8 
                 N15 
                 C16 
                 117.6(3)° 
               
               
                 N15 
                 C16 
                 C17 
                 105.7(3)° 
                 N15 
                 C16 
                 C23 
                 110.8(3)° 
               
               
                 C17 
                 C16 
                 C23 
                 115.7(3)° 
                 N15 
                 C16 
                 H161 
                 107.681° 
               
               
                 C17 
                 C16 
                 H161 
                 107.726° 
                 C23 
                 C16 
                 H161 
                 108.910° 
               
               
                 C16 
                 C17 
                 N18 
                 120.7(3)° 
                 C16 
                 C17 
                 N21 
                 131.2(3)° 
               
               
                 N18 
                 C17 
                 N21 
                 108.0(3)° 
                 C5 
                 N18 
                 C17 
                 122.3(3)° 
               
               
                 C5 
                 N18 
                 C19 
                 128.6(3)° 
                 C17 
                 N18 
                 C19 
                 109.0(3)° 
               
               
                 N18 
                 C19 
                 C20 
                 105.7(3)° 
                 N18 
                 C19 
                 C22 
                 124.9(3)° 
               
               
                 C20 
                 C19 
                 C22 
                 129.3(3)° 
                 C19 
                 C20 
                 N21 
                 108.6(3)° 
               
               
                 C19 
                 C20 
                 H201 
                 127.007° 
                 N21 
                 C20 
                 H201 
                 124.433° 
               
               
                 C17 
                 N21 
                 C20 
                 108.7(3)° 
                 C17 
                 N21 
                 H211 
                 125.926° 
               
               
                 C20 
                 N21 
                 H211 
                 125.351° 
                 C19 
                 C22 
                 H221 
                 110.223° 
               
               
                 C19 
                 C22 
                 H222 
                 109.368° 
                 H221 
                 C22 
                 H222 
                 108.664° 
               
               
                 C19 
                 C22 
                 H223 
                 111.184° 
                 H221 
                 C22 
                 H223 
                 109.452° 
               
               
                 H222 
                 C22 
                 H223 
                 107.885° 
                 C16 
                 C23 
                 C24 
                 107.9(3)° 
               
               
                 C16 
                 C23 
                 H231 
                 107.712° 
                 C24 
                 C23 
                 H231 
                 110.073° 
               
               
                 C16 
                 C23 
                 H232 
                 111.123° 
                 C24 
                 C23 
                 H232 
                 109.430° 
               
               
                 H231 
                 C23 
                 H232 
                 110.583° 
                 C23 
                 C24 
                 C25 
                 118.8(3)° 
               
               
                 C23 
                 C24 
                 H241 
                 107.661° 
                 C25 
                 C24 
                 H241 
                 104.516° 
               
               
                 C23 
                 C24 
                 H242 
                 109.365° 
                 C25 
                 C24 
                 H242 
                 106.503° 
               
               
                 H241 
                 C24 
                 H242 
                 109.671° 
                 C24 
                 C25 
                 O26 
                 123.3(3)° 
               
               
                 C24 
                 C25 
                 O27 
                 114.4(3)° 
                 O26 
                 C25 
                 O27 
                 122.4(3)° 
               
               
                 C25 
                 O27 
                 C28 
                 115.2(3)° 
                 O27 
                 C28 
                 H281 
                 108.952° 
               
               
                 O27 
                 C28 
                 H282 
                 110.269° 
                 H281 
                 C28 
                 H282 
                 109.738° 
               
               
                 O27 
                 C28 
                 H283 
                 108.681° 
                 H281 
                 C28 
                 H283 
                 110.225° 
               
               
                 H282 
                 C28 
                 H283 
                 108.963° 
                 O81 
                 S80 
                 O82 
                 111.9(2)° 
               
               
                 O81 
                 S80 
                 O83 
                 115.1(2)° 
                 O82 
                 S80 
                 O83 
                 111.2(3)° 
               
               
                 O81 
                 S80 
                 C84 
                 106.30(18)° 
                 O82 
                 S80 
                 C84 
                 104.5(2)° 
               
               
                 O83 
                 S80 
                 C84 
                 107.0(2)° 
                 S80 
                 C84 
                 C85 
                 117.6(4)° 
               
               
                 S80 
                 C84 
                 C89 
                 122.1(4)° 
                 C85 
                 C84 
                 C89 
                 120.2(5)° 
               
               
                 C84 
                 C85 
                 C86 
                 121.6(6)° 
                 C84 
                 C85 
                 H851 
                 119.148° 
               
               
                 C86 
                 C85 
                 H851 
                 119.275° 
                 C85 
                 C86 
                 C87 
                 117.5(8)° 
               
               
                 C85 
                 C86 
                 H861 
                 121.859° 
                 C87 
                 C86 
                 H861 
                 120.606° 
               
               
                 C86 
                 C87 
                 C88 
                 124.9(7)° 
                 C86 
                 C87 
                 H871 
                 117.763° 
               
               
                 C88 
                 C87 
                 H871 
                 117.376° 
                 C87 
                 C88 
                 C89 
                 116.0(7)° 
               
               
                 C87 
                 C88 
                 H881 
                 122.592° 
                 C89 
                 C88 
                 H881 
                 121.435° 
               
               
                 C84 
                 C89 
                 C88 
                 119.8(8)° 
                 C84 
                 C89 
                 H891 
                 120.080° 
               
               
                 C88 
                 C89 
                 H891 
                 120.078°