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WO2022189280A1 - Solvates of (4s)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoro-methyl)-32 h-6- aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide - Google Patents

Solvates of (4s)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoro-methyl)-32 h-6- aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide Download PDF

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Publication number
WO2022189280A1
WO2022189280A1 PCT/EP2022/055524 EP2022055524W WO2022189280A1 WO 2022189280 A1 WO2022189280 A1 WO 2022189280A1 EP 2022055524 W EP2022055524 W EP 2022055524W WO 2022189280 A1 WO2022189280 A1 WO 2022189280A1
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formula
compound
chloro
methoxy
ethyl
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Inventor
Tia JACOBS
Ziem KRISCHAN
Michal SOWA
Julian Egger
Dominique GOPALAKRISCHNAN
Matthias Valentin Westphal
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Bayer AG
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Bayer AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the compound of the formula (I) acts as a factor XIa inhibitor and, owing to this specific mechanism of action, is, after oral administration, useful in the treatment and/or prophylaxis of disorders, preferably thrombotic or thromboembolic disorders and/or thrombotic or thromboembolic complications, in particular cardiovascular disorders including coronary artery disease, angina pectoris, myocardial infarction or stent thrombosis, as well as disorders in the cerebrovascular arteries and other disorders, leading to transitory ischaemic attacks (TIA), ischemic strokes including cardioembolic as well as non-cardioembolic strokes, and/or disorders of peripheral arteries, leading to peripheral artery disease, including peripheral artery occlusion, acute limb ischemia, amputation, reocclusions and restenoses after interventions such as angioplasty, stent implantation or surgery and bypass, and/or stent thrombosis.
  • disorders preferably thrombotic or
  • a pharmaceutical composition according to the present invention comprises (4S)-2 4 -chloro-4-ethyl-7 3 - fluoro-3 5 -methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola- 2(1,2),7(1)-dibenzenaheptaphane-7 4 -carboxamide 1,4-dioxane (compound of the formula (Ia)) and optionally further pharmaceutically acceptable excipients.
  • a pharmaceutical composition according to the present invention comprises (4S)-2 4 -chloro-4-ethyl-7 3 - fluoro-3 5 -methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola- 2(1,2),7(1)-dibenzenaheptaphane-7 4 -carboxamide propan-2-ol (compound of the formula (Ib)) and optionally further pharmaceutically acceptable excipients.
  • a pharmaceutical composition according to the present invention comprises (4S)-2 4 -chloro-4-ethyl-7 3 - fluoro-3 5 -methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola- 2(1,2),7(1)-dibenzenaheptaphane-7 4 -carboxamide butyl acetate (compound of the formula (Ic)) and optionally further pharmaceutically acceptable excipients.
  • a pharmaceutical composition according to the present invention comprises (4S)-2 4 -chloro-4-ethyl-7 3 - fluoro-3 5 -methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola- 2(1,2),7(1)-dibenzenaheptaphane-7 4 -carboxamide 2-methylpyridine (compound of the formula (Id)) and optionally further pharmaceutically acceptable excipients.
  • a pharmaceutical composition according to the present invention comprises (4S)-2 4 -chloro-4-ethyl-7 3 - fluoro-3 5 -methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola- 2(1,2),7(1)-dibenzenaheptaphane-7 4 -carboxamide butan-2-one (compound of the formula (Ie)) and optionally further pharmaceutically acceptable excipients.
  • a pharmaceutical composition according to the present invention comprises (4S)-2 4 -chloro-4-ethyl-7 3 - fluoro-3 5 -methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola- 2(1,2),7(1)-dibenzenaheptaphane-7 4 -carboxamide 4-methylpentan-2-one (compound of the formula (If)) and optionally further pharmaceutically acceptable excipients.
  • a pharmaceutical composition according to the present invention comprises (4S)-2 4 -chloro-4-ethyl-7 3 - fluoro-3 5 -methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola- 2(1,2),7(1)-dibenzenaheptaphane-7 4 -carboxamide ethyl acetate (compound of the formula (Ig)) and optionally further pharmaceutically acceptable excipients.
  • a pharmaceutical composition according to the present invention comprises (4S)-2 4 -chloro-4-ethyl-7 3 - fluoro-3 5 -methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola- 2(1,2),7(1)-dibenzenaheptaphane-7 4 -carboxamide 2-methyltetrahydrofuran (compound of the formula (Ih)) and optionally further pharmaceutically acceptable excipients.
  • any compound specified in the form of a solvate is generally a solvate of unknown exact stoichiometric composition, as obtained by the respective preparation process.
  • Compound of the formula (Ia) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-7 4 -carboxamide 1,4-dioxane (compound of the formula (Ia)) can be characterized by Raman spectroscopy which displays at least the following values of the band maxima (cm -1 ): 1619, 1333, 1245, preferably at least the following values of the band maxima (cm -1 ): 1619, 1603, 1529, 1333, 1245, more preferably at least the following values of the band maxima (cm -1 ): 1664, 1619, 1603, 1529, 1333, 1245, 980, most preferably at least the
  • 4-methylpentan-2- one can be characterized by a X-Ray powder diffractogram (at 20 ⁇ 5°C and with Cu-K alpha 1 as radiation) which displays at least the following reflections: 7.6, 10.2, 17.7, preferably at least the following reflections: 7.6, 7.8, 10.2, 15.7, 17.7, more preferably at least the following reflections: 7.6, 7.8, 10.2, 15.7, 17.7, 20.1, 23.7, most preferably at least the following reflections: 7.6, 7.8, 10.2, 12.1, 13.2, 15.7, 17.7, 20.1, 21.2 and 2
  • Compound of the formula (Ig) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-7 4 -carboxamide ethyl acetate (compound of the formula (Ig)) can be characterized by Raman spectroscopy which displays at least the following values of the band maxima (cm -1 ): 1615, 1335, 1246, preferably at least the following values of the band maxima (cm -1 ): 1615, 1603, 1531, 1335, 1246, more preferably at least the following values of the band maxima (cm -1 ): 1664, 1615, 1603, 1531, 1335, 1246, 980, most preferably at least the following
  • solvent-forming solvents are selected from the group consisting of 1,4-dioxane, propan-2-ol, butyl acetate, 2-methylpyridine, butan-2-one, 4-methylpentan-2-one, ethyl acetate and 2-methyltetrahydrofuran.
  • the solvent-forming solvents can also be used in a mixture with one or more of other solvents selected from the group consisting of methanol, ethanol, propan-1-ol, butan-1-ol, butan-2-ol, 2- methylpropan-1-ol, acetonitrile, n-heptane, cyclohexane, methylcyclohexane, 2-(propan-2- yloxy)propane, 2-methoxy-2-methylpropane and water.
  • other solvents selected from the group consisting of methanol, ethanol, propan-1-ol, butan-1-ol, butan-2-ol, 2- methylpropan-1-ol, acetonitrile, n-heptane, cyclohexane, methylcyclohexane, 2-(propan-2- yloxy)propane, 2-methoxy-2-methylpropane and water.
  • the invention further relates to a process for the preparation of the compounds of the formula (Ia) to (Ih), by dissolving the compound of the formula (I) in the crystalline modification I or in the crystalline modification II or in the amorphous form or a combination of the modifications in a solvent.
  • the compounds of the formula (Ia) to (Ih) can also be prepared by dissolving a compound of the formula (Ia) to (Ih) or a mixture of these compounds in a solvent-forming solvent other than the solvent mentioned as solvate to receive another solvate according to the solvent-forming solvent used.
  • the present invention further relates to the use of the compounds of the formula (Ia) to (Ih) for the treatment and/or prophylaxis of diseases, preferably of thrombotic or thromboembolic disorders and/or thrombotic or thromboembolic complications.
  • the present invention further relates to the use of the compounds of the formula (Ia) to (Ih) for the treatment and/or prophylaxis of cardiovascular disorders including coronary artery disease, angina pectoris, myocardial infarction or stent thrombosis, as well as disorders in the cerebrovascular arteries and other disorders, leading to transitory ischaemic attacks (TIA), ischemic strokes including cardioembolic as well as non-cardioembolic strokes, and/or disorders of peripheral arteries, leading to peripheral artery disease, including peripheral artery occlusion, acute limb ischemia, amputation, reocclusions and restenoses after interventions such as angioplasty, stent implantation or surgery and bypass, and/or stent thrombosis.
  • cardiovascular disorders including coronary artery disease, angina pectoris, myocardial infarction or stent thrombosis, as well as disorders in the cerebrovascular arteries and other disorders, leading to transitory ischae
  • compositions It is possible for the compounds of the formula (Ia) to (Ih) according to the present invention to have systemic and/or local activity. For this purpose, it can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent. For these administration routes, it is possible for the compounds of the formula (Ia) to (Ih) according to the present invention to be administered in suitable administration forms.
  • the compounds of the formula (Ia) to (Ih) for oral administration, it is possible to formulate the compounds of the formula (Ia) to (Ih) according to the present invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally- disintegrating tablets, films/wafers, films/lyophilisates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compound according to the invention in crystalline and/or amorphous and/or dissolved form into said dosage forms.
  • Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • absorption step for example intravenous, intraarterial, intracardial, intraspinal or intralumbal
  • absorption for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal.
  • Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.
  • Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
  • inhalation inter alia powder inhalers, nebulizers
  • nasal drops nasal solutions, nasal sprays
  • tablets/films/wafers/capsules for lingual, sublingual or buccal
  • compositions of the formula (Ia) to (Ih) can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients.
  • Pharmaceutically suitable excipients include, inter alia, • fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel ® ), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos ® )), • ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), • bases for suppositories (for example polyethylene glycols, cacao butter, hard fat), • solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene
  • Dosage of the pharmaceutical compositions of the present invention Based upon laboratory techniques known to evaluate compounds useful for the treatment of disorders, by pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compound of this invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredient to be administered will generally range from about 5 to 250 mg every 24 hours for parenteral administration to achieve effective results and from about 5 to 500 mg every 24 hours for oral administration to achieve effective results. In spite of this, it may be necessary, if appropriate, to deviate from the amounts specified, specifically depending on body weight, administration route, individual behaviour towards the active ingredient, type of formulation, and time or interval of administration.
  • the weight data in the tests and examples which follow are, unless stated otherwise, percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid/liquid solutions are based on each case on the volume, unless otherwise stated.
  • Method 2 Instrument: Thermo Scientific FT-MS; UHPLC: Thermo Scientific UltiMate 3000; column: Waters HSS T3 C181.8 ⁇ m, 75 mm ⁇ 2.1 mm; eluent A: water + 0.01% formic acid; eluent B: acetonitrile + 0.01% formic acid; gradient: 0.0 min 10% B ⁇ 2.5 min 95% B ⁇ 3.5 min 95% B; oven: 50°C; flow rate: 0.90 ml/min; UV detection: 210-400 nm.
  • 1H-NMR method 1H-NMR spectra were acquired on Bruker spectrometers (at 400 MHz, 500 MHz or 600 MHz as indicated) at room temperature in deuterated solvent (d 6 -DMSO). Information about the chemical shift ⁇ is given in ppm, relative to the irradiation frequency. The signal of the deuterated solvent is used as internal standard.
  • Example 1 Preparation of (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-1 4 - (trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane- 7 4 -carboxamide, also named as 4-( ⁇ (2S)-2-[4- ⁇ 5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1- yl]phenyl ⁇ -5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl ⁇ amino)-2-fluorobenzamide, (compound of the formula (I))
  • the compound of the formula (I) can be prepared as described in WO2017/005725 in Example 234 and Example 235.
  • Example 2 Preparation of 4-( ⁇ (2S)-2-[4- ⁇ 3-Chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3- triazol-1-yl]phenyl ⁇ -5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl ⁇ amino)-2-fluoro-benzamide (compound of the formula (II))
  • Example 2.1 1-(2-Bromo-4-chloro-3-fluorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole
  • 1-(2-Bromo-4-chloro-3-fluorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole is synthesized starting with 2-bromo-4-chloro-3-fluoroaniline (WO 2016/168098, page 59-60) by first generating the azido derivative (in the presence of tert-butyl nit
  • Example 2.2 4- ⁇ 3-Chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl ⁇ -2,5- dimethoxypyridine
  • reaction mixture was stirred at 100°C (oil bath already pre- heated to 100°C) overnight. Additional (2,5-dimethoxypyridin-4-yl)boronic acid (209 mg, 1.14 mmol, 0.4 eq.) and [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride monodichloromethane adduct (116 mg, 0.14 mmol, 0.05 eq.) were added. The reaction mixture was stirred at 100°C for additional 5 h, left at RT for the weekend and filtered through Celite ® which was washed with 1,4-dioxane. The combined filtrates were concentrated under reduced pressure.
  • Example 2.3 4- ⁇ 3-Chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl ⁇ -5- methoxypyridin-2(1H)-one Pyridine hydrobromide (429 mg, 2.68 mmol, 2.5 eq.) was added to a solution of 4- ⁇ 3-chloro-2- fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl ⁇ -2,5-dimethoxypyridine (432 mg, 1.07 mmol) in N,N-dimethylformamide (10 ml). The mixture was stirred at 100°C overnight and concentrated under reduced pressure.
  • Example 2.4 4-( ⁇ (2S)-2-[4- ⁇ 3-Chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1- yl]phenyl ⁇ -5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl ⁇ amino)-2-fluorobenzamide (compound of the formula (II)) 1,1,3,3-Tetramethylguanidine (420 ⁇ l, 3.35 mmol, 3.0 eq.) was added under argon atmosphere at RT to a solution of 4- ⁇ 3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl ⁇ -5- methoxypyridin-2(1H)-one (438 mg, 1.12 mmol) in 2-propanol / acetone (4:1, 7.5 ml).
  • Example 3 Preparation of 4-( ⁇ (2S)-2-[4- ⁇ 5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1- yl]phenyl ⁇ -5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl ⁇ -amino)-2-fluorobenzamide acetone (compound of the formula (III)
  • the compound of the formula (III) can be prepared as described in WO2019/175043 compound of the formula (IIc). Using the described process the compound of the formula (III) is obtained in the crystalline form.
  • Example 4 Preparation of the compound of the formula (II) in crystalline modification A 306 mg of compound of the formula (II) in amorphous form was dissolved in 20 mL of a mixture of 50 vol.-% ethanol and 50 vol.-% water at room temperature. The solution was stirred 24 hours at room temperature, resulting in the precipitation of a white solid. The solvent was evaporated in a rotary evaporator. The obtained solid was dried in a vacuum oven at 40°C for 16 hours.273 mg of compound of the formula (II) in the crystalline modification A was obtained.
  • Example 5 Preparation of the compound of the formula (I) in crystalline modification I 30 mg compound of the formula (I) in amorphous form was dissolved in 2 mL of ethanol at room temperature. 660 ⁇ L of water was added to the solution dropwise until a cloudy solution was observed. The solution was then seeded with 1 mg of crystalline modification A of compound of the formula (II). Shortly after seeding, the precipitation of further small particles was observed, but the particles rapidly disappeared upon stirring, resulting in a seemingly clear solution. After stirring at room temperature for 48 hours, a suspension was obtained. The solid was filtered under vacuum and dried overnight under ambient conditions. The XRPD pattern of the obtained solid corresponds to the crystalline modification I of compound of the formula (I).
  • Example 6 Preparation of the compound of the formula (I) in crystalline modification I as pure compound of the formula (I) 20.0 g compound of the formula (I) in amorphous form was dissolved in a mixture of 40.0 g of propan-2-ol and 10.0 g of acetone, at room temperature. The mixture was heated up to 60°C and to the resulting solution 126.0 g of water was added during 60 minutes. The resulting mixture was seeded with 100.0 mg of crystalline modification I of compound of the formula (I) and stirred at 60°C for 3 hours.
  • Example 7 Preparation of the compound of the formula (I) in crystalline modification II 40 mg of the compound of the formula (III) was dried at 50°C under reduced pressure to obtain solid in the crystalline modification II.
  • Example 8 Preparation of the compounds of the formula (Ia) to (Ih) A range of solvates of the compound of the formula (I) that display isomorphism (1,4-dioxane, propan-2-ol, butyl acetate, 2-methylpyridine, butan-2-one, 4-methylpentan-2-one, ethyl acetate and 2-methyltetrahydrofuran) could be obtained by slurrying and/or crystallization from solution using the crystalline modification I or the amorphous form of the compound of the formula (I).
  • Example 8.1 Preparation of the compound of the formula (Ia), 1,4-dioxane solvate 30 mg of the crystalline modification I of the compound of the formula (I) and 50 ⁇ L 1,4-dioxane were added to a vial. The vial was sealed and stirred with a magnetic stirrer at room temperature. After 1 week the slurry was filtered and air-dried.
  • Example 8.2 Preparation of the compound of the formula (Ib), propan-2-ol solvate 30 mg of the amorphous form of the compound of the formula (I) and 50 ⁇ L propan-2-ol were added to a vial. The vial was sealed and stirred with a magnetic stirrer at room temperature. After 4 hours the slurry was filtered and air-dried.
  • Example 8.3 Preparation of the compound of the formula (Ic), butyl acetate solvate 30 mg of the amorphous form of the compound of the formula (I) and 50 ⁇ L butyl acetate were added to a vial. The vial was sealed and stirred with a magnetic stirrer at room temperature. After 4 hours the slurry was filtered and air-dried.
  • Example 8.4 Preparation of the compound of the formula (Id), 2-methylpyridine solvate 30 mg of the crystalline modification I of the compound of the formula (I) and 200 ⁇ L 2-methylpyridine were added to a vial. The vial was sealed and stirred with for 10 minutes at 50°C. The resulting solution was filtered and transferred to a new sealed vial. The vial was placed in a temperature block preheated to 50°C and cooled to 4°C at 0.1°C/min.
  • Example 8.5 Preparation of the compound of the formula (Ie), butan-2-one solvate 40 mg of the crystalline modification I of the compound of the formula (I) and 200 ⁇ L butan-2-one/water 1:9 (v:v) were added to a vial. The vial was sealed and stirred with a magnetic stirrer at 60°C. After 1 week the slurry was filtered and air-dried.
  • a cooling crystallization in butan-2-one was used: 30 mg of the crystalline modification I of the compound of the formula (I) and 1350 ⁇ L 2-butanone were added to a vial. The vial was sealed and stirred with for 10 minutes at 50°C. The resulting solution was filtered and transferred to a new sealed vial. The vial was placed in a temperature block preheated to 50°C and cooled to 4°C at 0.1°C/min. The resulting slurry was filtered and air-dried.
  • Example 8.6 Preparation of the compound of the formula (If), 4-methylpentan-2-one solvate 1.0 g of the amorphous form of the compound of the formula (I) was mixed with 2.0 g of 4- methylpentan-2-one at room temperature. The resulting mixture was stirred at 20°C until a clear solution was obtained after ca. 45 minutes. The clear solution was seeded with 10 mg of the compound of the formula (III). After ca.30 minutes a suspension was formed and was stirred overnight at 20°C. The final suspension was filtered under vacuum, washed with 1 mL of 4-methylpentan-2-one and dried overnight in vacuum, at 50°C.
  • Example 8.7 Preparation of the compound of the formula (Ig), ethyl acetate solvate 25.0 g of amorphous compound of formula (I) was mixed with 75 g of ethyl acetate at room temperature. The resulting mixture was stirred at 85°C until a clear solution was obtained. The clear solution was cooled to 40°C and seeded with the compound of the formula (III). The resulting suspension was stirred for a further 60 minutes, before decreasing the temperature to 0°C over 7.5 hours.
  • Example 8.8 Preparation of the compound of the formula (Ih), 2-methyltetrahydrofuran solvate 1.25 g of amorphous compound of formula (I) was mixed with 3.75 g of 2-methyltetrahydrofuran at room temperature. The so-obtained mixture was stirred at 20°C overnight. The resulting suspension was filtered under vacuum, washed with 2.0 g 2-methyltetrahydrofuran and dried overnight under vacuum, at 50°C.
  • Example 9 Physical characterization of the compounds of the formula (Ia) to (Ih)
  • Example 9.1 Thermogravimetric analysis (TGA) Thermogravimetric analysis (TGA) was performed with either a Perkin Elmer Pyris 6 or a Mettler Toledo TGA/DSC 3+. The instrument was purged with nitrogen gas at a flow rate of 10 or 20 or 50 ml.min -1 . Approximately 1 – 15 mg of each sample was placed into either an aluminum or an aluminum oxide crucible and heated at a heating rate of 10°C.min -1 starting from 25°C. No sample preparation. TGA thermograms are shown in figures 1 to 6 and 29 and 30.
  • Example 9.2 Differential scanning calorimetry (DSC) Differential scanning calorimetry (DSC) was performed with either a Netzsch Phoenix DSC 204 F1 or a Mettler Toledo DSC3+. The calorimeter was purged with nitrogen gas at a flow rate of 10 or 20 or 50 ml.min -1 . Approximately 1 – 15 mg of each sample was placed into an aluminum crucible and heated at a rate of 10 or 20°C.min -1 starting from -10 or 25°C. No sample preparation. DSC thermograms are shown in figures 7 to 12 and 31 and 32.
  • Example 9.3 Raman spectroscopy Raman measurements were performed with a Bruker MultiRAM spectrometer.
  • Table 1B Raman spectroscopy of the compounds of the formula (Ig) and (Ih) Band maxima (cm -1 ) Compound of the formula (Ig) Compound of the formula (Ih) 494 992 1603 448 919 1287 1699 524 1032 1615 494 980 1333 2842 618 1098 1664 524 992 1383 2878 655 1213 1699 552 1004 1445 2940 710 1249 2842 584 1032 1485 2980 747 1334 2943 618 1098 1497 3075 757 1383 3074 655 1142 1531
  • Example 9.4 X-ray powder diffraction (XRPD) X-ray powder diffraction (XRPD) data were recorded on either a STOE STADI P or a D8 Bruker Advance diffractometer using monochromatized Cu-K alpha 1 radiation, a position sensitive detector, at generator settings of 40 kV and 40 mA.
  • the samples were collected in transition mode, being either prepared into a standard glass capillary or as a thin layer between two foils.
  • the scanning rage was between 2° and 40° 2 theta with a 0.5° step at 15 seconds/step for the STOE STADI P and a 0.009194171° step at 1.28 seconds/step for the D8 Bruker Advance.
  • Table 2A X-ray powder diffraction (XRPD) of the compounds of the formula (Ia) to (Ig) Diffraction angle (2 ⁇ , °)
  • XRPD X-ray powder diffraction
  • Table 2A Compound Compound Compound Compound Compound of the of the of the of the of the of the of the formula formula formula formula (Ic) formula (Id) formula (Ie) formula formula (Ia) (Ib) (If) (Ig) 7.6 7.6 7.6 30.3 7.6 29.3 7.7 26.2 7.6 7.8 7.7 8.1 8.0 31.3 7.9 29.4 8.0 26.7 7.8 8.2 8.3 8.5 8.2 32.2 8.2 29.8 8.5 26.9 8.8 10.5 9.1 10.4 9.1 34.1 9.1 29.9 10.4 27.2 10.2 12.0 10.1 10.8 10.3 34.5 10.2 30.2 10.7 27.6 10.9 12.4 11.2 11.8 10.6 35.2 11.1 30.5 11.8 27.7 12.1 13.4 13.1 12.4 11.1

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Abstract

The present invention relates to solvates of (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5- dioxo-14-(trifluoromcthyl)-32 H-6-aza-3(4,1)-pyridina-1(1)-[1.2.3]triazola-2(1,2),7(1)- dibenzenaheptaphane-74-carboxamide, to processes for their preparation, to pharmaceutical compositions comprising them and to their use in the control of disorders.

Description

Solvates of (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoro-methyl)-32H-6- aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide The present invention relates to solvates of (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5- dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)- dibenzenaheptaphane-74-carboxamide, to processes for their preparation, to pharmaceutical compositions comprising them and to their use in the control of disorders. Compound of the formula (I), (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14- (trifluoromethyl)-32H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane- 74-carboxamide, also named as 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1- yl]phenyl}-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2-fluorobenzamide, is known from WO2017/005725 and has the following formula: compound of the formula (I).
Figure imgf000002_0001
The compound of the formula (I) acts as a factor XIa inhibitor and, owing to this specific mechanism of action, is, after oral administration, useful in the treatment and/or prophylaxis of disorders, preferably thrombotic or thromboembolic disorders and/or thrombotic or thromboembolic complications, in particular cardiovascular disorders including coronary artery disease, angina pectoris, myocardial infarction or stent thrombosis, as well as disorders in the cerebrovascular arteries and other disorders, leading to transitory ischaemic attacks (TIA), ischemic strokes including cardioembolic as well as non-cardioembolic strokes, and/or disorders of peripheral arteries, leading to peripheral artery disease, including peripheral artery occlusion, acute limb ischemia, amputation, reocclusions and restenoses after interventions such as angioplasty, stent implantation or surgery and bypass, and/or stent thrombosis. An isopropyl acetate, tetrahydrofuran and acetone solvate of the compound of the formula (I) is described in WO2019/175043. The compound of the formula (I) can be prepared as described in WO2017/005725 in Example 234 and Example 235. Using the described process the compound of the formula (I) is obtained in the amorphous form. The amorphous form can be characterized by an X-ray powder diffractogram displaying no characteristic reflections, as well as a DSC thermogram displaying no melting events (Figure 27 and 26). The TGA thermogram is shown in figure 25. In the present invention the following solvates of the compound of the formula (I) have been identified: (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 1,4-dioxane (compound of the formula (Ia)), compound of the formula (Ia),
Figure imgf000003_0001
(4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide propan-2-ol (compound of the formula (Ib)), compound of the formula (Ib),
Figure imgf000003_0002
(4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide butyl acetate (compound of the formula (Ic)), compound of the formula (Ic),
Figure imgf000003_0003
(4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 2-methylpyridine (compound of the formula (Id)), compound of the formula (Id),
Figure imgf000004_0001
(4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide butan-2-one (compound of the formula (Ie)), compound of the formula (Ie),
Figure imgf000004_0002
(4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 4-methylpentan-2- one (compound of the formula (If)) compound of the formula (If),
Figure imgf000004_0003
(4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide ethyl acetate (compound of the formula (Ig)) compound of the formula (Ig),
Figure imgf000005_0001
and (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 2-methyltetrahydro- furan (compound of the formula (Ih)) compound of the formula (Ih).
Figure imgf000005_0002
The 1,4-dioxane solvate (Ia) of the compound of the formula (I), the propan-2-ol solvate (Ib) of the compound of the formula (I), the butyl acetate solvate (Ic) of the compound of the formula (I), the 2- methylpyridine solvate (Id) of the compound of the formula (I), the butan-2-one solvate (Ie) of the compound of the formula (I), the 4-methylpentan-2-one solvate (If) of the compound of the formula (I), the ethyl acetate solvate (Ig) of the compound of the formula (I) and/or the 2-methyltetrahydro- furan solvate (Ih) of the compound of the formula (I) is therefore suitable and preferred over other solvates of the compound of the formula (I) for use in the pharmaceutical field, in particular suitable for pharmaceutical compositions. A pharmaceutical composition according to the present invention comprises (4S)-24-chloro-4-ethyl-73- fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola- 2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 1,4-dioxane (compound of the formula (Ia)) and optionally further pharmaceutically acceptable excipients. A pharmaceutical composition according to the present invention comprises (4S)-24-chloro-4-ethyl-73- fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola- 2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide propan-2-ol (compound of the formula (Ib)) and optionally further pharmaceutically acceptable excipients. A pharmaceutical composition according to the present invention comprises (4S)-24-chloro-4-ethyl-73- fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola- 2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide butyl acetate (compound of the formula (Ic)) and optionally further pharmaceutically acceptable excipients. A pharmaceutical composition according to the present invention comprises (4S)-24-chloro-4-ethyl-73- fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola- 2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 2-methylpyridine (compound of the formula (Id)) and optionally further pharmaceutically acceptable excipients. A pharmaceutical composition according to the present invention comprises (4S)-24-chloro-4-ethyl-73- fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola- 2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide butan-2-one (compound of the formula (Ie)) and optionally further pharmaceutically acceptable excipients. A pharmaceutical composition according to the present invention comprises (4S)-24-chloro-4-ethyl-73- fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola- 2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 4-methylpentan-2-one (compound of the formula (If)) and optionally further pharmaceutically acceptable excipients. A pharmaceutical composition according to the present invention comprises (4S)-24-chloro-4-ethyl-73- fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola- 2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide ethyl acetate (compound of the formula (Ig)) and optionally further pharmaceutically acceptable excipients. A pharmaceutical composition according to the present invention comprises (4S)-24-chloro-4-ethyl-73- fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola- 2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 2-methyltetrahydrofuran (compound of the formula (Ih)) and optionally further pharmaceutically acceptable excipients. Due to similarities displayed among the different solvates of the compound of the formula (I) in the packing of molecules within these solid state forms, these forms display very similar powder X-ray diffractograms and Raman Spectra. The identity of the included solvent molecule can however be clearly elucidated by 1H NMR. TGA thermograms in addition show the release of the solvent molecules from the crystalline lattice upon heating, as registered by the mass loss as a function of temperature. Furthermore, differential scanning calorimetry (DSC) thermograms are available displaying the melting events. In the case of working examples of the invention described hereinafter, any compound specified in the form of a solvate is generally a solvate of unknown exact stoichiometric composition, as obtained by the respective preparation process. Unless specified in more detail, additions to names and structural formulae, such as “1,4-dioxane”, “propan-2-ol”, “butyl acetate”, “2-methyl pyridine”, “butan-2-one”, “4-methylpentan-2-one”, “ethyl acetate” and “2-methyltetrahydrofuran” should not therefore be understood in a stoichiometric sense in the case of such solvates, but have merely descriptive character with regard to the solvate-forming components present therein. Compound of the formula (Ia) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 1,4-dioxane (compound of the formula (Ia)) can be characterized by Raman spectroscopy which displays at least the following values of the band maxima (cm-1): 1619, 1333, 1245, preferably at least the following values of the band maxima (cm-1): 1619, 1603, 1529, 1333, 1245, more preferably at least the following values of the band maxima (cm-1): 1664, 1619, 1603, 1529, 1333, 1245, 980, most preferably at least the following values of the band maxima (cm-1): 2941, 1664, 1619, 1603, 1529, 1333, 1245, 980, 747 and 223. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14- (trifluoromethyl)-32H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane- 74-carboxamide 1,4-dioxane (compound of the formula (Ia)) can also be characterized by Raman spectrum as shown in Figure 13. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 1,4-dioxane (compound of the formula (Ia)) can be characterized by a X-Ray powder diffractogram (at 20 ± 5°C and with Cu-K alpha 1 as radiation) which displays at least the following reflections: 7.7, 10.1, 20.5, preferably at least the following reflections: 7.7, 10.1, 13.1, 18.3, 20.5, more preferably at least the following reflections: 7.6, 7.7, 10.1, 13.1, 18.3, 20.0, 20.5, most preferably at least the following reflections: 7.6, 7.7, 10.1, 13.1, 15.5, 18.3, 19.4, 20.0, 20.5 and 21.2, each quoted as 2Ɵ value ± 0.2°. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 1,4-dioxane (compound of the formula (Ia)) can also be characterized by the X-Ray powder diffractogram (at 20 ± 5°C and with Cu-K alpha 1 as radiation) as shown in Figure 19. Compound of the formula (Ib) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide propan-2-ol (compound of the formula (Ib)) can be characterized by Raman spectroscopy which displays at least the following values of the band maxima (cm-1): 1617, 1334, 1246, preferably at least the following values of the band maxima (cm-1): 1617, 1604, 1532, 1334, 1246, more preferably at least the following values of the band maxima (cm-1): 1666, 1617, 1604, 1532, 1334, 1246, 979, most preferably at least the following values of the band maxima (cm-1): 2941, 1666, 1617, 1604, 1532, 1334, 1246, 979, 748 and 221. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoro- methyl)-32H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74- carboxamide propan-2-ol (compound of the formula (Ib)) can also be characterized by Raman spectrum as shown in Figure 14. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide propan-2-ol (compound of the formula (Ib)) can be characterized by a X-Ray powder diffractogram (at 20 ± 5°C and with Cu-K alpha 1 as radiation) which displays at least the following reflections: 8.1, 10.4, 21.4, preferably at least the following reflections: 7.6, 8.1, 10.4, 16.7, 21.4, more preferably at least the following reflections: 7.6, 8.1, 10.4, 16.7, 18.9, 20.0, 21.4, most preferably at least the following reflections: 7.6, 8.1, 10.4, 13.5, 16.2, 16.7, 17.8, 18.9, 20.0 and 21.4, each quoted as 2Ɵ value ± 0.2°. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide propan-2-ol (compound of the formula (Ib)) can also be characterized by the X-Ray powder diffractogram (at 20 ± 5°C and with Cu-K alpha 1 as radiation) as shown in Figure 20. Compound of the formula (Ic) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide butyl acetate (compound of the formula (Ic)) can be characterized by Raman spectroscopy which displays at least the following values of the band maxima (cm-1): 1620, 1334, 1246, preferably at least the following values of the band maxima (cm-1): 1620, 1604, 1531, 1334, 1246, more preferably at least the following values of the band maxima (cm-1): 1664, 1620, 1604, 1531, 1334, 1246, 980, most preferably at least the following values of the band maxima (cm-1): 2939, 1664, 1620, 1604, 1531, 1334, 1246, 980, 748 and 221. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza- 3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide butyl acetate (compound of the formula (Ic)) can also be characterized by Raman spectrum as shown in Figure 15. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide butyl acetate (compound of the formula (Ic)) can be characterized by a X-Ray powder diffractogram (at 20 ± 5°C and with Cu-K alpha 1 as radiation) which displays at least the following reflections: 8.0, 10.3, 21.2, preferably at least the following reflections: 8.0, 10.3, 16.1, 18.4, 21.2, more preferably at least the following reflections: 7.6, 8.0, 10.3, 16.1, 18.4, 20.5, 21.2, most preferably at least the following reflections: 7.6, 8.0, 10.3, 14.6, 16.1, 17.0, 18.4, 20.5, 21.2 and 23.1, each quoted as 2Ɵ value ± 0.2°. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide butyl acetate (compound of the formula (Ic)) can also be characterized by the X-Ray powder diffractogram (at 20 ± 5°C and with Cu-K alpha 1 as radiation) as shown in Figure 21. Compound of the formula (Id) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 2-methylpyridine (compound of the formula (Id)) can be characterized by Raman spectroscopy which displays at least the following values of the band maxima (cm-1): 1619, 1331, 1246, preferably at least the following values of the band maxima (cm-1): 1619, 1602, 1529, 1331, 1246, more preferably at least the following values of the band maxima (cm-1): 1665, 1619, 1602, 1529, 1331, 1246, 979, most preferably at least the following values of the band maxima (cm-1): 2941, 1665, 1619, 1602, 1529, 1331, 1246, 979, 747 and 222. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza- 3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 2- methylpyridine (compound of the formula (Id)) can also be characterized by Raman spectrum as shown in Figure 16. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 2-methylpyridine (compound of the formula (Id)) can be characterized by a X-Ray powder diffractogram (at 20 ± 5°C and with Cu-K alpha 1 as radiation) which displays at least the following reflections: 7.9, 10.2, 20.9, preferably at least the following reflections: 7.9, 10.2, 13.5, 18.3, 20.9, more preferably at least the following reflections: 7.6, 7.9, 10.2, 13.5, 18.3, 20.0, 20.9, most preferably at least the following reflections: 7.6, 7.9, 10.2, 13.5, 15.8, 17.0, 18.3, 20.0, 20.9 and 23.8, each quoted as 2Ɵ value ± 0.2°. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 2-methylpyridine (compound of the formula (Id)) can also be characterized by the X-Ray powder diffractogram (at 20 ± 5°C and with Cu-K alpha 1 as radiation) as shown in Figure 22. Compound of the formula (Ie) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide butan-2-one (compound of the formula (Ie)) can be characterized by Raman spectroscopy which displays at least the following values of the band maxima (cm-1): 1616, 1333, 1246, preferably at least the following values of the band maxima (cm-1): 1616, 1603, 1531, 1333, 1246, more preferably at least the following values of the band maxima (cm-1): 1664, 1616, 1603, 1531, 1333, 1246, 979, most preferably at least the following values of the band maxima (cm-1): 2942, 1664, 1616, 1603, 1531, 1333, 1246, 979, 747 and 221. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza- 3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide butan-2-one (compound of the formula (Ie)) can also be characterized by Raman spectrum as shown in Figure 17. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide butan-2-one (compound of the formula (Ie)) can be characterized by a X-Ray powder diffractogram (at 20 ± 5°C and with Cu-K alpha 1 as radiation) which displays at least the following reflections: 8.0, 16.6, 21.3, preferably at least the following reflections: 7.7, 8.0, 10.4, 16.6, 21.3, more preferably at least the following reflections: 7.7, 8.0, 10.4, 16.6, 18.7, 20.0, 21.3, most preferably at least the following reflections: 7.7, 8.0, 10.4, 16.6, 17.4, 18.7, 20.0, 21.3, 24.1 and 24.7, each quoted as 2Ɵ value ± 0.2°. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide butan-2-one (compound of the formula (Ie)) can also be characterized by the X-Ray powder diffractogram (at 20 ± 5°C and with Cu-K alpha 1 as radiation) as shown in Figure 23. Compound of the formula (If) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 4-methylpentan-2- one (compound of the formula (If)) can be characterized by Raman spectroscopy which displays at least the following values of the band maxima (cm-1): 1620, 1335, 1246, preferably at least the following values of the band maxima (cm-1): 1620, 1603, 1529, 1333, 1246, more preferably at least the following values of the band maxima (cm-1): 1664, 1620, 1603, 1529, 1335, 1246, 980, most preferably at least the following values of the band maxima (cm-1): 2939, 1664, 1620, 1603, 1529, 1335, 1246, 980, 747 and 221. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14- (trifluoromethyl)-32H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane- 74-carboxamide 4-methylpentan-2-one (compound of the formula (If)) can also be characterized by Raman spectrum as shown in Figure 18. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 4-methylpentan-2- one (compound of the formula (If)) can be characterized by a X-Ray powder diffractogram (at 20 ± 5°C and with Cu-K alpha 1 as radiation) which displays at least the following reflections: 7.6, 10.2, 17.7, preferably at least the following reflections: 7.6, 7.8, 10.2, 15.7, 17.7, more preferably at least the following reflections: 7.6, 7.8, 10.2, 15.7, 17.7, 20.1, 23.7, most preferably at least the following reflections: 7.6, 7.8, 10.2, 12.1, 13.2, 15.7, 17.7, 20.1, 21.2 and 23.7, each quoted as 2Ɵ value ± 0.2°. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 4-methylpentan-2- one (compound of the formula (If)) can also be characterized by the X-Ray powder diffractogram (at 20 ± 5°C and with Cu-K alpha 1 as radiation) as shown in Figure 24. Compound of the formula (Ig) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide ethyl acetate (compound of the formula (Ig)) can be characterized by Raman spectroscopy which displays at least the following values of the band maxima (cm-1): 1615, 1335, 1246, preferably at least the following values of the band maxima (cm-1): 1615, 1603, 1531, 1335, 1246, more preferably at least the following values of the band maxima (cm-1): 1664, 1615, 1603, 1531, 1335, 1246, 980, most preferably at least the following values of the band maxima (cm-1): 2943, 1664, 1615, 1603, 1531, 1335, 1246, 980, 747 and 220. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza- 3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide ethyl acetate (compound of the formula (Ig)) can also be characterized by Raman spectrum as shown in Figure 33. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide ethyl acetate (compound of the formula (Ig)) can be characterized by a X-Ray powder diffractogram (at 20 ± 5°C and with Cu-K alpha 1 as radiation) which displays at least the following reflections: 8.2, 16.3, 21.4, preferably at least the following reflections: 7.8, 8.2, 10.5, 16.3, 21.4, more preferably at least the following reflections: 7.8, 8.2, 10.5, 16.3, 16.7, 20.1, 21.4, most preferably at least the following reflections: 7.8, 8.2, 10.5, 13.9, 16.3, 16.7, 20.1, 21.4, 24.3 and 24.5, each quoted as 2Ɵ value ± 0.2°. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide ethyl acetate (compound of the formula (Ig)) can also be characterized by the X-Ray powder diffractogram (at 20 ± 5°C and with Cu-K alpha 1 as radiation) as shown in Figure 28. Compound of the formula (Ih) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 2-methyltetrahydro- furan (compound of the formula (Ih)) can be characterized by Raman spectroscopy which displays at least the following values of the band maxima (cm-1): 1619, 1333, 1249, preferably at least the following values of the band maxima (cm-1): 1619, 1603, 1531, 1333, 1249, more preferably at least the following values of the band maxima (cm-1): 1664, 1619, 1603, 1531, 1333, 1249, 980, most preferably at least the following values of the band maxima (cm-1): 2940, 1664, 1619, 1603, 1531, 1333, 1249, 980, 747 and 221. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14- (trifluoromethyl)-32H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane- 74-carboxamide 2-methyltetrahydrofuran (compound of the formula (Ih)) can also be characterized by Raman spectrum as shown in Figure 34. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 2-methyltetrahydro- furan (compound of the formula (Ih)) can be characterized by a X-Ray powder diffractogram (at 20 ± 5°C and with Cu-K alpha 1 as radiation) which displays at least the following reflections: 8.0, 10.3, 21.2, preferably at least the following reflections: 7.7, 8.0, 10.3, 20.1, 21.2, more preferably at least the following reflections: 7.7, 8.0, 10.3, 16.1, 20.1, 21.2, 24.2, most preferably at least the following reflections: 7.7, 8.0, 10.3, 13.7, 16.1, 16.8, 17.4, 20.1, 21.2 and 24.2, each quoted as 2Ɵ value ± 0.2°. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)- pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 2-methyltetrahydro- furan (compound of the formula (Ih)) can also be characterized by the X-Ray powder diffractogram (at 20 ± 5°C and with Cu-K alpha 1 as radiation) as shown in Figure 35. Process for preparing: The compound of the formula (I) can be converted into the respective compounds of the formula (Ia) to (Ih) by treatment with the corresponding solvent-forming solvents. Solvent-forming solvents are selected from the group consisting of 1,4-dioxane, propan-2-ol, butyl acetate, 2-methylpyridine, butan-2-one, 4-methylpentan-2-one, ethyl acetate and 2-methyltetrahydrofuran. The solvent-forming solvents can also be used in a mixture with one or more of other solvents selected from the group consisting of methanol, ethanol, propan-1-ol, butan-1-ol, butan-2-ol, 2- methylpropan-1-ol, acetonitrile, n-heptane, cyclohexane, methylcyclohexane, 2-(propan-2- yloxy)propane, 2-methoxy-2-methylpropane and water. The invention further relates to a process for the preparation of the compounds of the formula (Ia) to (Ih), by dissolving the compound of the formula (I) in the crystalline modification I or in the crystalline modification II or in the amorphous form or a combination of the modifications in a solvent. The compounds of the formula (Ia) to (Ih) can also be prepared by dissolving a compound of the formula (Ia) to (Ih) or a mixture of these compounds in a solvent-forming solvent other than the solvent mentioned as solvate to receive another solvate according to the solvent-forming solvent used. Method for treatment: The present invention further relates to the use of the compounds of the formula (Ia) to (Ih) for the treatment and/or prophylaxis of diseases, preferably of thrombotic or thromboembolic disorders and/or thrombotic or thromboembolic complications. The present invention further relates to the use of the compounds of the formula (Ia) to (Ih) for the treatment and/or prophylaxis of cardiovascular disorders including coronary artery disease, angina pectoris, myocardial infarction or stent thrombosis, as well as disorders in the cerebrovascular arteries and other disorders, leading to transitory ischaemic attacks (TIA), ischemic strokes including cardioembolic as well as non-cardioembolic strokes, and/or disorders of peripheral arteries, leading to peripheral artery disease, including peripheral artery occlusion, acute limb ischemia, amputation, reocclusions and restenoses after interventions such as angioplasty, stent implantation or surgery and bypass, and/or stent thrombosis. Pharmaceutical compositions: It is possible for the compounds of the formula (Ia) to (Ih) according to the present invention to have systemic and/or local activity. For this purpose, it can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent. For these administration routes, it is possible for the compounds of the formula (Ia) to (Ih) according to the present invention to be administered in suitable administration forms. For oral administration, it is possible to formulate the compounds of the formula (Ia) to (Ih) according to the present invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally- disintegrating tablets, films/wafers, films/lyophilisates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compound according to the invention in crystalline and/or amorphous and/or dissolved form into said dosage forms. Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders. Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents. The compounds of the formula (Ia) to (Ih) can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia, • fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel®), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos®)), • ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), • bases for suppositories (for example polyethylene glycols, cacao butter, hard fat), • solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins), • surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette®), sorbitan fatty acid esters (such as, for example, Span®), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic®), • buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine), • isotonicity agents (for example glucose, sodium chloride), • adsorbents (for example highly-disperse silicas), • viscosity-increasing agents, gel formers, thickeners and/or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl- cellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol®); alginates, gelatine), • disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab®), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSol®)), • flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil®)), • coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropyl- methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®)), • capsule materials (for example gelatine, hydroxypropylmethylcellulose), • synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit®), polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers), • plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate), • penetration enhancers, • stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate), • preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), • colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide), • flavourings, sweeteners, flavour- and/or odour-masking agents. Dosage of the pharmaceutical compositions of the present invention: Based upon laboratory techniques known to evaluate compounds useful for the treatment of disorders, by pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compound of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated. The total amount of the active ingredient to be administered will generally range from about 5 to 250 mg every 24 hours for parenteral administration to achieve effective results and from about 5 to 500 mg every 24 hours for oral administration to achieve effective results. In spite of this, it may be necessary, if appropriate, to deviate from the amounts specified, specifically depending on body weight, administration route, individual behaviour towards the active ingredient, type of formulation, and time or interval of administration. The weight data in the tests and examples which follow are, unless stated otherwise, percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid/liquid solutions are based on each case on the volume, unless otherwise stated. Working examples Abbreviations: br s broad singlet (in NMR) br d broad doublet (in NMR) br t broad triplet (in NMR) d day(s), doublet (in NMR) DCI direct chemical ionization (in MS) dd doublet of doublets (in NMR) DMSO dimethyl sulfoxide eq. equivalent(s) ESI electrospray ionization (in MS) h hour(s) HPLC high-pressure, high-performance liquid chromatography LC/MS liquid chromatography-coupled mass spectroscopy m multiplet (in NMR) min minute(s) MS mass spectroscopy NMR nuclear magnetic resonance spectroscopy q quartet or quadruplet (in NMR) RP reverse phase (in HPLC) RT room temperature Rt retention time (in HPLC) s singlet (in NMR) t triplet (in NMR) T3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide HPLC, LC-MS and GC methods: Method 1: Instrument: Waters ACQUITY SQD UPLC system; column: Waters Acquity UPLC HSS T3 C181.8 µm, 50 mm × 1.0 mm; eluent A: water + 0.025 % formic acid, eluent B: acetonitrile + 0.025 % formic acid; gradient: 0.0 min 10% B → 1.2 min 95% B → 2.0 min 95% B; oven: 50°C; flow rate: 0.40 ml/min; UV detection: 210-400 nm. Method 2: Instrument: Thermo Scientific FT-MS; UHPLC: Thermo Scientific UltiMate 3000; column: Waters HSS T3 C181.8 µm, 75 mm × 2.1 mm; eluent A: water + 0.01% formic acid; eluent B: acetonitrile + 0.01% formic acid; gradient: 0.0 min 10% B → 2.5 min 95% B → 3.5 min 95% B; oven: 50°C; flow rate: 0.90 ml/min; UV detection: 210-400 nm. ¹H-NMR method: ¹H-NMR spectra were acquired on Bruker spectrometers (at 400 MHz, 500 MHz or 600 MHz as indicated) at room temperature in deuterated solvent (d6-DMSO). Information about the chemical shift δ is given in ppm, relative to the irradiation frequency. The signal of the deuterated solvent is used as internal standard. Example 1: Preparation of (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14- (trifluoromethyl)-32H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane- 74-carboxamide, also named as 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1- yl]phenyl}-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2-fluorobenzamide, (compound of the formula (I)) The compound of the formula (I) can be prepared as described in WO2017/005725 in Example 234 and Example 235. Using the described process the compound of the formula (I) is obtained in the amorphous form. The 1H-NMR of the compound of the formula (I) as racemate is shown in WO2017/005725 in Example 234: 1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 10.76 (br s, 1H), 9.13 (s, 1H), 7.86-7.80 (m, 2H), 7.79- 7.77 (m, 1H), 7.69 (t, 1H), 7.66-7.61 (m, 1H), 7.56-7.49 (m, 2H), 7.37 (dd, 1H), 7.13 (s, 1H), 6.53 (s, 1H), 5.55-5.49 (m, 1H), 3.26 (s, 3H), 2.14-2.02 (m, 2H), 0.79 (t, 3H). Example 2: Preparation of 4-({(2S)-2-[4-{3-Chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3- triazol-1-yl]phenyl}-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)-2-fluoro-benzamide (compound of the formula (II)) Example 2.1: 1-(2-Bromo-4-chloro-3-fluorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole
Figure imgf000017_0001
1-(2-Bromo-4-chloro-3-fluorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole is synthesized starting with 2-bromo-4-chloro-3-fluoroaniline (WO 2016/168098, page 59-60) by first generating the azido derivative (in the presence of tert-butyl nitrite and trimethylsilyl azide, in analogy to the synthesis of example 2.18A, WO 2017/005725, page 92-93) and second performing a cycloaddition of the azido derivative with trifluoropropyne (in the presence of copper(I) oxide, in analogy to the synthesis of example 2.26A, WO 2017/005725, page 102). Example 2.2: 4-{3-Chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-2,5- dimethoxypyridine
Figure imgf000018_0001
A mixture of 1-(2-bromo-4-chloro-3-fluorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (982 mg, 2.85 mmol), (2,5-dimethoxypyridin-4-yl)boronic acid (WO 2019/175043, page 23-24) (626 mg, 3.42 mmol, 1.2 eq.) and potassium carbonate (1.18 g, 8.55 mmol, 3.0 eq.) was dissolved in 1,4- dioxane (50 ml) and flushed with argon for 10 min before [1,1- bis(diphenylphosphino)ferrocene]palladium(II) chloride monodichloromethane adduct (233 mg, 0.29 mmol, 0.1 eq.) was added. The reaction mixture was stirred at 100°C (oil bath already pre- heated to 100°C) overnight. Additional (2,5-dimethoxypyridin-4-yl)boronic acid (209 mg, 1.14 mmol, 0.4 eq.) and [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride monodichloromethane adduct (116 mg, 0.14 mmol, 0.05 eq.) were added. The reaction mixture was stirred at 100°C for additional 5 h, left at RT for the weekend and filtered through Celite® which was washed with 1,4-dioxane. The combined filtrates were concentrated under reduced pressure. The residue was purified by chromatography (silica gel, eluent: cyclohexane / ethyl acetate gradient). Yield: 432 mg (38% of theory). LC-MS (method 2): Rt = 2.13 min; MS (ESIpos): m/z = 403 [M+H]+ ¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 9.17 / 9.16 (2x s, 1H), 8.03 / 8.01 (2x d, 1H), 7.86 (s, 1H), 7.75 / 7.75 (2x d, 1H), 6.82 (s, 1H), 3.79 (s, 3H), 3.54 (s, 3H). Example 2.3: 4-{3-Chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-5- methoxypyridin-2(1H)-one
Figure imgf000018_0002
Pyridine hydrobromide (429 mg, 2.68 mmol, 2.5 eq.) was added to a solution of 4-{3-chloro-2- fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-2,5-dimethoxypyridine (432 mg, 1.07 mmol) in N,N-dimethylformamide (10 ml). The mixture was stirred at 100°C overnight and concentrated under reduced pressure. The residue was dissolved in water. After addition of ethyl acetate and phase separation, the aqueous phase was extracted two times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, eluent: dichloromethane / methanol gradient). Yield: 285 mg (68% of theory). LC-MS (method 2): Rt = 1.46 min; MS (ESIpos): m/z = 389 [M+H]+ ¹H-NMR (600 MHz, DMSO-d6): δ [ppm] = 11.3 (br s, 1H), 9.23 (s, 1H), 8.10-7.99 (m, 1H), 7.77 (m, 1H), 7.15 (s, 1H), 6.41 (s, 1H), 3.45 (s, 3H). Example 2.4: 4-({(2S)-2-[4-{3-Chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1- yl]phenyl}-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)-2-fluorobenzamide (compound of the formula (II))
Figure imgf000019_0001
1,1,3,3-Tetramethylguanidine (420 µl, 3.35 mmol, 3.0 eq.) was added under argon atmosphere at RT to a solution of 4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-5- methoxypyridin-2(1H)-one (438 mg, 1.12 mmol) in 2-propanol / acetone (4:1, 7.5 ml). The mixture was stirred at RT for 15 min, followed by addition of 4-{[(2R)-2-bromopropanoyl]amino}-2- fluorobenzamide (WO 2020/127504, example 1.19A, page 76) (355 mg, 1.23 mmol, 1.1 eq.) and further 2-propanol / acetone (4:1, 7.5 ml). The reaction mixture was stirred at RT overnight and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, eluent: dichloromethane / methanol gradient) and preparative HPLC (reversed phase, eluent: acetonitrile / water gradient). Yield: 539 mg (81% of theory). LC-MS (method 2): Rt = 1.65 min; MS (ESIpos): m/z = 597 [M+H]+ ¹H-NMR (500 MHz, DMSO-d6): δ [ppm] = 10.72 / 10.63 (2x s, 1H), 9.24 / 9.13 (2x s, 1H), 8.06- 7.99 (m, 1H), 7.79-7.74 (m, 1H), 7.72-7.60 (m, 2H), 7.56-7.48 (m, 2H), 7.38-7.32 (m, 1H), 7.27 / 7.25 (2x s, 1H), 6.48 / 6.47 (2x s, 1H), 5.51-5.44 (m, 1H), 3.47 / 3.45 (2x s, 3H), 1.65 / 1.64 (2x s, 3H). Example 3: Preparation of 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1- yl]phenyl}-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}-amino)-2-fluorobenzamide acetone (compound of the formula (III) The compound of the formula (III) can be prepared as described in WO2019/175043 compound of the formula (IIc). Using the described process the compound of the formula (III) is obtained in the crystalline form. compound of the formula (III)
Figure imgf000020_0001
Example 4: Preparation of the compound of the formula (II) in crystalline modification A 306 mg of compound of the formula (II) in amorphous form was dissolved in 20 mL of a mixture of 50 vol.-% ethanol and 50 vol.-% water at room temperature. The solution was stirred 24 hours at room temperature, resulting in the precipitation of a white solid. The solvent was evaporated in a rotary evaporator. The obtained solid was dried in a vacuum oven at 40°C for 16 hours.273 mg of compound of the formula (II) in the crystalline modification A was obtained. Example 5: Preparation of the compound of the formula (I) in crystalline modification I 30 mg compound of the formula (I) in amorphous form was dissolved in 2 mL of ethanol at room temperature. 660 µL of water was added to the solution dropwise until a cloudy solution was observed. The solution was then seeded with 1 mg of crystalline modification A of compound of the formula (II). Shortly after seeding, the precipitation of further small particles was observed, but the particles rapidly disappeared upon stirring, resulting in a seemingly clear solution. After stirring at room temperature for 48 hours, a suspension was obtained. The solid was filtered under vacuum and dried overnight under ambient conditions. The XRPD pattern of the obtained solid corresponds to the crystalline modification I of compound of the formula (I). The 1H-NMR analysis of the resulting solid indicates that the solid contained approximately 5 wt-% of compound of the formula (II). Example 6: Preparation of the compound of the formula (I) in crystalline modification I as pure compound of the formula (I) 20.0 g compound of the formula (I) in amorphous form was dissolved in a mixture of 40.0 g of propan-2-ol and 10.0 g of acetone, at room temperature. The mixture was heated up to 60°C and to the resulting solution 126.0 g of water was added during 60 minutes. The resulting mixture was seeded with 100.0 mg of crystalline modification I of compound of the formula (I) and stirred at 60°C for 3 hours. Additional 4.8 g of compound of the formula (I) in amorphous form was then added and the mixture was stirred at 60°C overnight. The resulting suspension was cooled down to 20°C in 60 minutes and stirred at 20°C for 90 minutes. So-obtained suspension was filtered under vacuum, washed twice with 42.5 g of propan-2-ol : acetone : water mixture in the mass ratio 4:1:12 and dried in vacuum, at 40°C. Yield: 22.4 g (90.3% of theoretical yield) of pale-white solid. Example 7: Preparation of the compound of the formula (I) in crystalline modification II 40 mg of the compound of the formula (III) was dried at 50°C under reduced pressure to obtain solid in the crystalline modification II. Example 8: Preparation of the compounds of the formula (Ia) to (Ih) A range of solvates of the compound of the formula (I) that display isomorphism (1,4-dioxane, propan-2-ol, butyl acetate, 2-methylpyridine, butan-2-one, 4-methylpentan-2-one, ethyl acetate and 2-methyltetrahydrofuran) could be obtained by slurrying and/or crystallization from solution using the crystalline modification I or the amorphous form of the compound of the formula (I). Example 8.1: Preparation of the compound of the formula (Ia), 1,4-dioxane solvate 30 mg of the crystalline modification I of the compound of the formula (I) and 50 µL 1,4-dioxane were added to a vial. The vial was sealed and stirred with a magnetic stirrer at room temperature. After 1 week the slurry was filtered and air-dried. 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 10.77 (br s, 1H), 9.13 (s, 1H), 7.85 (d, 1H), 7.83 (d, 1H) 7.78 (d, 1H), 7.68 (t, 1H), 7.64 (dd, 1H), 7.53 (m, 2H), 7.37 (dd, 1H), 7.14 (s, 1H), 6.54 (s, 1H), 5.53 (br s, 1H), 3.57 (s, 6H), 3.26 (s, 3H), 2.10 (m, 2H), 0.79 (t, 3H). The solvent peak is at δ [ppm] = 3.57 (s, 6H). Example 8.2: Preparation of the compound of the formula (Ib), propan-2-ol solvate 30 mg of the amorphous form of the compound of the formula (I) and 50 µL propan-2-ol were added to a vial. The vial was sealed and stirred with a magnetic stirrer at room temperature. After 4 hours the slurry was filtered and air-dried. 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 10.77 (br s, 1H), 9.13 (s, 1H), 7.85 (d, 1H), 7.83 (d, 1H) 7.78 (d, 1H), 7.68 (t, 1H), 7.64 (dd, 1H), 7.53 (m, 2H), 7.37 (dd, 1H), 7.14 (s, 1H), 6.54 (s, 1H), 5.53 (br s, 1H), 4.35 (d, 0.25H), 3.78 (sep, 0.25H), 3.26 (s, 3H), 2.10 (m, 2H), 1.04 (d, 1.4H), 0.79 (t, 3H). The solvent peaks are at δ [ppm] = 4.35 (d, 0.25H), 3.78 (sep, 0.25H) and 1.04 (d, 1.4H). Example 8.3: Preparation of the compound of the formula (Ic), butyl acetate solvate 30 mg of the amorphous form of the compound of the formula (I) and 50 µL butyl acetate were added to a vial. The vial was sealed and stirred with a magnetic stirrer at room temperature. After 4 hours the slurry was filtered and air-dried. 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 10.77 (br s, 1H), 9.13 (s, 1H), 7.85 (d, 1H), 7.83 (d, 1H) 7.78 (d, 1H), 7.68 (t, 1H), 7.64 (dd, 1H), 7.53 (m, 2H), 7.37 (dd, 1H), 7.14 (s, 1H), 6.54 (s, 1H), 5.53 (br s, 1H), 3.99 (t, 1.75H), 3.26 (s, 3H), 2.10 (m, 2H), 1.97 (s, 2H), 1.53 (m, 2H), 1.32 (m, 2H), 0.88 (t, 2.5H), 0.79 (t, 3H). The solvent peaks are at δ [ppm] = 3.99 (t, 1.75H), 1.97 (s, 2H), 1.53 (m, 2H), 1.32 (m, 2H) and 0.88 (t, 2.5H). Example 8.4: Preparation of the compound of the formula (Id), 2-methylpyridine solvate 30 mg of the crystalline modification I of the compound of the formula (I) and 200 µL 2-methylpyridine were added to a vial. The vial was sealed and stirred with for 10 minutes at 50°C. The resulting solution was filtered and transferred to a new sealed vial. The vial was placed in a temperature block preheated to 50°C and cooled to 4°C at 0.1°C/min. After 7 days storage at 4°C the slurry was filtered and air-dried. 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 10.77 (br s, 1H), 9.13 (s, 1H), 8.55 (s, 1H), 8.44 (d, 1H), 7.85 (d, 1H), 7.83 (d, 1H) 7.78 (d, 1H), 7.68 (t, 1H), 7.64 (dd, 1H), 7.53 (m, 2H), 7.37 (dd, 1H), 7.26 (s, 2H), 7.14 (s, 1H), 6.54 (s, 1H), 5.53 (br s, 1H), 3.26 (s, 3H), 2.45 (s, 3H), 2.10 (m, 2H), 0.79 (t, 3H). The solvent peaks are at δ [ppm] = 8.55 (s, 1H), 8.44 (d, 1H), 7.26 (s, 2H) and 2.45 (s, 3H). Example 8.5: Preparation of the compound of the formula (Ie), butan-2-one solvate 40 mg of the crystalline modification I of the compound of the formula (I) and 200 µL butan-2-one/water 1:9 (v:v) were added to a vial. The vial was sealed and stirred with a magnetic stirrer at 60°C. After 1 week the slurry was filtered and air-dried. 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 10.77 (br s, 1H), 9.13 (s, 1H), 7.85 (d, 1H), 7.83 (d, 1H) 7.78 (d, 1H), 7.68 (t, 1H), 7.64 (dd, 1H), 7.53 (m, 2H), 7.37 (dd, 1H), 7.14 (s, 1H), 6.54 (s, 1H), 5.53 (br s, 1H), 3.26 (s, 3H), 2.43 (q, 2H), 2.10 (m, 2H), 2.07 (s, 3H), 0.91 (t, 3 H), 0.79 (t, 3H). The solvent peaks are at δ [ppm] = 2.43 (q, 2H), 2.07 (s, 3H) and 0.91 (t, 3 H). Alternatively, a slurry of the amorphous form of the compound of the formula (I) at room temperature in butan-2-one was used: 30 mg of the amorphous form of the compound of the formula (I) and 50 µL butan-2-one were added to a vial. The vial was sealed and stirred with a magnetic stirrer at room temperature. After 4 hours the slurry was filtered and air-dried. Alternatively, a cooling crystallization in butan-2-one was used: 30 mg of the crystalline modification I of the compound of the formula (I) and 1350 µL 2-butanone were added to a vial. The vial was sealed and stirred with for 10 minutes at 50°C. The resulting solution was filtered and transferred to a new sealed vial. The vial was placed in a temperature block preheated to 50°C and cooled to 4°C at 0.1°C/min. The resulting slurry was filtered and air-dried. Example 8.6: Preparation of the compound of the formula (If), 4-methylpentan-2-one solvate 1.0 g of the amorphous form of the compound of the formula (I) was mixed with 2.0 g of 4- methylpentan-2-one at room temperature. The resulting mixture was stirred at 20°C until a clear solution was obtained after ca. 45 minutes. The clear solution was seeded with 10 mg of the compound of the formula (III). After ca.30 minutes a suspension was formed and was stirred overnight at 20°C. The final suspension was filtered under vacuum, washed with 1 mL of 4-methylpentan-2-one and dried overnight in vacuum, at 50°C. 1H NMR (500 MHz, DMSO-d6) δ [ppm] = 10.78 (br s, 1H), 9.14 (s, 1H), 7.85 (d, 1H), 7.83 (d, 1H) 7.79 (d, 1H), 7.70 (t, 1H), 7.65 (dd, 1H), 7.53 (m, 2H), 7.38 (dd, 1H), 7.15 (s, 1H), 6.55 (s, 1H), 5.54 (br s, 1H), 3.27 (s, 3H), 2.29 (d, 1H), 2.11 (m, 2H), 2.06 (s, 1.5H), 2.00 (m, 0.5H), 0.85 (d, 3H), 0.79 (t, 3H). The solvent peaks are at δ [ppm] = 2.29 (d, 1H), 2.06 (s, 1.5H), 2.00 (m, 0.5H) and 0.85 (d, 3H). Example 8.7: Preparation of the compound of the formula (Ig), ethyl acetate solvate 25.0 g of amorphous compound of formula (I) was mixed with 75 g of ethyl acetate at room temperature. The resulting mixture was stirred at 85°C until a clear solution was obtained. The clear solution was cooled to 40°C and seeded with the compound of the formula (III). The resulting suspension was stirred for a further 60 minutes, before decreasing the temperature to 0°C over 7.5 hours. After a further 8 hours of stirring at 0°C, the final suspension was filtered under vacuum and dried overnight under vacuum. 1H NMR (500 MHz, DMSO-d6) δ [ppm] = 10.78 (br s, 1H), 9.14 (s, 1H), 7.85 (d, 1H), 7.83 (d, 1H), 7.79 (d, 1H), 7.70 (t, 1H), 7.65 (dd, 1H), 7.53 (m, 2H), 7.38 (dd, 1H), 7.15 (s, 1H), 6.55 (s, 1H), 5.54 (br s, 1H), 4.03 (q, 1H), 3.27 (s, 3H), 2.11 (m, 2H), 1.99 (s, 2H), 1.18 (t, 2H), 0.79 (t, 3H). The solvent peaks are at δ [ppm] = 4.03 (q, 1H), 1.99 (s, 2H) and 1.18 (t, 2H). Example 8.8: Preparation of the compound of the formula (Ih), 2-methyltetrahydrofuran solvate 1.25 g of amorphous compound of formula (I) was mixed with 3.75 g of 2-methyltetrahydrofuran at room temperature. The so-obtained mixture was stirred at 20°C overnight. The resulting suspension was filtered under vacuum, washed with 2.0 g 2-methyltetrahydrofuran and dried overnight under vacuum, at 50°C. Example 9: Physical characterization of the compounds of the formula (Ia) to (Ih) Example 9.1: Thermogravimetric analysis (TGA) Thermogravimetric analysis (TGA) was performed with either a Perkin Elmer Pyris 6 or a Mettler Toledo TGA/DSC 3+. The instrument was purged with nitrogen gas at a flow rate of 10 or 20 or 50 ml.min-1. Approximately 1 – 15 mg of each sample was placed into either an aluminum or an aluminum oxide crucible and heated at a heating rate of 10°C.min -1 starting from 25°C. No sample preparation. TGA thermograms are shown in figures 1 to 6 and 29 and 30. Example 9.2: Differential scanning calorimetry (DSC) Differential scanning calorimetry (DSC) was performed with either a Netzsch Phoenix DSC 204 F1 or a Mettler Toledo DSC3+. The calorimeter was purged with nitrogen gas at a flow rate of 10 or 20 or 50 ml.min-1. Approximately 1 – 15 mg of each sample was placed into an aluminum crucible and heated at a rate of 10 or 20°C.min -1 starting from -10 or 25°C. No sample preparation. DSC thermograms are shown in figures 7 to 12 and 31 and 32. Example 9.3: Raman spectroscopy Raman measurements were performed with a Bruker MultiRAM spectrometer. No sample preparation was performed, and each individual measurement consisted of 64 or 128 scans using a laser power of between 200 and 700 mW. Raman spectra are shown in figures 13 to 18 and 33 and 34. Table 1A: Raman spectroscopy of the compounds of the formula (Ia) to (If)
Figure imgf000024_0001
Figure imgf000025_0001
Table 1B: Raman spectroscopy of the compounds of the formula (Ig) and (Ih)
Figure imgf000025_0002
Band maxima (cm-1) Compound of the formula (Ig) Compound of the formula (Ih) 494 992 1603 448 919 1287 1699 524 1032 1615 494 980 1333 2842 618 1098 1664 524 992 1383 2878 655 1213 1699 552 1004 1445 2940 710 1249 2842 584 1032 1485 2980 747 1334 2943 618 1098 1497 3075 757 1383 3074 655 1142 1531 Example 9.4: X-ray powder diffraction (XRPD) X-ray powder diffraction (XRPD) data were recorded on either a STOE STADI P or a D8 Bruker Advance diffractometer using monochromatized Cu-K alpha 1 radiation, a position sensitive detector, at generator settings of 40 kV and 40 mA. The samples were collected in transition mode, being either prepared into a standard glass capillary or as a thin layer between two foils. The scanning rage was between 2° and 40° 2 theta with a 0.5° step at 15 seconds/step for the STOE STADI P and a 0.009194171° step at 1.28 seconds/step for the D8 Bruker Advance. Table 2A: X-ray powder diffraction (XRPD) of the compounds of the formula (Ia) to (Ig) Diffraction angle (2θ, °) Compound Compound Compound Compound Compound Compound Compound of the of the of the of the of the of the of the formula formula formula (Ic) formula (Id) formula (Ie) formula formula (Ia) (Ib) (If) (Ig) 7.6 7.6 7.6 30.3 7.6 29.3 7.7 26.2 7.6 7.8 7.7 8.1 8.0 31.3 7.9 29.4 8.0 26.7 7.8 8.2 8.3 8.5 8.2 32.2 8.2 29.8 8.5 26.9 8.8 10.5 9.1 10.4 9.1 34.1 9.1 29.9 10.4 27.2 10.2 12.0 10.1 10.8 10.3 34.5 10.2 30.2 10.7 27.6 10.9 12.4 11.2 11.8 10.6 35.2 11.1 30.5 11.8 27.7 12.1 13.4 13.1 12.4 11.1 36.2 11.3 30.9 12.3 28.1 12.4 13.9 13.3 13.5 11.3 36.5 11.4 32.0 13.3 28.4 13.2 14.3 14.2 13.8 11.5 37.0 13.1 32.4 13.7 28.6 14.8 14.9 15.2 14.2 13.1 37.8 13.2 32.6 14.2 28.9 15.7 15.6 15.5 15.0 13.3 38.3 13.5 33.3 14.9 29.0 16.8 16.3 16.0 15.5 13.7 39.0 14.4 34.0 15.5 29.2 17.1 16.7 16.6 15.9 14.6 15.3 34.3 15.6 29.4 17.7 17.1
Figure imgf000027_0001
Diffraction angle (2θ, °) Compound Compound Compound Compound Compound Compound Compound of the of the of the of the of the of the of the formula formula formula (Ic) formula (Id) formula (Ie) formula formula (Ia) (Ib) (If) (Ig) 31.3 26.9 26.2 24.7 33.4 31.7 27.1 26.6 24.8 34.1 32.5 27.7 26.8 25.1 35.3 34.0 28.3 27.3 25.2 38.3 35.1 28.6 27.7 25.4 38.8 36.7 29.0 28.3 25.5 37.8 29.2 28.6 25.7 38.1 29.5 28.8 25.9 39.6 30.1 29.2 26.0 Table 2B: X-ray powder diffraction (XRPD) of the compound of the formula (Ih) Diffraction angle (2θ, °) Compound of the formula (Ih) 7.7 15.5 18.0 20.8 26.0 30.1 8.0 16.1 18.4 21.2 26.9 31.3 10.3 16.5 18.8 22.1 27.6 34.1 11.8 16.8 19.1 23.1 29.1 13.7 17.4 20.1 24.2 29.3 Explanation of the figures: Figure 1: TGA Curve of compound of the formula (Ia), 1,4-dioxane solvate Figure 2: TGA Curve of compound of the formula (Ib), propan-2-ol solvate Figure 3: TGA Curve of compound of the formula (Ic), butyl acetate solvate Figure 4: TGA Curve of compound of the formula (Id), 2-methylpyridine solvate Figure 5: TGA Curve of compound of the formula (Ie), butan-2-one solvate Figure 6: TGA Curve of compound of the formula (If), 4-methylpentan-2-one solvate Figure 7: DSC Curve of compound of the formula (Ia), 1,4-dioxane solvate Figure 8: DSC Curve of compound of the formula (Ib), propan-2-ol solvate Figure 9: DSC Curve of compound of the formula (Ic), butyl acetate solvate Figure 10: DSC Curve of compound of the formula (Id), 2-methylpyridine solvate Figure 11: DSC Curve of compound of the formula (Ie), butan-2-one solvate Figure 12: DSC Curve of compound of the formula (If), 4-methylpentan-2-one solvate Figure 13: Raman spectrum of compound of the formula (Ia), 1,4-dioxane solvate Figure 14: Raman spectrum of compound of the formula (Ib), propan-2-ol solvate Figure 15: Raman spectrum of compound of the formula (Ic), butyl acetate solvate Figure 16: Raman spectrum of compound of the formula (Id), 2-methylpyridine solvate Figure 17: Raman spectrum of compound of the formula (Ie), butan-2-one solvate Figure 18: Raman spectrum of compound of the formula (If), 4-methylpentan-2-one solvate Figure 19: X-ray powder diffraction (XRPD) of compound of the formula (Ia), 1,4-dioxane solvate Figure 20: X-ray powder diffraction (XRPD) of compound of the formula (Ib), propan-2-ol solvate Figure 21: X-ray powder diffraction (XRPD) of compound of the formula (Ic), butyl acetate solvate Figure 22: X-ray powder diffraction (XRPD) of compound of the formula (Id), 2-methylpyridine solvate Figure 23: X-ray powder diffraction (XRPD) of compound of the formula (Ie), butan-2-one solvate Figure 24: X-ray powder diffraction (XRPD) of compound of the formula (If), 4-methylpentan-2- one solvate Figure 25: TGA Curve of compound of the formula (I), amorphous form Figure 26: DSC Curve of compound of the formula (I), amorphous form Figure 27: X-ray powder diffraction (XRPD) of compound of the formula (I), amorphous form Figure 28: X-ray powder diffraction (XRPD) of compound of the formula (Ig), ethyl acetate solvate Figure 29: TGA Curve of compound of the formula (Ig), ethyl acetate solvate Figure 30: TGA Curve of compound of the formula (Ih), 2-methyltetrahydrofuran solvate Figure 31: DSC Curve of compound of the formula (Ig), ethyl acetate solvate Figure 32: DSC Curve of compound of the formula (Ih), 2-methyltetrahydrofuran solvate Figure 33: Raman spectrum of compound of the formula (Ig), ethyl acetate solvate Figure 34: Raman spectrum of compound of the formula (Ih), 2-methyltetrahydrofuran solvate Figure 35: X-ray powder diffraction (XRPD) of compound of the formula (Ih), 2-methyltetrahydro- furan solvate

Claims

What is claimed is: 1. A solvate of the compound of the formula (I)
Figure imgf000030_0001
which is (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza- 3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 1,4-dioxane having the formula (Ia)
Figure imgf000030_0002
or (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza- 3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide propan-2-ol having the formula (Ib)
Figure imgf000030_0003
or (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza- 3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide butyl acetate having the formula (Ic)
Figure imgf000031_0001
or (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza- 3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 2-methylpyridine having the formula (Id)
Figure imgf000031_0002
or (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza- 3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide butan- 2-one having the formula (Ie)
Figure imgf000031_0003
or (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza- 3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 4- methylpentan-2-one having the formula (If)
Figure imgf000032_0001
or (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza- 3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide ethyl acetate having the formula (Ig)
Figure imgf000032_0002
or (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza- 3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide 2- methyltetrahydrofuran (compound of the formula (Ih))
Figure imgf000032_0003
2. The compound of the formula (Ia) of claim 1 characterized by a X-ray powder diffractogram measured at 20 ± 5°C and with Cu-K alpha 1 as radiation displaying at least the following reflections, quoted as 2Ɵ value ± 0.
2°: 7.7, 10.1, 20.5.
3. The compound of the formula (Ib) of claim 1 characterized by a X-ray powder diffractogram measured at 20 ± 5°C and with Cu-K alpha 1 as radiation displaying at least the following reflections, quoted as 2Ɵ value ± 0.2°: 8.1, 10.4, 21.4.
4. The compound of the formula (Ic) of claim 1 characterized by a X-ray powder diffractogram measured at 20 ± 5°C and with Cu-K alpha 1 as radiation displaying at least the following reflections, quoted as 2Ɵ value ± 0.2°: 8.0, 10.3, 21.2.
5. The compound of the formula (Id) of claim 1 characterized by a X-ray powder diffractogram measured at 20 ± 5°C and with Cu-K alpha 1 as radiation displaying at least the following reflections, quoted as 2Ɵ value ± 0.2°: 7.9, 10.2, 20.9.
6. The compound of the formula (Ie) of claim 1 characterized by a X-ray powder diffractogram measured at 20 ± 5°C and with Cu-K alpha 1 as radiation displaying at least the following reflections, quoted as 2Ɵ value ± 0.2°: 8.0, 16.6, 21.3.
7. The compound of the formula (If) of claim 1 characterized by a X-ray powder diffractogram measured at 20 ± 5°C and with Cu-K alpha 1 as radiation displaying at least the following reflections, quoted as 2Ɵ value ± 0.2°: 7.6, 10.2, 17.7.
8. The compound of the formula (Ig) of claim 1 characterized by a X-ray powder diffractogram measured at 20 ± 5°C and with Cu-K alpha 1 as radiation displaying at least the following reflections, quoted as 2Ɵ value ± 0.2°: 8.2, 16.3, 21.4.
9. The compound of the formula (Ih) of claim 1 characterized by a X-ray powder diffractogram measured at 20 ± 5°C and with Cu-K alpha 1 as radiation displaying at least the following reflections, quoted as 2Ɵ value ± 0.2°: 8.0,
10.3, 21.2. 10. A pharmaceutical composition comprising a compound selected from the compounds of the formula (Ia) to (Ih) of claim 1 and optionally further pharmaceutically acceptable excipients.
11. A compound selected from the compounds of the formula (Ia) to (Ih) of claim 1 for use in the treatment and/or prophylaxis of thrombotic or thromboembolic disorders and/or thrombotic or thromboembolic complications.
12. Process for preparing the compounds of the formula (Ia) to (Ih) of claim 1, characterized in that the compound of the formula (I) is converted into the respective compounds of the formula (Ia) to (Ih) by treatment with the corresponding solvent-forming solvent.
13. Process according to Claim 12, characterized in that the solvent-forming solvent is selected from the group consisting of 1,4-dioxane, propan-2-ol, butyl acetate, 2-methylpyridine, butan- 2-one, 4-methylpentan-2-one, ethyl acetate and 2-methyltetrahydrofuran.
14. Process according to Claim 12, characterized in that the solvent-forming solvent is used in a mixture with one or more of other solvents selected from the group consisting of methanol, ethanol, propan-1-ol, butan-1-ol, butan-2-ol, 2-methylpropan-1-ol, acetonitrile, n-heptane, cyclohexane, methylcyclohexane, 2-(propan-2-yloxy)propane, 2-methoxy-2-methylpropane and water.
PCT/EP2022/055524 2021-03-09 2022-03-04 Solvates of (4s)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoro-methyl)-32 h-6- aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide Ceased WO2022189280A1 (en)

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