WO2019042485A1 - Solid forms of roxadustat - Google Patents

Solid forms of roxadustat Download PDF

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Publication number
WO2019042485A1
WO2019042485A1 PCT/CZ2018/000039 CZ2018000039W WO2019042485A1 WO 2019042485 A1 WO2019042485 A1 WO 2019042485A1 CZ 2018000039 W CZ2018000039 W CZ 2018000039W WO 2019042485 A1 WO2019042485 A1 WO 2019042485A1
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WIPO (PCT)
Prior art keywords
roxadustat
salt
coformer
crystalline
ray powder
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PCT/CZ2018/000039
Other languages
French (fr)
Inventor
Igor CERNA
Filip SEMBERA
Lukas KREJCIK
Ondrej Dammer
Michal Zapadlo
Stefano Lucas GIAFFREDA
Enrico MODENA
Cristina IANNI
Original Assignee
Zentiva, K.S.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority claimed from CZ2017-503A external-priority patent/CZ2017503A3/en
Priority claimed from CZ2018-277A external-priority patent/CZ2018277A3/en
Application filed by Zentiva, K.S. filed Critical Zentiva, K.S.
Publication of WO2019042485A1 publication Critical patent/WO2019042485A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

Definitions

  • the invention relates to solid forms of roxadustat with the systematic name of (4-hydroxy-l- methyl-7-phenoxyisoquinoline-3-carbonyl)glycine of formula I, methods of their preparation and use in a drug form.
  • Roxadustat (CAS no. 808118-40-3) is a hypoxia inducible factor prolyl hydroxylase (HIF-PH) inhibitor, which increases endogenous production of erythropoetin which stimulates production of red blood cells (erythropoiesis).
  • HIF-PH hypoxia inducible factor prolyl hydroxylase
  • roxadustat Preparation of roxadustat and its isolation was first described in the patent application WO 2004/108681 (compound 81).
  • the patent application WO 2014/014835 discloses a preparation method and characterization of crystalline forms of roxadustat free acid (form A-D) and its amorphous form. It further discloses a crystalline sodium salt of roxadustat, amorphous potassium salt, crystalline (hemi) calcium and (hemi) magnesium salt as well as salts of roxadustat with L-arginine, L-lysine, ethanolamine, diethanolarnine, tromethamine, bis- triethylamine, sulphuric and methanesulfonic acid.
  • the invention provides pharmaceutically acceptable salts of roxadustat (I) and a method of their preparation.
  • These solid forms of roxadustat of formula I are prepared by a reaction of roxadustat free acid with suitable coformers (inorganic or organic acids, bases, neutral molecules or possibly salts or ion pairs) in a suitable solvent or mixtures of solvents; or salts of roxadustat are prepared through cation exchange in a suitable solvent or mixtures of solvents, especially through exchange of the cation of the sodium salt of roxadustat.
  • the prepared solid forms have suitable physicochemical characteristics for use in pharmacy and formulation of new drug forms.
  • An object of this invention is a solid form of roxadustat with a coformer wherein the coformer is selected from the group consisting of meglumine, N,N'-dibenzylethylenediamine, tert- butylamine, diethylamine, dicyclohexylamine, ammonia, lithium, potassium, calcium, magnesium, iron, 2-naphtalenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 3- ethyl-l-methyl-lH-imidazol-3-ium acetate and caffeine.
  • the coformer is selected from the group consisting of meglumine, N,N'-dibenzylethylenediamine, tert- butylamine, diethylamine, dicyclohexylamine, ammonia, lithium, potassium, calcium, magnesium, iron, 2-naphtalenesulfonic acid, benzenesulfonic acid, p-tol
  • Another object of this invention is a salt of roxadustat with a coformer in a solid form wherein the coformer is selected from the group consisting of meglumine, ⁇ , ⁇ '- dibenzylethylenediamine, tert-butylamine, diethylamine, dicyclohexylamine, ammonia, potassium hydroxide, calcium salt, magnesium salt, iron (III) salt, iron (II) salt, 2- naphtalenesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.
  • the coformer is selected from the group consisting of meglumine, ⁇ , ⁇ '- dibenzylethylenediamine, tert-butylamine, diethylamine, dicyclohexylamine, ammonia, potassium hydroxide, calcium salt, magnesium salt, iron (III) salt, iron (II) salt, 2- naphtalenesulfonic acid, benzenesulfonic acid and p-to
  • Another object of the invention is a salt of roxadustat with meglumine, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 3.3; 11.8; 16.8; 22.8; 25.1 and 27.7 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with meglumine is further characterized by a differential scanning calorimetric curve with the melting point at 181°C.
  • Another object of the invention is a salt of roxadustat with N,N -dibenzylethylenediamine in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 5.0; 10.9; 13.3; 18.1; 19.8; 23.8 and 26,1 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with ⁇ , ⁇ '- dibenzylethylenediamine in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 126°C.
  • Another object of the invention is a salt of roxadustat with N,N-dibenzylemylenediarnine in the form of crystalline modification II, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 7.1; 9.9; 17.1; 19.9; 24.1 and 26.5 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with N,N -dibenzylethylenediamine in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 115°C.
  • Another object of the invention is a salt of roxadustat with tert-butylamine in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 6.6; 10.5; 12.9; 16.3; 20.1 and 22.7 ⁇ 0.2° 2- theta.
  • the salt of roxadustat with tert-butylamine in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 159°C.
  • Another object of the invention is a salt of roxadustat with tert-butylamine in the form of crystalline modification II, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 5.7; 11.1; 18.1; 19.6; 21.7 and 26.1 ⁇ 0.2° 2- theta.
  • the salt of roxadustat with tert-butylamine in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 169°C.
  • Another object of the invention is a salt of roxadustat with diethylamine, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 10.0; 13.3; 15.7; 20.2; 24.0 and 29.1 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with diethylamine is further characterized by a differential scanning calorimetric curve with the melting point at 183°C.
  • Another object of the invention is a salt of roxadustat with dicyclohexylamine in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 9.9; 16.8; 19.8; 22.5; 24.4 and 29.9 ⁇ 0.2° 2- theta.
  • the salt of roxadustat with dicyclohexylamine in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 190°C.
  • Another object of the invention is a salt of roxadustat with dicyclohexylamine in the form of crystalline modification II, the coformer being dicyclohexylamine, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 8.5; 9.9; 12.4; 18.7; 20.6; 23.8 and 27.5 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with dicyclohexylamine in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 189°C.
  • Another object of the invention is a salt of roxadustat with ammonia in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 6.2; 9.7; 15.9; 18.8; 23.3 and 27.9 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with ammonia in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 159°C.
  • Another object of the invention is a salt of roxadustat with ammonia in the form of crystalline modification II, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 4.9; 11.6; 14.9; 16.7; 18.9 and 22.4 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with ammonia in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 164°C.
  • Another object of the invention is a salt of roxadustat with Hthium in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 2.7; 5.5; 10.6; 17.6; 24.0 and 26.0 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with lithium in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 125°C.
  • Another object of the invention is a salt of roxadustat with lithium in the form of crystalline modification II, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 2.6; 7.8; 10.3; 15.6; 20.7 and 26.5 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with hthium in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 226.1°C.
  • Another object of the invention is a salt of roxadustat with lithium in the form of crystalline modification III, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 2.7; 5,4; 8.4; 11.3; 14.8 and 22.4 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with lithium in the form of crystalline modification III is further characterized by a differential scanning calorimetric curve with the melting point at 227°C.
  • Another object of the invention is a potassium salt of roxadustat in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 2.6; 5.2; 10.8; 18.1; 20.8 and 24.4 ⁇ 0.2° 2-theta.
  • the potassium salt of roxadustat in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 63°C.
  • Another object of the invention is a potassium salt of roxadustat in the form of crystalline modification II, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 3.0; 11.0; 13.8; 18.2; 22.4 and 27.8 ⁇ 0.2° 2-theta
  • the potassium salt of roxadustat in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 288°C.
  • Another object of the invention is a salt of roxadustat with potassium in the form of crystalline modification III, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 5.0; 9.9; 13.0; 19.5 a 24.8 ⁇ 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 7.3; 17.0; 21.3 and 27.3 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with potassium in the form of crystalline modification III is further characterized by a differential scanning calorimetric curve with the melting point at 308.3°C.
  • Another object of the invention is a salt of roxadustat with potassium in the form of crystalline modification IV, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 4.9; 7.3; 11.9; 19.8 and 22.7 ⁇ 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 10.8; 15.1; 17.8 and 27.1 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with potassium in the form of crystalline modification IV is further characterized by a differential scanning calorimetric curve with the melting point at 120.5°C.
  • Another object of the invention is a (hemi) calcium salt of roxadustat in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 3.0; 11.5; 12.9; 16.6; 20.1; 23.7 and 26.3 ⁇ 0.2° 2-theta.
  • the hemi-calcium salt of roxadustat in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 96°C.
  • Another object of the invention is a (hemi) calcium salt of roxadustat in the form of crystalline modification II, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 2.9; 12.1; 16.6; 20.6 and 25.9 ⁇ 0.2° 2-theta.
  • Another object of the invention is a (hemi) calcium salt of roxadustat in the form of crystalline modification III, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 3.5; 9.5; 21.5; 27.0 and 28.8 ⁇ 0.2° 2-theta.
  • Another object of the invention is a salt of roxadustat with calcium in the form of crystalline modification IV, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 3.9; 11.6; 16.4; 19.3; 22.5 and 27.7 ⁇ 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 15.3; 21.2; 24.1; 24.9 and 30.8 ⁇ 0.2° 2-theta.
  • Another object of the invention is an amorphous (hemi) calcium salt of roxadustat, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 3.6; 10.2 and 25.8 ⁇ 0.5° 2-theta.
  • the amorphous hemi- calcium salt of roxadustat is further characterized by a differential scanning calorimetric curve with the glass transition temperature of 205°C.
  • Another object of the invention is a (hemi) magnesium salt of roxadustat, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 8.1; 12.0; 14.0; 18.6; 25.5 and 28.0 ⁇ 0.2° 2-theta.
  • the hemi-magnesium salt of roxadustat is further characterized by a differential scanning calorimetric curve with the melting point at 85°C.
  • Another object of the invention is an amorphous (hemi) potasssium salt of roxadustat, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 2.5; 5.2; 7.5; 12.0 and 25.4 ⁇ 0.5° 2-theta.
  • the amorphous hemi-magnesium salt of roxadustat is further characterized by a differential scanning calorimetric curve with the glass transition temperature of 62°C.
  • Another object of the invention is an amorphous salt of roxadustat with magnesium, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 2.5; 5.2; 7.5; 12.0 and 25.4 ⁇ 0.5° 2-theta.
  • the amorphous salt of roxadustat with calcium is further characterized by a differential scanning calorimetric curve with the glass transition temperature of 62°C.
  • Another object of the invention is a semicrystalline iron (III) salt of roxadustat characterized by a diffraction peak in an X-ray powder pattern with the use of CuK ⁇ radiation of 6.5 ⁇ 0.2° 2-theta and amorphous halo with the band maximum of 22.0° ⁇ 1.0° 2-theta.
  • the semicrystalline iron (III) salt of roxadustat is further characterized by a differential scanning calorimetric curve with the melting point at 183°C.
  • Another object of the invention is an amorphous (hemi) iron salt of roxadustat, exhibiting a characteristics amorphous halo in an X-ray powder pattern with the use of CuK ⁇ radiation in the range of 4.5 to 21.0 ⁇ 0.5° 2-theta.
  • the amorphous hemi-iron salt of roxadustat is further characterized by a differential scanning calorimetric curve with the glass transition temperature of 60°C.
  • Another object of the invention is a salt of roxadustat with 2-naphtalenesulfonic acid in the form of crystalline modification I, exhibiting the following characteristic reflections in an X- ray powder pattern with the use of CuK ⁇ radiation: 6.6; 10.1; 18.2; 21.7; 25.2 and 27.8 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with 2-naphtalenesulfonic acid in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 147°C.
  • Another object of the invention is a salt of roxadustat with 2-naphtalenesulfonic acid in the form of crystalline modification II, exhibiting the following characteristic reflections in an X- ray powder pattern with the use of CuK ⁇ radiation: 6.4; 9.9; 13.5; 19.8; 22.0 and 26.5 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with 2-naphtalenesulfonic acid in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 142°C.
  • Another object of the invention is a salt of roxadustat with benzenesulfonic acid, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 6.6; 10.5; 13.4; 20.2; 23.2; 26.1 and 28.3 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with benzenesulfonic acid is further characterized by a differential scanning calorimetric curve with the melting point at 155°C.
  • Another object of the invention is a salt of roxadustat with p-toluenesulfonic acid in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 5.7; 11.7; 15.8; 18.4; 21.9 and 26.0 ⁇ 0.2° 2- theta.
  • the salt of roxadustat with p-toluenesulfonic acid in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 150°C.
  • Another object of the invention is a salt of roxadustat with p-toluenesulfonic acid in the form of crystalline modification ⁇ , exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 5.8; 9.9; 14.1; 19.8; 22.0 and 26.8 ⁇ 0.2° 2- theta.
  • the salt of roxadustat with p-toluenesulfonic acid in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 149°C.
  • Another object of the invention is a salt of roxadustat with p-toluenesulfonic acid in the form of crystalline modification III, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 6.3; 10.9; 12.9; 17.3; 19.3 and 25.4 ⁇ 0,2° 2- theta.
  • the salt of roxadustat with p-toluenesulfonic acid in the form of crystalline modification III is further characterized by a differential scanning calorimetric curve with the melting point at 183°C.
  • Another object of the invention is crystalline 3-ethyl-l-methyl-lH-imidazol-3-ium roxadustat, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 5.1; 11.2; 15.6; 20.8; 23.1 and 25.7 ⁇ 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 9.8; 14.3; 17.2; 20.0 and 28.6 ⁇ 0.2° 2-theta.
  • 3 -ethyl- 1 -methyl- lH-imidazol-3-ium roxadustat is further characterized by a differential scanning calorimetric curve with the melting point at 160°C.
  • Another object of the invention is a cocrystal of roxadustat with caffeine in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 8.2; 10.1; 13.1; 16.7; 19.7 and 26.0 ⁇ 0.2° 2- theta, or possibly these characteristic peaks maybe supplemented with more diffraction peaks: 9.6; 12.1; 17.4; 22.6 and 28.0 ⁇ 0.2° 2-theta.
  • the cocrystal of roxadustat with caffeine in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 177.2°C.
  • Another object of the invention is a cocrystal of roxadustat with caffeine in the form of crystalline modification II, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 7.8; 10.1; 12.8; 15.7; 19.4 and 26.0 ⁇ 0.2° 2- theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 11.3; 18.4; 23.2 and 27.2 ⁇ 0.2° 2-theta.
  • the cocrystal od roxadustat .
  • caffeine in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 178°C.
  • Another object of the invention is a cocrystal of roxadustat with caffeine in the form of crystalline modification III, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 10.0; 11.8; 16.8; 20.1 and 26.6 ⁇ 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 14.8; 18.0; 21.4 and 24.9 ⁇ 0.2° 2-theta.
  • the cocrystal of roxadustat with caffeine in the form of crystalline modification III is further characterized by a differential scanning calorimetric curve with the melting point at 175.3°C.
  • Another object of the invention is a preparation method of solid forms of roxadustat with a coformer according to the present invention wherein roxadustat free acid is dissolved in a suitable solvent and subsequently, a coformer is added that is selected from the group consisting of meglumine, N,N-dibenzylethylenediamine, tert-butylamine, diemylamine, dicyclohexylamine, aqueous ammonia, lithium hydroxide, potassium hydroxide, 2- naphtalenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 3-ethyl-l -methyl- 1H- imidazol-3-ium acetate and caffeine.
  • a coformer is added that is selected from the group consisting of meglumine, N,N-dibenzylethylenediamine, tert-butylamine, diemylamine, dicyclohexylamine, aqueous ammonia,
  • Another object of the invention is a preparation method of salts of roxadustat with a coformer according to the present invention wherein roxadustat free acid is dissolved in a suitable solvent and subsequently, a coformer is added that is selected from the group consisting of meglumine, N,N -dibenzylethylenediamine, tert-butylamine, diethylamine, dicyclohexylamine, aqueous ammonia, potassium hydroxide, 2-naphtalenesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.
  • Another object of the invention is a preparation method of salts of roxadustat with a coformer according to the present invention wherein a sodium salt of roxadustat is dissolved in a suitable solvent and subsequently a coformer is added that is selected from the group consisting of a calcium salt, magnesium salt, iron (II) salt and iron (III) salt, preferably of calcium chloride, magnesium chloride, iron (II) chloride and iron (III) chloride.
  • a suitable solvent is a solvent selected from the group consisting of aliphatic C1-C4 alcohols, ketones, ethers, nitriles, water or their mixture, preferably tetrahydrofuran, methanol, acetone, acetonitrile, water or their mixture.
  • Another object of the invention is the use of solid forms of roxadustat with a coformer according to the present invention for the preparation of a pharmaceutical composition.
  • Another object of the invention is the use of salts of roxadustat with a coformer according to the present invention for the preparation of a pharmaceutical composition.
  • Another object of the invention is a pharmaceutical composition comprising a solid form of roxadustat with a coformer according to the present invention and at least one pharmaceutically acceptable excipient.
  • Another object of the invention is a pharmaceutical composition comprising a salt of roxadustat with a coformer according to the present invention and at least one pharmaceutically acceptable excipient.
  • Figure 1 X-ray powder pattern of the crystalline meglumine salt of roxadustat
  • Figure 5 X-ray powder pattern of the crystalline (hemi) NN-dibenzylethylenediammonium salt of roxadustat - form II
  • Figure 8 DSC record of the crystalline tert-butylammonium salt of roxadustat - form
  • Figure 9 X-ray powder pattern of the crystalline tert-butylammonium salt of roxadustat - form II
  • Figure 10 DSC record of the crystalline tert-butylammonium salt of roxadustat - form II
  • Figure 11 X-ray powder pattern of the crystalline diethylammonium salt of roxadustat
  • Figure 14 DSC record of the crystalline dicyclohexylammonium salt of roxadustat - form
  • Figure 15 X-ray powder pattern of the crystalline dicyclohexylammonium salt of roxadustat - form II
  • Figure 16 DSC record of the crystalline dicyclohexylammonium salt of roxadustat - form II
  • Figure 17 X-ray powder pattern of the crystalline ammonium salt of roxadustat - form I
  • Figure 19 X-ray powder pattern of the crystalline ammonium salt of roxadustat - form II
  • Figure 20 DSC record of the crystalline ammonium salt of roxadustat - form II
  • Figure 25 X-ray powder pattern of the crystalline lithium salt of roxadustat - form HI
  • Figure 31 X-ray powder pattern of the crystalline potassium salt of roxadustat - form III
  • Figure 32 DSC record of the crystalline potassium salt of roxadustat - form III
  • Figure 35 X-ray powder pattern of the crystalline (hemi-)calcium salt of roxadustat - form
  • Figure 36 DSC record of the crystalline (hemi-)calcium salt of roxadustat - form I
  • Figure 37 X-ray powder pattern of the crystalline (hemi-)calcium salt of roxadustat - form II
  • Figure 38 X-ray powder pattern of the crystalline (hemi-)calcium salt of roxadustat - form III
  • Figure 39 X-ray powder pattern of the amorphous (hemi-)calcium salt of roxadustat
  • Figure 40 DSC record of the amorphous (hemi-)calcium salt of roxadustat
  • Figure 41 X-ray powder pattern of the crystalline (hemi-)calcium salt of roxadustat - form IV
  • Figure 42 X-ray powder pattern of the crystalline (hemi-)magnesium salt of roxadustat
  • Figure 44 X-ray powder pattern of the amorphous (hemi-)magnesium salt of roxadustat
  • Figure 45 DSC record of the amorphous (hemi-)magnesium salt of roxadustat
  • Figure 46 X-ray powder pattern of the crystalline iron (III) salt of roxadustat
  • Figure 48 X-ray powder pattern of the amorphous (hemi-)iron (II) salt of roxadustat
  • Figure 54 X-ray powder pattern of crystalline besylate of roxadustat
  • Figure 58 X-ray powder pattern of crystalline tosylate of roxadustat - form II
  • Figure 60 X-ray powder pattern of crystalline tosylate of roxadustat - form III
  • Figure 62 X-ray powder pattern of crystalline 3-ethyl-l-methyl-lH-imidazol-3-ium roxadustat
  • Figure 64 X-ray powder pattern of a crystalline form of a caffeine cocrystal of roxadustat - form I
  • Figure 65 DSC record of a crystalline form of a caffeine cocrystal of roxadustat - form
  • Figure 66 X-ray powder pattern of a crystalline form of a caffeine cocrystal of roxadustat - form II
  • Figure 67 DSC record of a crystalline form of a caffeine cocrystal of roxadustat - form II
  • Figure 68 X-ray powder pattern of a crystalline form of a caffeine cocrystal of roxadustat - form III
  • roxadustat is structurally a very interesting molecule.
  • pKa it is a relatively strong acid, ready to form salts with inorganic as well as organic bases (II), but basic regions are also present, especially the isoquinoline nitrogen, which may be the source of interactions between roxadustat and a suitable acid (III).
  • the molecule comprises several donor and acceptor groups of electrons prone to form hydrogen bridges as well as an isoquinoline heterocycle and a phenoxy group suitable for aromatic interactions of the ⁇ - ⁇ stacking type with a suitable coformer.
  • the present invention provides multiple solid-phase crystalline salts of roxadustat and three solid-state amorphous salts. Within the invention, crystalline forms of salts of roxadustat are preferred.
  • the invention provides solid crystalline forms of roxadustat with meglumine, N ⁇ -dibenzylemylenediamine, tert-butylamine, diethylamine, dicyclohexylamine and ammonia, further a crystalline potassium salt, crystalline and amorphous forms of a calcium and potassium salt of roxadustat, iron (II) and iron (III) salts of roxadustat and salts of roxadustat with 2-naphtalenesulfonic acid, benzenesulfonic acid, />-toluenesulfonic acid, 3- ethyl-l-methyl-lH-imidazol-3-ium and caffeine in various molar ratios.
  • the molar ratios of 1:1, 2:1, 3:1 and 1:1,5 are preferred. Solid forms of roxadustat with these coformers can be prepared in adequate ratios and yields with high chemical purity in a crystalline or amorphous form.
  • solid forms can be both anhydrous or non-solvated and in the form of hydrates/solvates of the respective solvents.
  • the prepared solid forms of roxadustat can have various internal arrangements (polymorphism) with different physicochemical characteristics depending on the conditions of their preparation. For this reason, the invention relates to individual crystals or their mixtures in any ratio.
  • Preparation of the solid forms of roxadustat of formula I according to the present invention is conducted by means of a reaction of roxadustat free acid with meglumine, ⁇ , ⁇ '- dibenzylethylenediamine, tert-butylamine, diethylamine, dicyclohexylamine, aqueous ammonia, lithium hydroxide, potassium hydroxide, 2-naphtalenesulfonic acid, benzenesulfonic acid, aad j>toluenesulfonic acid, 3-ethyl-l-methyl-lH-imidazol-3-ium and caffeine.
  • the forms of the calcium, magnesium iron (III) and iron ( ⁇ ) salt of roxadustat were prepared by cation exchange through a reaction of the sodium salt of roxadustat with calcium chloride, magnesium chloride, iron (III) chloride or iron (II) chloride.
  • calcium acetate, magnesium acetate or iron (II) acetate can alternatively be used for the preparation of the said salts.
  • the reactions can be conducted in a suitable solvent, which may be ketones, esters, ethers, amides, nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water or their mixtures. Aliphatic O-C4 alcohols, ketones, ethers, nitriles, water or their mixtures are preferred.
  • the most commonly used solvents are THF, MeOH, acetone, ACN, water or their mixtures.
  • the final product is precipitated or crystallized, or the solution is inoculated, typically at temperatures in the range of -30°C to the boiling point of the solvent.
  • Roxadustat free acid (form A) was prepared in accordance with the procedures disclosed in the patent application WO 2014/014835.
  • Salts of roxadustat according to the present invention especially salts with meglumine, N,N''- dibenzylemylenediamine, p-toluenesulfonic acid, potassium and hemi-calcium salt exhibit better solubility compared to the thermodynamically most stable form of roxadustat free acid (form A) as well as compared to known salts disclosed in the patent application WO 2014/014835.
  • Another advantage is increased photostability of the prepared salts of roxadustat compared to hitherto known forms of roxadustat.
  • Solid forms of roxadustat according to the present invention especially salts with meglumine, N,N'-dibenzylemylenediamine, p-toluenesulfonic acid, potassium, hemi-calcium salt and the cocrystal of roxadustat with caffeine exhibit better solubility compared to the thermodynamically most stable form of roxadustat free acid (form A) as well as compared to known salts disclosed in the patent application WO 2014/014835.
  • Another advantage is that the solid forms of roxadustat according to the present invention are suitable for the preparation of roxadustat with high chemical purity.
  • roxadustat was mixed in a suitable solvent or mixture of solvents and in a suitable ratio with a coformer and isolated by filtration of the crystalline product in the form of a salt or cocrystal with meglumine, N,N''- dibenzylethylenediamine, potassium hydroxide, p-toluenesulfonic acid and caffeine, the purity of which was much higher than the purity of the input roxadustat.
  • the examples and results of the purification effect of the conversion of roxadustat to a salt or cocrystal are presented in the table:
  • the crystalline form of the meglumine salt of roxadustat (prepared according to Example 1) is characterized by the reflections presented in Table 1.
  • Table 1 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline form of roxadustat meglumine salt according to the present invention with the use of CuK ⁇ radiation are: 3.3; 11.8; 16.8; 22.8; 25.1 and 27.7 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • the characteristic diffraction peaks of the crystalline (hemi) N,N'-dibenzylethylene diammonium salt of roxadustat of form I according to the present invention with the use of CuK ⁇ radiation are: 5.0; 10.9; 13.3; 18.1; 19.8; 23.8 and 26,1 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • the characteristic diffraction peaks of the crystalline hemi N,N-dibenzylethylene diammonium salt of roxadustat of form II according to the present invention with the use of CuK ⁇ radiation are: 7.1 ; 9.9; 17.1 ; 19.9; 24.1 and 26.5 ⁇ 0.2° 2-theta
  • Differential scanning calorimetry was used to measure the melting point of form II of the crystalline hemi N.N-dibenzylethylenediammonium salt of roxadustat of 115°C.
  • the tert-butylammonium salt of roxadustat in the form of crystalline modification I (prepared according to Example 4) is characterized by the reflections presented in Table 4.
  • Table 4 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline tert-butylammonium salt of roxadustat of form I according to the present invention with the use of CuK ⁇ radiation are: 6.6; 10.5; 12.9; 16.3; 20.1 and 22.7 ⁇ 0.2° 2-theta.
  • Differential scanning calorimetry was used to measure the melting point of the crystalline tert-butylammonium salt of roxadustat of form I of 159°C.
  • the tert-butylammonium salt of roxadustat in the form of crystalline modification II is characterized by the reflections presented in Table 5.
  • Table 5 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline tert-butylammonium salt of roxadustat of form II according to the present invention with the use of CuK ⁇ radiation are: 5.7; 11.1; 18.1; 19.6; 21.7 and 26.1 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • the crystalline diethylammonium salt of roxadustat (prepared according to Example 6) is characterized by the reflections presented in Table 6.
  • Table 6 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peals of the crystalline diethylammonium salt of roxadustat according to the present invention wim the use of CuK ⁇ radiation are: 10.0; 13.3; 15.7; 20.2; 24.0 and 29.1 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • DSC Differential scanning calorimetry
  • DSC Differential scanning calorimetry
  • the ammonium salt of roxadustat in the form of crystalline modification I (prepared according to Example 9) is characterized by the reflections presented in Table 9.
  • Table 9 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline ammonium salt of roxadustat of form I according to the present invention with the use of CuK ⁇ radiation are: 6.2; 9.7; 15.9; 18.8; 23.3 and 27.9 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • DSC Differential scanning calorimetry
  • the lithium salt of roxadustat in the form of crystalline modification I (prepared according to Example 11) is characterized by the reflections presented in Table 11.
  • Table 11 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline lithium salt of roxadustat of form I according to the present invention with the use of CuK ⁇ radiation are: 2.7; 5.5; 10.6; 17.6; 24.0 and 26.0 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • DSC Differential scanning calorimetry
  • the lithium salt of roxadustat in the form of crystalline modification III is characterized by the reflections presented in Table 13.
  • Table 13 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline lithium salt of roxadustat of form III according to the present invention with the use of CuK ⁇ radiation are: 2.7; 5,4; 8.4; 11.3; 14.8 and 22.4 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • DSC Differential scanning calorimetry
  • the potassium salt of roxadustat in the form of crystalline modification II (prepared according to Example 15) is characterized by the reflections presented in Table 15.
  • Table 15 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline potassium salt of roxadustat according to the present invention with the use of CuK ⁇ radiation are: 3.0; 11.0; 13.8; 18.2; 22.4 and 27.8 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • the potassium salt of roxadustat in the form of crystalline modification III (prepared according to Example 16) is characterized by the reflections presented in Table 16.
  • Table 16 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline potassium salt of roxadustat of form III according to the present invention with the use of CuK ⁇ radiation are: 5.0; 9.9; 13.0; 19.5 a 24.8 ⁇ 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 7.3; 17.0; 21.3 and 27.3 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • the characteristic diffraction peaks of the crystalline potassium salt of roxadustat of form IV according to the present invention with the use of CuK ⁇ radiation are: 4.9; 7.3; 11.9; 19.8 and 22.7 ⁇ 0.2° 2- theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 10.8; 15.1; 17.8 and 27.1 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • the hemi-calcium salt of roxadustat in the form of crystalline modification I (prepared according to Example 18) is characterized by the reflections presented in Table 18.
  • Table 18 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline hemi-calcium salt of roxadustat according to the present invention with the use of CuK ⁇ radiation are: 3.0; 11.5; 12.9; 16.6; 20.1; 23.7 and 26.3 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • the hemi-calcium salt of roxadustat in the form of crystalline modification III (prepared according to Example 20) is characterized by the reflections presented in Table 20.
  • Table 20 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline hemi-calcium salt of roxadustat according to the present invention with the use of CuK ⁇ radiation are: 3.5; 9.5; 21.5; 27.0 and 28.8 ⁇ 0.2° 2-theta.
  • the hemi-calcium salt of roxadustat in the form of crystalline modification IV (prepared according to Example 21) is characterized by the reflections presented in Table 21.
  • Table 21 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline hemi-calcium salt of roxadustat of form IV according to the present invention with the use of CuK ⁇ radiation are: 3.9; 11.6; 16.4; 19.3; 22.5 and 27.7 ⁇ 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 15.3; 21.2; 24.1; 24.9 and 30.8 ⁇ 0.2° 2-theta.
  • the amorphous (hemi) calcium salt of roxadustat (prepared according to Example 22) is characterized by the following diffraction peaks with the use of CuK ⁇ radiation: 3.6; 10.2 and 25.8 ⁇ 0.5° 2-theta.
  • DSC Differential scanning calorimetry
  • the crystalline (hemi) magnesium salt of roxadustat (prepared according to Example 23) is characterized by the reflections presented in Table 22.
  • Table 22 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline hemi-magnesium salt of roxadustat according to the present invention with the use of CuK ⁇ radiation are: 8.1; 12.0; 14.0; 18.6; 25.5 and 28.0 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • the amorphous (hemi) magnesium salt of roxadustat (prepared according to Example 24) is characterized by the following diffraction peaks with the use of CuK ⁇ radiation: 2.5; 5.2; 7.5; 12.0 and 25.4 ⁇ 0.5° 2-theta.
  • Differential scanning calorimetry (DSC) was used to measure the glass transition temperatute of the amorphous hemi-magnesium salt of roxadustat of 62°C.
  • the semicrystalline iron ( ⁇ ) salt of roxadustat (prepared according to Example 25) is characterized by the reflections presented in Table 23.
  • Table 23 comprises reflections whose relative intensity value is higher than 1%.
  • the semicrystalline form of the iron (III) salt of roxadustat is characterized by a diffraction peak with the use of CuK ⁇ radiation of 6.5 ⁇ 0.2 °2-theta and amorphous halo with the band maximum of 22.0° ⁇ 1.0° 2-theta.
  • DSC Differential scanning calorimetry
  • the amorphous (hemi) iron (II) salt of roxadustat (prepared according to Example 26) is characterized by an amorphous halo in the range of 4.5 to 21.0 ⁇ 0.5° 2-theta.
  • DSC Differential scanning calorimetry
  • Roxadustat napsylate in the form of crystalline modification I (prepared according to Example 27) is characterized by the reflections presented in Table 24.
  • Table 24 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of crystalline roxadustat napsylate of form I according to the present invention with the use of CuK ⁇ radiation are: 6.6; 10.1; 18.2; 21.7; 25.2 and 27.8 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • Roxadustat napsylate in the form of crystalline modification II (prepared according to Example 28) is characterized by the reflections presented in Table 25.
  • Table 25 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of crystalline roxadustat napsylate of form II according to the present invention with the use of CuK ⁇ radiation are: 6.4; 9.9; 13.5; 19.8; 22.0 and 26.5 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • Crystalline roxadustat besylate (prepared according to Example 29) is characterized by the reflections presented in Table 26.
  • Table 26 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of crystalline roxadustat besylate according to the present invention with the use of CuK ⁇ radiation are: 6.6; 10.5; 13.4; 20.2; 23.2; 26.1 and 28.3 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • Roxadustat tosylate in the form of crystalline modification II (prepared according to Example 31) is characterized by the reflections presented in Table 28.
  • Table 28 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of crystalline roxadustat tosylate of form II according to the present invention with the use of CuK ⁇ radiation are: 5.8; 9.9; 14.1; 19.8; 22.0 and 26.8 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • Roxadustat tosylate in the form of crystalline modification III (prepared according to Example 32) is characterized by the reflections presented in Table 29.
  • Table 29 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of crystalline roxadustat tosylate of form III according to the present invention with the use of CuK ⁇ radiation are: 6.3; 10.9; 12.9; 17.3; 19.3 and 25.4 ⁇ 0,2° 2-theta.
  • DSC Differential scanning calorimetry
  • Crystalline 3-ethyl-l-methyl-lH-imidazol-3-ium roxadustat (prepared according to Example 33) is characterized by the reflections presented in Table 30.
  • Table 30 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of crystalline 3-ethyl-l-methyl-lH-imidazol-3-ium roxadustat according to the present invention with the use of CuK ⁇ radiation are: 5.1; 11.2; 15.6; 20.8; 23.1 and 25.7 ⁇ 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 9.8; 14.3; 17.2; 20.0 and 28.6 ⁇ 0.2° 2-theta.
  • Table 30 comprises
  • DSC Differential scanning calorimetry
  • the characteristic diffraction peaks of the crystalline caffeine cocrystal of roxadustat of form I according to the present invention with the use of CuK ⁇ radiation are: 8.2; 10.1; 13.1; 16.7; 19.7 and 26.0 ⁇ 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 9.6; 12.1; 17.4; 22.6 and 28.0 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • the characteristic diffraction peaks of the crystalline caffeine cocrystal of roxadustat of form II according to the present invention with the use of CuK ⁇ radiation are: 7.8; 10.1; 12.8; 15.7; 19.4 and 26.0 ⁇ 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 11.3; 18.4; 23.2 and 27.2 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • the characteristic diffraction peaks of the crystalline caffeine cocrystal of roxadustat of form III according to the present invention with the use of CuK ⁇ radiation are: 10.0; 11.8; 16.8; 20.1 and 26.6 ⁇ 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 14.8; 18.0; 21.4 and 24.9 ⁇ 0.2° 2-theta.
  • the prepared solid forms of the salts of roxadustat according to the present invention can be used for the preparation of pharmaceutical compositions, especially solid drug forms, e.g. tablets or capsules.
  • Such pharmaceutical compositions can comprise at least one excipient from the group of fillers (e.g. lactose), binders (e.g. macrocrystalline cellulose), disintegrants (e.g. sodium salt of croscarmellose), lubricants (e.g. magnesium stearate), surfactants etc.
  • a salt or cocrystal of roxadustat can be mixed with the above-mentioned excipients, screened through a sieve and the final mixture can be tabletted or filled into capsules.
  • the tablets can be further coated with conventional layers of e.g. polyvinyl alcohol or polyethylene glycol.
  • 0.02 rad Soller slits, a 10 mm mask and a 1/4° fixed anti- dispersion slit were used.
  • the irradiated area of a sample is 10 mm, programmable divergency slits were used.
  • 0.02 rad Soller slits and a 5.0 mm anti-dispersion slit were used.
  • DSC Differential scanning calorimetry
  • DSC differential scanning calorimetry
  • the charge of the sample in a standard Al pot was 2-3 mg and the heating rate was 10°C/min.
  • the used temperature program consists of 1 stabilization minute at 0°C and then of heating up to 250°C at the heating rate of 10°C/min.
  • As the carrier gas 4.0 N2 was used at the flow of 20 ml / min.
  • Ultra high performance liquid chromatography UHPLC
  • IR spectra were measured on a Nicolet 6700 FTIR spectrometer (Thermo, USA) using the single-reflection ATR technique (ZnSe). Each spectrum was accumulated with 12 scans with the resolution of 4 cm “1 . The spectra were collected and processed by the Opus 8.2 software (Thermo, USA). Thermogravimetry (TGA)
  • thermogravimetric analysis were measured using a TGA 6 device made by Perking Elmer.
  • the charge of the sample in a corundum pot was 13-20 mg and the heating rate was 10°C/min.
  • the used temperature program consists of 1 stabilization minute at 15°C and then of heating up to 300°C at the heating rate of 10°C/min.
  • As the carrier gas 4.0 N 2 was used at the flow of 20 ml / min.
  • Roxadustat free acid (crystalline form A) was prepared in accordance with the procedure disclosed in the patent application WO 2004/108681, or in accordance with the procedure disclosed in the patent application WO 2014/014835.
  • the sodium salt of roxadustat was prepared in accordance with the procedure disclosed in the patent application WO 2014/014835.
  • Roxadustat 40 mg, form A was dissolved in THF (1 ml) at 50°C.
  • Meglumine 1.1 equivalents in the form of a solution of 25 mg of meglumine in 1 ml of water
  • the solution was stirred for 20 min at 50°C.
  • the solution was subsequently left to cool down freely to 25°C and stirred at this temperature in an open vial.
  • the solid fraction was filtered, washed with water and dried for 0.5 h at the temperature of 45°C in vacuum.
  • the product was isolated in the yield of 86% (53 mg) in the form of white powder.
  • An IR measurement confirmed formation of a salt.
  • the ratio of roxadustat:meglumine 1:1 was determined by means of NMR.
  • the X-ray powder pattern is shown in Fig. 1
  • the DSC record is shown in Fig. 2
  • Tt 181°C
  • Roxadustat (10 mg, form A) was dissolved in THF and the solvent was evaporated in a vacuum drier at 25°C. Then, N,N'-dibenzylethylenediamine was added in the form of a solution in methanol (1 equivalent, 341 ⁇ l of a stock solution at the concentration of 0.0832M) and the solvent was evaporated again in a vacuum drier at the temperature of 25°C. 1 ml of a solvent (acetone or acetonitrile) was added to the prepared mixture and the mixture was stirred up until a solution was obtained. The solution was subsequently left to crystallize for 20 h at 7- 8°C. Then, the solvent was evaporated using a nitrogen stream for 48 h at the temperature of 25°C and subsequently for 22 h at the temperature of 25°C in vacuum. An ER measurement confirmed formation of a salt.
  • the X-ray powder pattern is shown in Fig. 13
  • Roxadustat (1.0 g, form A), which had been dissolved in a mixture of ethanol and tetrahydrofuran in the ratio of 8:3 (total volume 30 ml), was dosed into a flask at the temperature of 80°C and subsequently, aqueous LiOH was added (1.5 equivalents, 0.102 g of LiOH dissolved in 3 ml of water). Then, the solution was left to freely cool down to the room temperature (25°C) and at this temperature it was stirred for another 48 hours. The crystalline product was aspirated on frit, washed with a minimal quantity cooled ethanol and dried freely at the temperature of 25°C. The product was obtained in the form of beige powder in the yield of 0.367 g (34%). An IR measurement confirmed formation of a salt.
  • Roxadustat (1.0 g, form A), which had been dissolved in a mixture of acetone and tetrahydrofuran in the ratio of 8:2 (total volume 27 ml), was dosed into a flask at the temperature of 85°C and subsequently, aqueous LiOH was added (1.5 equivalents, 0.102 g of LiOH dissolved in 5 ml of water). Then, the solution was left to freely cool down to the room temperature (25 °C) and at this temperature it was stirred for another 48 hours. The crystalline product was aspirated on frit, washed with a minimal quantity of acetone and dried freely at the temperature of 25°C. The product was obtained in the form of beige powder in the yield of 0.484 g (47%). An IR measurement confirmed formation of a salt. 13.3% of water were measured by means of TGA.
  • the lithium salt of roxadustat (0.1 g, form II from the previous example) was dried at 60°C in vacuum (200 mbar) for 22 hours.
  • the product was obtained in the form of beige powder in the yield of 0.09 g (90%). 4.2% of water were measured by means of TGA.
  • Roxadustat (1.0 g, form A), which had been dissolved in acetone (66 ml) was dosed into a flask at the temperature of 50°C and subsequently, aqueous KOH was added (approx. 1.5 equivalents, 0.2 g of KOH dissolved in 6 ml of water). The product precipitated immediately after the addition. Then, the suspension was stirred at the temperature of 50°C for 17 h and for another 3 h at the temperature of 25°C. The crystalline product was aspirated on frit, washed with a minimal quantity of acetone and dried at a temperature of 35-40°C for 1 h in vacuum.
  • the product in the form of yellow powder was obtained in the yield of 0.87 g (78%), chemical purity 99.5% (measured with UHPLC).
  • the content of potassium was determined to be 8.6% by titration (10% theoretically).
  • An IR measurement confirmed formation of a salt.
  • Example 11 The mother liquor of Example 11 (containing 3.80 g of the potassium salt of roxadustat) was concentrated on a vacuum evaporator and ethanol was added by dripping to the obtained aqueous solution. The final mixture was concentrated on a rotary vacuum evaporator and the suspension was filtered and washed with ethanol. The product in the form of green powder was obtained in the yield of 3.78 g (99%), chemical purity 99.0% (measured with UHPLC).
  • the X-ray powder pattern is shown in Fig. 33
  • the DSC record is shown in Fig. 34
  • T t 120.5°C.
  • the sodium salt of roxadustat (10 g) was dissolved at 50°C in a methanohwater mixture with the ratio of 1:1 (280 ml).
  • a solution of calcium chloride (CaCl2-2H 2 0, 0.6 equivalents, 2.36 g) in a methanohwater mixture with the ratio of 1:1 (100 ml) was added to this solution by dripping at the temperature of 50°C.
  • the mixture was subsequently slowly cooled down to the laboratory temperature and stirred for 22 h.
  • the product was isolated by filtration and washed with 100 ml of a methanol: water mixture with the ratio of 1 :1 and dried in a vacuum drier at the temperature of 45°C for 20 h.
  • the crystalline product in the form of fine yellowish green powder was obtained in the yield of 6.4 g, chemical purity 99.74% (measured with UHPLC).
  • the X-ray powder pattern is shown in Fig. 38.
  • the X-ray powder pattern is shown in Fig. 40
  • the DSC record is shown in Fig. 41
  • T g 205°C.
  • the X-ray powder pattern is shown in Fig. 46
  • the DSC record is shown in Fig. 47
  • Tt 183°C.
  • the X-ray powder pattern is shown in Fig. 50
  • the DSC record is shown in Fig. 51
  • Tt 147°C.
  • Fig. 52 The X-ray powder pattern of roxadustat napsylate of form II is shown in Fig. 52, the DSC record is shown in Fig. 53; this is a non-solvated form with the melting point of 142°C.
  • the X-ray powder pattern is shown in Fig. 54
  • the DSC record is shown in Fig. 55
  • T t 155°C.
  • Fig. 58 The X-ray powder pattern of roxadustat tosylate of form II is shown in Fig. 58, the DSC record is shown in Fig. 59; this is a non-solvated form with the melting point of 149°C.
  • Fig. 60 The X-ray powder pattern of roxadustat tosylate of form III is shown in Fig. 60, the DSC record is shown in Fig. 61; this is a non-solvated form with the melting point of 183°C.
  • Fig. 62 The X-ray powder pattern of 3 -ethyl- 1 -methyl- lH-imidazol-3-ium roxadustat is shown in Fig. 62, the DSC record is shown in Fig. 63; this is a crystalline form with the melting point of 160°C.
  • Roxadustat 500 g, purity 99.34%) and caffeine (303 mg, 1.1 equiv.) were dosed into a flask and then suspended in acetonitrile (5 ml). The reaction mixture was stirred for 22 hours without the access of light at the room temperature (25°C). Then, the crystals were aspirated on frit, washed with acetonitrile (1 ml) and dried at 45 °C in vacuum (200 mbar) for 18 hours. This way, the amount of 715 mg (92%) of the product was obtained with the purity of 99.64%.
  • Fig. 68 The X-ray powder pattern of the caffeine cocrystal of roxadustat of form III is shown in Fig. 68, the DSC record is shown in Fig. 69; this is a crystalline form with the melting point of 175.3°C.

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Abstract

The solution relates to solid forms of roxadustat with the systematic name of (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)glycine of formula (I), methods of their preparation and use in a drug form. These solid forms of roxadustat of formula (I) are prepared by a reaction of roxadustat free acid with suitable coformers (inorganic or organic acids, bases, neutral molecules, or salts or ion pairs) in a suitable solvent or mixtures of solvents, the coformer is selected from the group consisting of meglumine, Ν,Ν'-dibenzylethylenediamine, tert-butylamine, diethylamine, dicyclohexylamine, ammonia, lithium, potassium hydroxide, calcium salt, magnesium salt, iron (III) salt, iron (II) salt, 2-naphtalenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 3-ethyl-1 -methyl- 1H-imidazol-3-ium acetate and caffeine.

Description

Solid forms of roxadustat
Field of the Invention
The invention relates to solid forms of roxadustat with the systematic name of (4-hydroxy-l- methyl-7-phenoxyisoquinoline-3-carbonyl)glycine of formula I, methods of their preparation and use in a drug form.
Background Art
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Roxadustat (CAS no. 808118-40-3) is a hypoxia inducible factor prolyl hydroxylase (HIF-PH) inhibitor, which increases endogenous production of erythropoetin which stimulates production of red blood cells (erythropoiesis). A drug comprising roxadustat is found in the third phase of clinical trials for the treatment of anaemia.
Preparation of roxadustat and its isolation was first described in the patent application WO 2004/108681 (compound 81). The patent application WO 2014/014835 discloses a preparation method and characterization of crystalline forms of roxadustat free acid (form A-D) and its amorphous form. It further discloses a crystalline sodium salt of roxadustat, amorphous potassium salt, crystalline (hemi) calcium and (hemi) magnesium salt as well as salts of roxadustat with L-arginine, L-lysine, ethanolamine, diethanolarnine, tromethamine, bis- triethylamine, sulphuric and methanesulfonic acid. All the prepared crystalline salts are characterized by means of X-ray powder diffraction, differential scanning calorimetry (DSC) and thermogravimetry (TGA). Stoichiometry of the salts of roxadustat (ion of reoxadustatrcounterion) was described by means of nuclear magnetic resonance (NMR), in the case of inorganic salts by means of ion chromatography. Disclosure of the Invention
The invention provides pharmaceutically acceptable salts of roxadustat (I) and a method of their preparation. These solid forms of roxadustat of formula I are prepared by a reaction of roxadustat free acid with suitable coformers (inorganic or organic acids, bases, neutral molecules or possibly salts or ion pairs) in a suitable solvent or mixtures of solvents; or salts of roxadustat are prepared through cation exchange in a suitable solvent or mixtures of solvents, especially through exchange of the cation of the sodium salt of roxadustat.
The prepared solid forms have suitable physicochemical characteristics for use in pharmacy and formulation of new drug forms.
An object of this invention is a solid form of roxadustat with a coformer wherein the coformer is selected from the group consisting of meglumine, N,N'-dibenzylethylenediamine, tert- butylamine, diethylamine, dicyclohexylamine, ammonia, lithium, potassium, calcium, magnesium, iron, 2-naphtalenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 3- ethyl-l-methyl-lH-imidazol-3-ium acetate and caffeine.
Another object of this invention is a salt of roxadustat with a coformer in a solid form wherein the coformer is selected from the group consisting of meglumine, Ν,Ν'- dibenzylethylenediamine, tert-butylamine, diethylamine, dicyclohexylamine, ammonia, potassium hydroxide, calcium salt, magnesium salt, iron (III) salt, iron (II) salt, 2- naphtalenesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.
Another object of the invention is a salt of roxadustat with meglumine, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 3.3; 11.8; 16.8; 22.8; 25.1 and 27.7 ± 0.2° 2-theta. In some embodiments, the salt of roxadustat with meglumine is further characterized by a differential scanning calorimetric curve with the melting point at 181°C. Another object of the invention is a salt of roxadustat with N,N -dibenzylethylenediamine in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 5.0; 10.9; 13.3; 18.1; 19.8; 23.8 and 26,1 ± 0.2° 2-theta. In some embodiments, the salt of roxadustat with Ν,Ν'- dibenzylethylenediamine in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 126°C.
Another object of the invention is a salt of roxadustat with N,N-dibenzylemylenediarnine in the form of crystalline modification II, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 7.1; 9.9; 17.1; 19.9; 24.1 and 26.5 ± 0.2° 2-theta. In some embodiments, the salt of roxadustat with N,N -dibenzylethylenediamine in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 115°C.
Another object of the invention is a salt of roxadustat with tert-butylamine in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 6.6; 10.5; 12.9; 16.3; 20.1 and 22.7 ± 0.2° 2- theta. In some embodiments, the salt of roxadustat with tert-butylamine in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 159°C.
Another object of the invention is a salt of roxadustat with tert-butylamine in the form of crystalline modification II, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 5.7; 11.1; 18.1; 19.6; 21.7 and 26.1 ± 0.2° 2- theta. In some embodiments, the salt of roxadustat with tert-butylamine in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 169°C. Another object of the invention is a salt of roxadustat with diethylamine, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 10.0; 13.3; 15.7; 20.2; 24.0 and 29.1 ± 0.2° 2-theta. In some embodiments, the salt of roxadustat with diethylamine is further characterized by a differential scanning calorimetric curve with the melting point at 183°C.
Another object of the invention is a salt of roxadustat with dicyclohexylamine in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 9.9; 16.8; 19.8; 22.5; 24.4 and 29.9 ± 0.2° 2- theta. In some embodiments, the salt of roxadustat with dicyclohexylamine in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 190°C. Another object of the invention is a salt of roxadustat with dicyclohexylamine in the form of crystalline modification II, the coformer being dicyclohexylamine, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 8.5; 9.9; 12.4; 18.7; 20.6; 23.8 and 27.5 ± 0.2° 2-theta. In some embodiments, the salt of roxadustat with dicyclohexylamine in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 189°C.
Another object of the invention is a salt of roxadustat with ammonia in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 6.2; 9.7; 15.9; 18.8; 23.3 and 27.9 ± 0.2° 2-theta. In some embodiments, the salt of roxadustat with ammonia in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 159°C.
Another object of the invention is a salt of roxadustat with ammonia in the form of crystalline modification II, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 4.9; 11.6; 14.9; 16.7; 18.9 and 22.4 ± 0.2° 2-theta. In some embodiments, the salt of roxadustat with ammonia in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 164°C.
Another object of the invention is a salt of roxadustat with Hthium in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 2.7; 5.5; 10.6; 17.6; 24.0 and 26.0 ± 0.2° 2-theta. In some embodiments, the salt of roxadustat with lithium in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 125°C. Another object of the invention is a salt of roxadustat with lithium in the form of crystalline modification II, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 2.6; 7.8; 10.3; 15.6; 20.7 and 26.5 ± 0.2° 2-theta. In some embodiments, the salt of roxadustat with hthium in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 226.1°C.
Another object of the invention is a salt of roxadustat with lithium in the form of crystalline modification III, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 2.7; 5,4; 8.4; 11.3; 14.8 and 22.4 ± 0.2° 2-theta. In some embodiments, the salt of roxadustat with lithium in the form of crystalline modification III is further characterized by a differential scanning calorimetric curve with the melting point at 227°C. Another object of the invention is a potassium salt of roxadustat in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 2.6; 5.2; 10.8; 18.1; 20.8 and 24.4 ± 0.2° 2-theta. In some embodiments, the potassium salt of roxadustat in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 63°C.
Another object of the invention is a potassium salt of roxadustat in the form of crystalline modification II, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 3.0; 11.0; 13.8; 18.2; 22.4 and 27.8 ± 0.2° 2-theta In some embodiments, the potassium salt of roxadustat in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 288°C.
Another object of the invention is a salt of roxadustat with potassium in the form of crystalline modification III, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 5.0; 9.9; 13.0; 19.5 a 24.8 ± 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 7.3; 17.0; 21.3 and 27.3 ± 0.2° 2-theta. In some embodiments, the salt of roxadustat with potassium in the form of crystalline modification III is further characterized by a differential scanning calorimetric curve with the melting point at 308.3°C.
Another object of the invention is a salt of roxadustat with potassium in the form of crystalline modification IV, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 4.9; 7.3; 11.9; 19.8 and 22.7 ± 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 10.8; 15.1; 17.8 and 27.1 ± 0.2° 2-theta. In some embodiments, the salt of roxadustat with potassium in the form of crystalline modification IV is further characterized by a differential scanning calorimetric curve with the melting point at 120.5°C.
Another object of the invention is a (hemi) calcium salt of roxadustat in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 3.0; 11.5; 12.9; 16.6; 20.1; 23.7 and 26.3 ± 0.2° 2-theta. In some embodiments, the hemi-calcium salt of roxadustat in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 96°C.
Another object of the invention is a (hemi) calcium salt of roxadustat in the form of crystalline modification II, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 2.9; 12.1; 16.6; 20.6 and 25.9 ± 0.2° 2-theta.
Another object of the invention is a (hemi) calcium salt of roxadustat in the form of crystalline modification III, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 3.5; 9.5; 21.5; 27.0 and 28.8 ± 0.2° 2-theta.
Another object of the invention is a salt of roxadustat with calcium in the form of crystalline modification IV, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 3.9; 11.6; 16.4; 19.3; 22.5 and 27.7 ± 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 15.3; 21.2; 24.1; 24.9 and 30.8 ± 0.2° 2-theta. Another object of the invention is an amorphous (hemi) calcium salt of roxadustat, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 3.6; 10.2 and 25.8 ± 0.5° 2-theta. In some embodiments, the amorphous hemi- calcium salt of roxadustat is further characterized by a differential scanning calorimetric curve with the glass transition temperature of 205°C.
Another object of the invention is a (hemi) magnesium salt of roxadustat, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 8.1; 12.0; 14.0; 18.6; 25.5 and 28.0 ± 0.2° 2-theta. In some embodiments, the hemi-magnesium salt of roxadustat is further characterized by a differential scanning calorimetric curve with the melting point at 85°C.
Another object of the invention is an amorphous (hemi) potasssium salt of roxadustat, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 2.5; 5.2; 7.5; 12.0 and 25.4 ± 0.5° 2-theta. In some embodiments, the amorphous hemi-magnesium salt of roxadustat is further characterized by a differential scanning calorimetric curve with the glass transition temperature of 62°C.
Another object of the invention is an amorphous salt of roxadustat with magnesium, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 2.5; 5.2; 7.5; 12.0 and 25.4 ± 0.5° 2-theta. In some embodiments, the amorphous salt of roxadustat with calcium is further characterized by a differential scanning calorimetric curve with the glass transition temperature of 62°C. Another object of the invention is a semicrystalline iron (III) salt of roxadustat characterized by a diffraction peak in an X-ray powder pattern with the use of CuKα radiation of 6.5 ± 0.2° 2-theta and amorphous halo with the band maximum of 22.0° ± 1.0° 2-theta. In some embodiments, the semicrystalline iron (III) salt of roxadustat is further characterized by a differential scanning calorimetric curve with the melting point at 183°C.
Another object of the invention is an amorphous (hemi) iron salt of roxadustat, exhibiting a characteristics amorphous halo in an X-ray powder pattern with the use of CuKα radiation in the range of 4.5 to 21.0 ± 0.5° 2-theta. In some embodiments, the amorphous hemi-iron salt of roxadustat is further characterized by a differential scanning calorimetric curve with the glass transition temperature of 60°C.
Another object of the invention is a salt of roxadustat with 2-naphtalenesulfonic acid in the form of crystalline modification I, exhibiting the following characteristic reflections in an X- ray powder pattern with the use of CuKα radiation: 6.6; 10.1; 18.2; 21.7; 25.2 and 27.8 ± 0.2° 2-theta. In some embodiments, the salt of roxadustat with 2-naphtalenesulfonic acid in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 147°C.
Another object of the invention is a salt of roxadustat with 2-naphtalenesulfonic acid in the form of crystalline modification II, exhibiting the following characteristic reflections in an X- ray powder pattern with the use of CuKα radiation: 6.4; 9.9; 13.5; 19.8; 22.0 and 26.5 ± 0.2° 2-theta. In some embodiments, the salt of roxadustat with 2-naphtalenesulfonic acid in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 142°C.
Another object of the invention is a salt of roxadustat with benzenesulfonic acid, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 6.6; 10.5; 13.4; 20.2; 23.2; 26.1 and 28.3 ± 0.2° 2-theta. In some embodiments, the salt of roxadustat with benzenesulfonic acid is further characterized by a differential scanning calorimetric curve with the melting point at 155°C.
Another object of the invention is a salt of roxadustat with p-toluenesulfonic acid in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 5.7; 11.7; 15.8; 18.4; 21.9 and 26.0 ± 0.2° 2- theta. In some embodiments, the salt of roxadustat with p-toluenesulfonic acid in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 150°C.
Another object of the invention is a salt of roxadustat with p-toluenesulfonic acid in the form of crystalline modification Π, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 5.8; 9.9; 14.1; 19.8; 22.0 and 26.8 ± 0.2° 2- theta. In some embodiments, the salt of roxadustat with p-toluenesulfonic acid in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 149°C. Another object of the invention is a salt of roxadustat with p-toluenesulfonic acid in the form of crystalline modification III, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 6.3; 10.9; 12.9; 17.3; 19.3 and 25.4 ± 0,2° 2- theta. In some embodiments, the salt of roxadustat with p-toluenesulfonic acid in the form of crystalline modification III is further characterized by a differential scanning calorimetric curve with the melting point at 183°C.
Another object of the invention is crystalline 3-ethyl-l-methyl-lH-imidazol-3-ium roxadustat, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 5.1; 11.2; 15.6; 20.8; 23.1 and 25.7 ± 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 9.8; 14.3; 17.2; 20.0 and 28.6 ± 0.2° 2-theta. In some embodiments, 3 -ethyl- 1 -methyl- lH-imidazol-3-ium roxadustat is further characterized by a differential scanning calorimetric curve with the melting point at 160°C. Another object of the invention is a cocrystal of roxadustat with caffeine in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 8.2; 10.1; 13.1; 16.7; 19.7 and 26.0 ± 0.2° 2- theta, or possibly these characteristic peaks maybe supplemented with more diffraction peaks: 9.6; 12.1; 17.4; 22.6 and 28.0 ± 0.2° 2-theta. In some embodiments, the cocrystal of roxadustat with caffeine in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 177.2°C.
Another object of the invention is a cocrystal of roxadustat with caffeine in the form of crystalline modification II, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 7.8; 10.1; 12.8; 15.7; 19.4 and 26.0 ± 0.2° 2- theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 11.3; 18.4; 23.2 and 27.2 ± 0.2° 2-theta. In some embodiments, the cocrystal od roxadustat .
with caffeine in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 178°C.
Another object of the invention is a cocrystal of roxadustat with caffeine in the form of crystalline modification III, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 10.0; 11.8; 16.8; 20.1 and 26.6 ± 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 14.8; 18.0; 21.4 and 24.9 ± 0.2° 2-theta. In some embodiments, the cocrystal of roxadustat with caffeine in the form of crystalline modification III is further characterized by a differential scanning calorimetric curve with the melting point at 175.3°C.
Another object of the invention is a preparation method of solid forms of roxadustat with a coformer according to the present invention wherein roxadustat free acid is dissolved in a suitable solvent and subsequently, a coformer is added that is selected from the group consisting of meglumine, N,N-dibenzylethylenediamine, tert-butylamine, diemylamine, dicyclohexylamine, aqueous ammonia, lithium hydroxide, potassium hydroxide, 2- naphtalenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 3-ethyl-l -methyl- 1H- imidazol-3-ium acetate and caffeine. Another object of the invention is a preparation method of salts of roxadustat with a coformer according to the present invention wherein roxadustat free acid is dissolved in a suitable solvent and subsequently, a coformer is added that is selected from the group consisting of meglumine, N,N -dibenzylethylenediamine, tert-butylamine, diethylamine, dicyclohexylamine, aqueous ammonia, potassium hydroxide, 2-naphtalenesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.
Another object of the invention is a preparation method of salts of roxadustat with a coformer according to the present invention wherein a sodium salt of roxadustat is dissolved in a suitable solvent and subsequently a coformer is added that is selected from the group consisting of a calcium salt, magnesium salt, iron (II) salt and iron (III) salt, preferably of calcium chloride, magnesium chloride, iron (II) chloride and iron (III) chloride. A suitable solvent is a solvent selected from the group consisting of aliphatic C1-C4 alcohols, ketones, ethers, nitriles, water or their mixture, preferably tetrahydrofuran, methanol, acetone, acetonitrile, water or their mixture. Another object of the invention is the use of solid forms of roxadustat with a coformer according to the present invention for the preparation of a pharmaceutical composition.
Another object of the invention is the use of salts of roxadustat with a coformer according to the present invention for the preparation of a pharmaceutical composition.
Another object of the invention is a pharmaceutical composition comprising a solid form of roxadustat with a coformer according to the present invention and at least one pharmaceutically acceptable excipient. Another object of the invention is a pharmaceutical composition comprising a salt of roxadustat with a coformer according to the present invention and at least one pharmaceutically acceptable excipient.
Brief description of the Drawings
Figure 1: X-ray powder pattern of the crystalline meglumine salt of roxadustat
Figure 2: DSC record of the crystalline meglumine salt of roxadustat
Figure 3: X-ray powder pattern of the crystalline (hemi) N,N-dibenzylethylenediammonium salt of roxadustat - form I
Figure 4: DSC record of the crystalline (hemi) N,N-dibenzylethylenediammonium salt of roxadustat - form I
Figure 5: X-ray powder pattern of the crystalline (hemi) NN-dibenzylethylenediammonium salt of roxadustat - form II
Figure 6: DSC record of the crystalline (hemi) N,N'-dibenzylethylenediammonium salt of roxadustat - form II
Figure 7: X-ray powder pattern of the crystalline tert-butylammonium salt of roxadustat - form I
Figure 8: DSC record of the crystalline tert-butylammonium salt of roxadustat - form I Figure 9: X-ray powder pattern of the crystalline tert-butylammonium salt of roxadustat - form II
Figure 10: DSC record of the crystalline tert-butylammonium salt of roxadustat - form II Figure 11: X-ray powder pattern of the crystalline diethylammonium salt of roxadustat
Figure 12: DSC record of the crystalline diethylammonium salt of roxadustat
Figure 13: X-ray powder pattern of the crystalline dicyclohexylammonium salt of roxadustat - form I
Figure 14: DSC record of the crystalline dicyclohexylammonium salt of roxadustat - form I Figure 15: X-ray powder pattern of the crystalline dicyclohexylammonium salt of roxadustat - form II
Figure 16: DSC record of the crystalline dicyclohexylammonium salt of roxadustat - form II Figure 17: X-ray powder pattern of the crystalline ammonium salt of roxadustat - form I
Figure 18: DSC record of the crystalline ammonium salt of roxadustat - form I
Figure 19: X-ray powder pattern of the crystalline ammonium salt of roxadustat - form II Figure 20: DSC record of the crystalline ammonium salt of roxadustat - form II
Figure 21: X-ray powder pattern of the crystalline lithium salt of roxadustat - form I
Figure 22: DSC record of the crystalline lithium salt of roxadustat - form I
Figure 23: X-ray powder pattern of the crystalline lithium salt of roxadustat - form Π
Figure 24: DSC record of the crystalline lithium salt of roxadustat - form II
Figure 25: X-ray powder pattern of the crystalline lithium salt of roxadustat - form HI
Figure 26: DSC record of the crystalline lithium salt of roxadustat - form III
Figure 27: X-ray powder pattern of the crystalline potassium salt of roxadustat - form I
Figure 28: DSC record of the crystalline potassium salt of roxadustat - form I
Figure 29: X-ray powder pattern of the crystalline potassium salt of roxadustat - form II
Figure 30: DSC record of the crystalline potassium salt of roxadustat - form II
Figure 31: X-ray powder pattern of the crystalline potassium salt of roxadustat - form III Figure 32: DSC record of the crystalline potassium salt of roxadustat - form III
Figure 33: X-ray powder pattern of the crystalline potassium salt of roxadustat - form IV
Figure 34: DSC record of the crystalline potassium salt of roxadustat - form IV
Figure 35: X-ray powder pattern of the crystalline (hemi-)calcium salt of roxadustat - form I Figure 36: DSC record of the crystalline (hemi-)calcium salt of roxadustat - form I
Figure 37: X-ray powder pattern of the crystalline (hemi-)calcium salt of roxadustat - form II Figure 38: X-ray powder pattern of the crystalline (hemi-)calcium salt of roxadustat - form III Figure 39: X-ray powder pattern of the amorphous (hemi-)calcium salt of roxadustat
Figure 40: DSC record of the amorphous (hemi-)calcium salt of roxadustat
Figure 41: X-ray powder pattern of the crystalline (hemi-)calcium salt of roxadustat - form IV Figure 42: X-ray powder pattern of the crystalline (hemi-)magnesium salt of roxadustat
Figure 43: DSC record of the crystalline (hemi-)magnesium salt of roxadustat
Figure 44: X-ray powder pattern of the amorphous (hemi-)magnesium salt of roxadustat
Figure 45: DSC record of the amorphous (hemi-)magnesium salt of roxadustat
Figure 46: X-ray powder pattern of the crystalline iron (III) salt of roxadustat
Figure 47: DSC record of the crystalline iron (III) salt of roxadustat
Figure 48: X-ray powder pattern of the amorphous (hemi-)iron (II) salt of roxadustat
Figure 49: DSC record of the amorphous (hemi-)iron (II) salt of roxadustat
Figure 50: X-ray powder pattern of crystalline napsylate of roxadustat - form I
Figure 51: DSC record of crystalline napsylate of roxadustat - form I
Figure 52: X-ray powder pattern of crystalline napsylate of roxadustat - form II
Figure 53: DSC record of crystalline napsylate of roxadustat - form II
Figure 54: X-ray powder pattern of crystalline besylate of roxadustat
Figure 55: DSC record of crystalline besylate of roxadustat
Figure 56: X-ray powder pattern of crystalline tosylate of roxadustat - form I
Figure 57: DSC record of crystalline tosylate of roxadustat - form I
Figure 58: X-ray powder pattern of crystalline tosylate of roxadustat - form II
Figure 59: DSC record of crystalline tosylate of roxadustat - form II
Figure 60: X-ray powder pattern of crystalline tosylate of roxadustat - form III
Figure 61: DSC record of crystalline tosylate of roxadustat - form ΙΠ
Figure 62: X-ray powder pattern of crystalline 3-ethyl-l-methyl-lH-imidazol-3-ium roxadustat
Figure 63: DSC record of crystalline 3-emyl-l-methyl-lH-imidazol-3-ium roxadustat
Figure 64: X-ray powder pattern of a crystalline form of a caffeine cocrystal of roxadustat - form I
Figure 65: DSC record of a crystalline form of a caffeine cocrystal of roxadustat - form I Figure 66: X-ray powder pattern of a crystalline form of a caffeine cocrystal of roxadustat - form II
Figure 67: DSC record of a crystalline form of a caffeine cocrystal of roxadustat - form II Figure 68: X-ray powder pattern of a crystalline form of a caffeine cocrystal of roxadustat - form III
Figure 69: DSC record of a crystalline form of a caffeine cocrystal of roxadustat - form III
Detailed description of the Invention
From the point of view of possible interactions, roxadustat is structurally a very interesting molecule. As regards pKa, it is a relatively strong acid, ready to form salts with inorganic as well as organic bases (II), but basic regions are also present, especially the isoquinoline nitrogen, which may be the source of interactions between roxadustat and a suitable acid (III). The molecule comprises several donor and acceptor groups of electrons prone to form hydrogen bridges as well as an isoquinoline heterocycle and a phenoxy group suitable for aromatic interactions of the π-π stacking type with a suitable coformer.
Figure imgf000015_0001
The present invention provides multiple solid-phase crystalline salts of roxadustat and three solid-state amorphous salts. Within the invention, crystalline forms of salts of roxadustat are preferred.
As an object the invention provides solid crystalline forms of roxadustat with meglumine, N^-dibenzylemylenediamine, tert-butylamine, diethylamine, dicyclohexylamine and ammonia, further a crystalline potassium salt, crystalline and amorphous forms of a calcium and potassium salt of roxadustat, iron (II) and iron (III) salts of roxadustat and salts of roxadustat with 2-naphtalenesulfonic acid, benzenesulfonic acid, />-toluenesulfonic acid, 3- ethyl-l-methyl-lH-imidazol-3-ium and caffeine in various molar ratios. Within the invention, the molar ratios of 1:1, 2:1, 3:1 and 1:1,5 (ion of roxadustatxounterion; roxadustat:coformer) are preferred. Solid forms of roxadustat with these coformers can be prepared in adequate ratios and yields with high chemical purity in a crystalline or amorphous form.
These solid forms can be both anhydrous or non-solvated and in the form of hydrates/solvates of the respective solvents.
The prepared solid forms of roxadustat can have various internal arrangements (polymorphism) with different physicochemical characteristics depending on the conditions of their preparation. For this reason, the invention relates to individual crystals or their mixtures in any ratio.
These solid forms are suitable for the preparation of roxadustat with high chemical purity.
Preparation of the solid forms of roxadustat of formula I according to the present invention is conducted by means of a reaction of roxadustat free acid with meglumine, Ν,Ν'- dibenzylethylenediamine, tert-butylamine, diethylamine, dicyclohexylamine, aqueous ammonia, lithium hydroxide, potassium hydroxide, 2-naphtalenesulfonic acid, benzenesulfonic acid, aad j>toluenesulfonic acid, 3-ethyl-l-methyl-lH-imidazol-3-ium and caffeine.
The forms of the calcium, magnesium iron (III) and iron (Π) salt of roxadustat were prepared by cation exchange through a reaction of the sodium salt of roxadustat with calcium chloride, magnesium chloride, iron (III) chloride or iron (II) chloride. Instead of the chloride, calcium acetate, magnesium acetate or iron (II) acetate can alternatively be used for the preparation of the said salts.
The reactions can be conducted in a suitable solvent, which may be ketones, esters, ethers, amides, nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water or their mixtures. Aliphatic O-C4 alcohols, ketones, ethers, nitriles, water or their mixtures are preferred. The most commonly used solvents are THF, MeOH, acetone, ACN, water or their mixtures. The final product is precipitated or crystallized, or the solution is inoculated, typically at temperatures in the range of -30°C to the boiling point of the solvent.
Roxadustat free acid (form A) was prepared in accordance with the procedures disclosed in the patent application WO 2014/014835.
Salts of roxadustat according to the present invention, especially salts with meglumine, N,N''- dibenzylemylenediamine, p-toluenesulfonic acid, potassium and hemi-calcium salt exhibit better solubility compared to the thermodynamically most stable form of roxadustat free acid (form A) as well as compared to known salts disclosed in the patent application WO 2014/014835. Another advantage is increased photostability of the prepared salts of roxadustat compared to hitherto known forms of roxadustat.
Solid forms of roxadustat according to the present invention, especially salts with meglumine, N,N'-dibenzylemylenediamine, p-toluenesulfonic acid, potassium, hemi-calcium salt and the cocrystal of roxadustat with caffeine exhibit better solubility compared to the thermodynamically most stable form of roxadustat free acid (form A) as well as compared to known salts disclosed in the patent application WO 2014/014835.
Another advantage is increased photostability of the prepared salts of roxadustat compared to form A of roxadustat free acid. It is a well-known fact that roxadustat is subject to photodegradation. According to literature (WO2014197660), this instability was solved through the selection of suitable coating which restricts the effects of light. However, suitable coating cannot solve possible degradation in the course of the formulation. Reduced photostability was demonstrated in comparative experiments where roxadustat form A and the salts of roxadustat with meglumine, N,N' -dibenzylethylenediamine, p-toluenesulfonic acid and the potassium salt of meglumine in a solid form were exposed to UV/VIS radiation for the period of one to seven days, when the increase of the hotoisomer IV was observed.
Figure imgf000017_0001
IV (fotoisomer) The results are shown in the table:
Figure imgf000018_0001
Similarly, higher photostability of the solid forms of roxadustat according to the present invention was observed compared to form A of roxadustat free acid in a solution, or a suspension in various solvents or mixtures of solvents. To demonstrate it, the table below summarizes results of stability in isopropanol after 3 hours and one day, the samples were exposed to UV/VIS radiation:
Figure imgf000018_0002
Another advantage is that the solid forms of roxadustat according to the present invention are suitable for the preparation of roxadustat with high chemical purity.
The purification effect is demonstrated with several examples wherein roxadustat was mixed in a suitable solvent or mixture of solvents and in a suitable ratio with a coformer and isolated by filtration of the crystalline product in the form of a salt or cocrystal with meglumine, N,N''- dibenzylethylenediamine, potassium hydroxide, p-toluenesulfonic acid and caffeine, the purity of which was much higher than the purity of the input roxadustat. The examples and results of the purification effect of the conversion of roxadustat to a salt or cocrystal are presented in the table:
Figure imgf000019_0001
In addition, it was experimentally proved that the conversion of roxadustat to a suitable salt or cocrystal and its subsequent release can be used in the process of preparation of roxadustat with the required high purity.
Using the preparation of a crystalline salt or cocrystal as a purification step for the preparation of roxadustat with high purity is demonstrated with examples of salts of roxadustat with meglumine, N,N'-dibenzylemylenediamine, potassium hydroxide, p-toluenesulfonic acid and a cocrystal of roxadustat with caffeine. The examples and results of the purification effect of the conversion of roxadustat to a salt or cocrystal and its subsequent release are presented in the table:
Figure imgf000019_0002
Figure imgf000020_0001
The crystalline form of the meglumine salt of roxadustat (prepared according to Example 1) is characterized by the reflections presented in Table 1. Table 1 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline form of roxadustat meglumine salt according to the present invention with the use of CuKα radiation are: 3.3; 11.8; 16.8; 22.8; 25.1 and 27.7 ± 0.2° 2-theta.
Table 1
Figure imgf000020_0002
Figure imgf000021_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of the crystalline form of roxadustat meglumine salt of 181 °C. The (hemi) N.N'-dibenzylethylenediamonnium salt of roxadustat in the form of crystalline modification I (prepared according to Example 2) is characterized by the reflections presented in Table 2. Table 2 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline (hemi) N,N'-dibenzylethylene diammonium salt of roxadustat of form I according to the present invention with the use of CuKα radiation are: 5.0; 10.9; 13.3; 18.1; 19.8; 23.8 and 26,1 ± 0.2° 2-theta.
Table 2
Figure imgf000021_0002
Figure imgf000022_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of form I of the crystalline hemi N,N -dibenzylethylenediammonium salt of roxadustat of 126°C. The hemi N,N-dibenzylethylenediamonnium salt of roxadustat in the form of crystalline modification II (prepared according to Example 3) is characterized by the reflections presented in Table 3. Table 3 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline hemi N,N-dibenzylethylene diammonium salt of roxadustat of form II according to the present invention with the use of CuKα radiation are: 7.1 ; 9.9; 17.1 ; 19.9; 24.1 and 26.5 ± 0.2° 2-theta
Table 3
Figure imgf000022_0002
Figure imgf000023_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of form II of the crystalline hemi N.N-dibenzylethylenediammonium salt of roxadustat of 115°C. The tert-butylammonium salt of roxadustat in the form of crystalline modification I (prepared according to Example 4) is characterized by the reflections presented in Table 4. Table 4 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline tert-butylammonium salt of roxadustat of form I according to the present invention with the use of CuKα radiation are: 6.6; 10.5; 12.9; 16.3; 20.1 and 22.7 ± 0.2° 2-theta.
Figure imgf000024_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of the crystalline tert-butylammonium salt of roxadustat of form I of 159°C.
The tert-butylammonium salt of roxadustat in the form of crystalline modification II (prepared according to Example 5) is characterized by the reflections presented in Table 5. Table 5 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline tert-butylammonium salt of roxadustat of form II according to the present invention with the use of CuKα radiation are: 5.7; 11.1; 18.1; 19.6; 21.7 and 26.1 ± 0.2° 2-theta.
Table 5
Figure imgf000025_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of the crystalline tert-butylammonium salt of roxadustat of form II of 169°C.
The crystalline diethylammonium salt of roxadustat (prepared according to Example 6) is characterized by the reflections presented in Table 6. Table 6 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peals of the crystalline diethylammonium salt of roxadustat according to the present invention wim the use of CuKα radiation are: 10.0; 13.3; 15.7; 20.2; 24.0 and 29.1 ± 0.2° 2-theta.
Table 6
Figure imgf000026_0001
Figure imgf000027_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of the crystalline diethylammonium salt of roxadustat of 183°C. The dicyclohexylammonium salt of roxadustat in the form of crystalline modification I (prepared according to Example 7) is characterized by the reflections presented in Table 7. Table 7 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline dicyclohexylammonium salt of roxadustat of form I according to the present invention with the use of CuKα radiation are: 9.9; 16.8; 19.8; 22.5; 24.4 and 29.9 ± 0.2° 2-theta.
Table 7
Figure imgf000027_0002
Figure imgf000028_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of the crystalline dicyclohexylammonium salt of roxadustat of form I of 190°C. The dicyclohexylammonium salt of roxadustat in the form of crystalline modification II (prepared according to Example 8) is characterized by the reflections presented in Table 8. Table 8 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline dicyclohexylammonium salt of roxadustat of form II according to the present invention with the use of CuKα radiation are: 8.5; 9.9; 12.4; 18.7; 20.6; 23.8 and 27.5 ± 0.2° 2-theta.
Table 8
Figure imgf000028_0002
Figure imgf000029_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of the c^stalline dicyclohexylammonium salt of roxadustat of form II of 189°C.
The ammonium salt of roxadustat in the form of crystalline modification I (prepared according to Example 9) is characterized by the reflections presented in Table 9. Table 9 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline ammonium salt of roxadustat of form I according to the present invention with the use of CuKα radiation are: 6.2; 9.7; 15.9; 18.8; 23.3 and 27.9 ± 0.2° 2-theta.
Table 9
Figure imgf000029_0002
Figure imgf000030_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of form I of the crystalline ammonium salt of roxadustat of 159°C. The ammonium salt of roxadustat in the form of crystalline modification II (prepared according to Example 10) is characterized by the reflections presented in Table 10. Table 10 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline ammonium salt of roxadustat of form II according to the present invention with the use of CuKα radiation are: 4.9; 11.6; 14.9; 16.7; 18.9 and 22.4 ± 0.2° 2-theta. Table 10
Figure imgf000031_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of form II the crystalline ammonium salt of roxadustat of 164°C.
The lithium salt of roxadustat in the form of crystalline modification I (prepared according to Example 11) is characterized by the reflections presented in Table 11. Table 11 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline lithium salt of roxadustat of form I according to the present invention with the use of CuKα radiation are: 2.7; 5.5; 10.6; 17.6; 24.0 and 26.0 ± 0.2° 2-theta.
Table 11
Figure imgf000032_0001
Figure imgf000033_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of form I of the crystalline lithium salt of roxadustat of 125°C. The lithium salt of roxadustat in the form of crystalline modification II (prepared according to Example 12) is characterized by the reflections presented in Table 12. Table 12 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline lithium salt of roxadustat of form II according to the present invention with the use of CuKα radiation are: 2.6; 7.8; 10.3; 15.6; 20.7 and 26.5 ± 0.2° 2-theta.
Table 12
Figure imgf000033_0002
Figure imgf000034_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of form II the crystalline lithium salt of roxadustat of 226.1 °C. The lithium salt of roxadustat in the form of crystalline modification III (prepared according to Example 13) is characterized by the reflections presented in Table 13. Table 13 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline lithium salt of roxadustat of form III according to the present invention with the use of CuKα radiation are: 2.7; 5,4; 8.4; 11.3; 14.8 and 22.4 ± 0.2° 2-theta.
Table 13
Figure imgf000034_0002
Figure imgf000035_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of form III of the crystalline lithium salt of roxadustat of 227°C. The potassium salt of roxadustat in the form of crystalline modification I (prepared according to Example 14) is characterized by the reflections presented in Table 14. Table 14 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline potassium salt of roxadustat according to the present invention with the use of CuKα radiation are: 2.6; 5.2; 10.8; 18.1; 20.8 and 24.4 ± 0.2° 2-theta. Table 14
Figure imgf000036_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of form I of the crystalline potassium salt of roxadustat of 63 °C.
The potassium salt of roxadustat in the form of crystalline modification II (prepared according to Example 15) is characterized by the reflections presented in Table 15. Table 15 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline potassium salt of roxadustat according to the present invention with the use of CuKα radiation are: 3.0; 11.0; 13.8; 18.2; 22.4 and 27.8 ± 0.2° 2-theta. Table 15
Figure imgf000037_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of form II of the crystalline potassium salt of roxadustat of 288°C.
The potassium salt of roxadustat in the form of crystalline modification III (prepared according to Example 16) is characterized by the reflections presented in Table 16. Table 16 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline potassium salt of roxadustat of form III according to the present invention with the use of CuKα radiation are: 5.0; 9.9; 13.0; 19.5 a 24.8 ± 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 7.3; 17.0; 21.3 and 27.3 ± 0.2° 2-theta.
Figure imgf000038_0001
Figure imgf000039_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of form III of the crystalline potassium salt of roxadustat of 308.3°C. The potassium salt of roxadustat in the form of crystalline modification IV (prepared according to Example 17) is characterized by the reflections presented in Table 17. Table 17 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline potassium salt of roxadustat of form IV according to the present invention with the use of CuKα radiation are: 4.9; 7.3; 11.9; 19.8 and 22.7 ± 0.2° 2- theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 10.8; 15.1; 17.8 and 27.1 ± 0.2° 2-theta.
Table 17
Figure imgf000039_0002
Figure imgf000040_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of form IV of the crystalline potassium salt of roxadustat of 120.5°C. The hemi-calcium salt of roxadustat in the form of crystalline modification I (prepared according to Example 18) is characterized by the reflections presented in Table 18. Table 18 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline hemi-calcium salt of roxadustat according to the present invention with the use of CuKα radiation are: 3.0; 11.5; 12.9; 16.6; 20.1; 23.7 and 26.3 ± 0.2° 2-theta.
Table 4318
Figure imgf000040_0002
Figure imgf000041_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of form I of the crystalline hemi-calcium salt of roxadustat of 96°C. The hemi-calcium salt of roxadustat in the form of crystalline modification II (prepared according to Example 19) is characterized by the reflections presented in Table 19. Table 19 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline hemi-calcium salt of roxadustat according to the present invention with the use of CuKα radiation are: 2.9; 12.1; 16.6; 20.6 and 25.9 ± 0.2° 2-theta.
Table 19
Figure imgf000041_0002
Figure imgf000042_0001
The hemi-calcium salt of roxadustat in the form of crystalline modification III (prepared according to Example 20) is characterized by the reflections presented in Table 20. Table 20 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline hemi-calcium salt of roxadustat according to the present invention with the use of CuKα radiation are: 3.5; 9.5; 21.5; 27.0 and 28.8 ± 0.2° 2-theta.
Table 20
Figure imgf000042_0002
Figure imgf000043_0001
The hemi-calcium salt of roxadustat in the form of crystalline modification IV (prepared according to Example 21) is characterized by the reflections presented in Table 21. Table 21 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline hemi-calcium salt of roxadustat of form IV according to the present invention with the use of CuKα radiation are: 3.9; 11.6; 16.4; 19.3; 22.5 and 27.7 ± 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 15.3; 21.2; 24.1; 24.9 and 30.8 ± 0.2° 2-theta.
Table 21
Figure imgf000043_0002
Figure imgf000044_0001
The amorphous (hemi) calcium salt of roxadustat (prepared according to Example 22) is characterized by the following diffraction peaks with the use of CuKα radiation: 3.6; 10.2 and 25.8 ± 0.5° 2-theta.
Differential scanning calorimetry (DSC) was used to measure the glass transition temperature of the amorphous hemi-calcium salt of roxadustat of 205°C.
The crystalline (hemi) magnesium salt of roxadustat (prepared according to Example 23) is characterized by the reflections presented in Table 22. Table 22 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline hemi-magnesium salt of roxadustat according to the present invention with the use of CuKα radiation are: 8.1; 12.0; 14.0; 18.6; 25.5 and 28.0 ± 0.2° 2-theta. Table 22
Figure imgf000045_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of the crystalline hemi-magnesium salt of roxadustat of 85°C.
The amorphous (hemi) magnesium salt of roxadustat (prepared according to Example 24) is characterized by the following diffraction peaks with the use of CuKα radiation: 2.5; 5.2; 7.5; 12.0 and 25.4 ± 0.5° 2-theta. Differential scanning calorimetry (DSC) was used to measure the glass transition temperatute of the amorphous hemi-magnesium salt of roxadustat of 62°C.
The semicrystalline iron (ΠΓ) salt of roxadustat (prepared according to Example 25) is characterized by the reflections presented in Table 23. Table 23 comprises reflections whose relative intensity value is higher than 1%. The semicrystalline form of the iron (III) salt of roxadustat is characterized by a diffraction peak with the use of CuKα radiation of 6.5 ± 0.2 °2-theta and amorphous halo with the band maximum of 22.0° ± 1.0° 2-theta.
Table 23
Figure imgf000046_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of the crystalline iron (III) salt of roxadustat of 183°C.
The amorphous (hemi) iron (II) salt of roxadustat (prepared according to Example 26) is characterized by an amorphous halo in the range of 4.5 to 21.0 ± 0.5° 2-theta.
Differential scanning calorimetry (DSC) was used to measure the glass transition temperature of the amorphous (hemi) iron (II) salt of roxadustat of 60°C.
Roxadustat napsylate in the form of crystalline modification I (prepared according to Example 27) is characterized by the reflections presented in Table 24. Table 24 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of crystalline roxadustat napsylate of form I according to the present invention with the use of CuKα radiation are: 6.6; 10.1; 18.2; 21.7; 25.2 and 27.8 ± 0.2° 2-theta.
Table 24
Figure imgf000046_0002
Figure imgf000047_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of crystalline roxadustat napsylate of form I of 147°C.
Roxadustat napsylate in the form of crystalline modification II (prepared according to Example 28) is characterized by the reflections presented in Table 25. Table 25 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of crystalline roxadustat napsylate of form II according to the present invention with the use of CuKα radiation are: 6.4; 9.9; 13.5; 19.8; 22.0 and 26.5 ± 0.2° 2-theta.
Table 25
Figure imgf000047_0002
Figure imgf000048_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of crystalline roxadustat napsylate of form II of 142°C.
Crystalline roxadustat besylate (prepared according to Example 29) is characterized by the reflections presented in Table 26. Table 26 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of crystalline roxadustat besylate according to the present invention with the use of CuKα radiation are: 6.6; 10.5; 13.4; 20.2; 23.2; 26.1 and 28.3 ± 0.2° 2-theta.
Table 26
Figure imgf000048_0002
Figure imgf000049_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of crystalline roxadustat besylate of 155°C. Roxadustat tosylate in the form of crystalline modification I (prepared according to Example 30) is characterized by the reflections presented in Table 27. Table 27 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of crystalline roxadustat tosylate of form I according to the present invention with the use of CuKα radiation are: 5.7; 11.7; 15.8; 18.4; 21.9 and 26.0 ± 0.2° 2-theta.
Table 27
Figure imgf000049_0002
Figure imgf000050_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of crystalline roxadustat tosylate of form I of 150°C.
Roxadustat tosylate in the form of crystalline modification II (prepared according to Example 31) is characterized by the reflections presented in Table 28. Table 28 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of crystalline roxadustat tosylate of form II according to the present invention with the use of CuKα radiation are: 5.8; 9.9; 14.1; 19.8; 22.0 and 26.8 ± 0.2° 2-theta.
Table 28
Figure imgf000050_0002
Figure imgf000051_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of crystalline roxadustat tosylate of form II of 149°C.
Roxadustat tosylate in the form of crystalline modification III (prepared according to Example 32) is characterized by the reflections presented in Table 29. Table 29 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of crystalline roxadustat tosylate of form III according to the present invention with the use of CuKα radiation are: 6.3; 10.9; 12.9; 17.3; 19.3 and 25.4 ± 0,2° 2-theta.
Table 29
Figure imgf000051_0002
Figure imgf000052_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of crystalline roxadustat tosylate of form III of 183°C.
Crystalline 3-ethyl-l-methyl-lH-imidazol-3-ium roxadustat (prepared according to Example 33) is characterized by the reflections presented in Table 30. Table 30 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of crystalline 3-ethyl-l-methyl-lH-imidazol-3-ium roxadustat according to the present invention with the use of CuKα radiation are: 5.1; 11.2; 15.6; 20.8; 23.1 and 25.7 ± 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 9.8; 14.3; 17.2; 20.0 and 28.6 ± 0.2° 2-theta. Table 30
Figure imgf000053_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of crystalline 3-ethyl-l -methyl- lH-imidazol-3-ium roxadustat of 160°C. A crystalline caffeine cocrystal of roxadustat of form I (prepared according to Example 34) is characterized by the reflections presented in Table 31. Table 31 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline caffeine cocrystal of roxadustat of form I according to the present invention with the use of CuKα radiation are: 8.2; 10.1; 13.1; 16.7; 19.7 and 26.0 ± 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 9.6; 12.1; 17.4; 22.6 and 28.0 ± 0.2° 2-theta.
Table 31
Figure imgf000054_0001
Figure imgf000055_0002
Differential scanning calorimetry (DSC) was used to measure the melting point of the crystalline caffeine cocrystal of roxadustat of form I of 177.2°C. A crystalline caffeine cocrystal of roxadustat of form II (prepared according to Example 35) is characterized by the reflections presented in Table 32. Table 32 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline caffeine cocrystal of roxadustat of form II according to the present invention with the use of CuKα radiation are: 7.8; 10.1; 12.8; 15.7; 19.4 and 26.0 ± 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 11.3; 18.4; 23.2 and 27.2 ± 0.2° 2-theta.
Table 32
Figure imgf000055_0001
Figure imgf000056_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of the crystalline caffeine cocrystal of roxadustat of form I of 178.0°C. A crystalline caffeine cocrystal of roxadustat of form III (prepared according to Example 36) is characterized by the reflections presented in Table 33. Table 33 comprises reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of the crystalline caffeine cocrystal of roxadustat of form III according to the present invention with the use of CuKα radiation are: 10.0; 11.8; 16.8; 20.1 and 26.6 ± 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 14.8; 18.0; 21.4 and 24.9 ± 0.2° 2-theta.
Figure imgf000057_0001
Figure imgf000058_0001
Differential scanning calorimetry (DSC) was used to measure the melting point of the crystalline caffeine cocrystal of roxadustat of form III of 175.3°C. The prepared solid forms of the salts of roxadustat according to the present invention can be used for the preparation of pharmaceutical compositions, especially solid drug forms, e.g. tablets or capsules. Such pharmaceutical compositions can comprise at least one excipient from the group of fillers (e.g. lactose), binders (e.g. macrocrystalline cellulose), disintegrants (e.g. sodium salt of croscarmellose), lubricants (e.g. magnesium stearate), surfactants etc. A salt or cocrystal of roxadustat can be mixed with the above-mentioned excipients, screened through a sieve and the final mixture can be tabletted or filled into capsules. The tablets can be further coated with conventional layers of e.g. polyvinyl alcohol or polyethylene glycol.
The invention is clarified in more detail in the embodiment examples below. These examples, which illustrate preparation of solid forms of roxadustat, exclusively have an illustrative character and do not restrict the scope of the invention in any respect.
Experimental part
List of abbreviations
Figure imgf000058_0002
Figure imgf000059_0001
X-ray powder diffraction
The diffractograms were obtained by means of a powder XTERT PRO MPD PANalytical diffractometer, used radiation CuKα (λ = 1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 2Θ, increment: 0.01° 2Θ at the reflection dwell time of 0.5 s, the measurement was carried out on a flat sample with the area/thickness of 10/0.5 mm. For the correction of the primary array, 0.02 rad Soller slits, a 10 mm mask and a 1/4° fixed anti- dispersion slit were used. The irradiated area of a sample is 10 mm, programmable divergency slits were used. For the correction of the secondary array, 0.02 rad Soller slits and a 5.0 mm anti-dispersion slit were used.
Differential scanning calorimetry (DSC)
The records of differential scanning calorimetry (DSC) were measured with a Discovery DSC device made by TA Instruments. The charge of the sample in a standard Al pot (40 μί) was between 3 5 mg and the heating rate was 5°C/min. The used temperature program consists of 1 stabilization minute at 0°C and then of heating up to 250°C at the heating rate of 5°C/rnin (amplitude = 0.8°C and period = 60 s). 5.0 N2 was used as the carrier gas at the flow of 50 ml/min. Forms I, II, III of the caffeine cocrystal of roxadustat were measured using a DSC Pyris 1 device made by Perkin Elmer. The charge of the sample in a standard Al pot was 2-3 mg and the heating rate was 10°C/min. The used temperature program consists of 1 stabilization minute at 0°C and then of heating up to 250°C at the heating rate of 10°C/min. As the carrier gas, 4.0 N2 was used at the flow of 20 ml / min. Ultra high performance liquid chromatography (UHPLC)
Chemicals: acetonitrile Rl
Water for chromatography R
Ammonium dihydrogen phosphate R
Phosphoric acid size: length = 100 mm, inner diameter 4.6 mm
stationary phase: Ascentis Express Phenyl-Hexyl, 100x4.6 mm; 2.7μιη (Supelco) temperature: 30°C
Mobile phase: A: 10 mM phosphate buffer - pH 2.5
B: acetonitrile R
elution: gradient
Figure imgf000060_0001
Flow rate: 1.0 mL/min
Detection: spectrophotometer at 220
sprayed quantity: 1.0 μl
sample temperature: 10°C
duration: 10 min
Nuclear magnetic resonance (NMR)
For the structural characterization, spectroscopies 1H NMR at 500 MHz and 13C NMR at 125.8 MHz were used. The measurements were carried out at the temperature of 298 K using a Bruker Avance 500 spectrometer made by Bruker. Deuterated <i6-dimethylsulfoxide was used as the solvent.
Infrared spectroscopy (IR)
IR spectra were measured on a Nicolet 6700 FTIR spectrometer (Thermo, USA) using the single-reflection ATR technique (ZnSe). Each spectrum was accumulated with 12 scans with the resolution of 4 cm"1. The spectra were collected and processed by the Opus 8.2 software (Thermo, USA). Thermogravimetry (TGA)
The records of thermogravimetric analysis were measured using a TGA 6 device made by Perking Elmer. The charge of the sample in a corundum pot was 13-20 mg and the heating rate was 10°C/min. The used temperature program consists of 1 stabilization minute at 15°C and then of heating up to 300°C at the heating rate of 10°C/min. As the carrier gas, 4.0 N2 was used at the flow of 20 ml / min.
Examples
Roxadustat free acid (crystalline form A) was prepared in accordance with the procedure disclosed in the patent application WO 2004/108681, or in accordance with the procedure disclosed in the patent application WO 2014/014835.
The sodium salt of roxadustat was prepared in accordance with the procedure disclosed in the patent application WO 2014/014835.
Example 1
Preparation of a crystalline form of roxadustat meglumine salt
Roxadustat (40 mg, form A) was dissolved in THF (1 ml) at 50°C. Meglumine (1.1 equivalents in the form of a solution of 25 mg of meglumine in 1 ml of water) was added to the solution and the solution was stirred for 20 min at 50°C. The solution was subsequently left to cool down freely to 25°C and stirred at this temperature in an open vial. The solid fraction was filtered, washed with water and dried for 0.5 h at the temperature of 45°C in vacuum. The product was isolated in the yield of 86% (53 mg) in the form of white powder. An IR measurement confirmed formation of a salt. The ratio of roxadustat:meglumine = 1:1 was determined by means of NMR. 1H-NMR (500 MHz, DMSO-d6): 8.78 (1H, t, J= 4.5 Hz, NH), 8.30 (1Η, d, J= 9.1 Hz, ArH), 7.63 (1H, s, ATH), 7.54 (1H, d, J = 9.1 Hz, ArH), 7.49 (2H, t, J = 7.7 Hz, ArH), 7.26 (1H, t, J = 7.3 Hz, ArH), 7.19 (2Η, d, J = 8.0 Hz, ArH), 5.81 (2Η, br. s), 4.73 (1Η, br. s, OH), 3.87 (1Η, m, CH), 3.73 (2Η, d, J = 4.5 Hz, CH2), 3.68 (1Η, d, J = 4.9 Hz, CH), 3.60 (1Η, dd, J = 10.8, 2.7 Hz, CHaHb), 3.50 (1H, m, CH), 3.44 (1Η, d, J = 8.8 Hz, CH), 3.41 (1Η, dd, J = 10.8, 5.6 Hz, CHaHb), 2.99 (1Η, dd, J = 12.3, 2.7 Hz, CHcHd), 2.89 (1Η, dd, J = 12.3, 9.1 Hz, CHcHd), 2.70 (3H, s, CHs), 2.51 (3Η, s, CH3).
13C NMR (125 MHz, DMSO-d6): 170.84, 168.68, 157.58, 155.59, 152.70, 146.59, 131.25, 130.35, 125.17, 124.47, 123.66, 122.39, 119.77, 119.43, 112.19, 71.24, 70.31(2x), 68.78, 63.39, 51.24, 42.81, 33.36, 21.55.
The X-ray powder pattern is shown in Fig. 1, the DSC record is shown in Fig. 2, Tt = 181°C
Example 2
Preparation of the crystalline hemi N,N -dibenzylethylenediammonium salt of roxadustat of form I
Roxadustat (10 mg, form A) was dissolved in THF and the solvent was evaporated in a vacuum drier at 25°C. Then, N,N'-dibenzylethylenediamine was added in the form of a solution in methanol (1 equivalent, 341 μl of a stock solution at the concentration of 0.0832M) and the solvent was evaporated again in a vacuum drier at the temperature of 25°C. 1 ml of a solvent (acetone or acetonitrile) was added to the prepared mixture and the mixture was stirred up until a solution was obtained. The solution was subsequently left to crystallize for 20 h at 7- 8°C. Then, the solvent was evaporated using a nitrogen stream for 48 h at the temperature of 25°C and subsequently for 22 h at the temperature of 25°C in vacuum. An ER measurement confirmed formation of a salt.
The X-ray powder pattern is shown in Fig. 3, the DSC record is shown in Fig. 4, Tt = 126°C.
Example 3
Preparation of the crystalline hemi N,N -dibenzylethylenediammonium salt of roxadustat of form II
Roxadustat (0.50 g, form A) was dissolved in THF (15 ml) and subsequently, N,N'- dibenzylethylenediamine (1.1 equivalents, 0.37 ml) was added. The solution was concentrated to approx. 2/3 of its volume and left to crystallize under stirring for 20 h at 25°C. The crystalline product was aspirated, washed with a minimal quantity of THF and dried at the temperature of 45°C for 20 h in vacuum. Form II was obtained in the yield of 0.44 g (66%). The ratio of roxadustat: NN'-dibenzylethylenediamine = 2:1 was determined by means of NMR.
1H-NMR (500 MHz, DMSO-d6): 8.94 (1H, t, J= 5.0 Hz, NH), 8.30 (1H, d, J= 9.0 Hz, ArH), 7.62 (1Η, d, J = 2.1 Hz, ArH), 7.54 (1Η, dd, J = 9.0, 2.1 Hz, ArH), 7.49 (2Η, t, J = 7.7 Hz, ArH), 7.41 (2Η, d, J = 7.3 Hz, ArH), 7.34 (2Η, t, J = 7.3 Hz, ArH), 7.29 (1Η, t, J = 7.3 Hz, ArH), 7.26 (1Η, t, J = 7.7 Hz, ArH), 7.19 (2Η, d, J = 8.0 Hz, ArH), 3.89 (2Η, d, J = 5.4 Hz, CH2), 3.88 (2Η, s, CH2), 2.84 (2Η, s, CH2), 2.70 (3Η, s, CH3).
13C NMR (125 MHz, DMSO-d6): 170.75, 169.20, 157.65, 155.56, 152.78, 146.66, 137.06, 131.30, 130.35, 128.76, 128.28, 127.47, 125.20, 124.49, 123.60, 122.39, 119.62, 119.44, 112.15, 51.36, 45.43, 41.86, 21.50.
The X-ray powder pattern is shown in Fig. 5, the DSC record is shown in Fig. 6, Tt = 115°C. Example 4
Preparation of the crystalline tert-butylammonium salt of roxadustat of form I
Roxadustat (0.10 g, form A), which had been dissolved in a minimal quantity of THF (1.3 ml), was dosed into a flask and subsequently, tert-butylamine (1.3 equivalents, 0.038 ml) was added. The solution was left to crystallize under stirring for 20 h at 25°C. The crystalline product was aspirated on frit, washed with a minimal quantity of THF (2 x 1 ml) and dried at the temperature of 45°C for 18 h in vacuum. The product was obtained in the yield of 0.11 g (94%). Ratio of roxadustat: tert-butylamine = 1.1, contents of solvents: 0.09 molar equivalents of THF, determined by means of NMR.
1H-NMR (500 MHz, DMSO-d6): 9.40 (3H, br. s, NH3 +), 8.75 (1H, t, J = 4.5 Hz, NH), 8.28 (1H, d, J = 9.0 Hz, ArH), 7.61 (1H, d, J = 2.2 Hz, ArH), 7.52 (1H, dd, J = 9.0, 2.2 Hz, ArH), 7.47 (2H, t, J = 7.7 Hz, ArH), 7.25 (1H, t, J = 7.4 Hz, ArH), 7.17 (2H, d, J = 8.0 Hz, ArH), 3.64 (2H, d, J = 4.5 Hz, CH2), 2.68 (3H, s, CH3), 1.26 (9H, s, C(CH3)3).
13C NMR (125 MHz, DMSO-d6): 169.94, 168.47, 157.53, 155.63, 152.67, 146.51, 131.22, 130.36, 125.16, 124.47, 123.69, 122.38, 119.86, 119.41, 112.20, 50.40, 43.23, 27.39, 21.58. The X-ray powder pattern is shown in Fig. 7, the DSC record is shown in Fig. 8, Tt = 159°C. Example 5
Preparation of the crystalline tert-butylammonium salt of roxadustat of form II
Roxadustat (1.00 g, form A), which had been dissolved in a rninimal quantity of THF (13 ml), was dosed into a flask and subsequently, tert-butylamine (1.3 equivalents, 0.38 ml) was added. The solution was left to crystallize under stirring for 20 h at 25°C. The reaction mixture almost solidified overnight. The crystalline product was stirred up and aspirated on frit, washed with a minimal quantity of ACN (2 x 3 ml) and dried at the temperature of 40°C for 18 h in vacuum. Form II of the tert-butylammonium salt of roxadustat was obtained with the purity of 99.2% in the yield of 1.07 g (89%). The NMR record was equal to form I. Ratio of roxadustatrtert- butylamine = 1:1, contents of residual solvents: 0.13 molar equivalents of ACN, determined by means of NMR.
The X-ray powder pattern is shown in Fig. 9, the DSC record is shown in Fig. 10, Tt = 169°C. Example 6
Preparation of the crystalline diethylammonium salt of roxadustat
Roxadustat (0.20 g, form A), which had been dissolved in a minimal quantity of THF (2.6 ml), was dosed into a flask and subsequently, diethylamine (1.3 equivalents, 0.076 ml) was added. The solution was left to crystallize under intensive stirring for 20 h at 25°C. The crystalline product was aspirated on frit, washed with a minimal quantity of THF (2 x 2 ml) and dried at the temperature of 40°C for 18 h in vacuum. The diethylammonium salt of roxadustat was obtained with the purity of 99.9% in the yield of 0.18 g (73%). The NMR record corresponds to the structure. Ratio of roxadustat:diethylamine = 1:1, contents of residual solvents: 0.01 molar equivalents of THF, determined by means of NMR.
1H-NMR (500 MHz, DMSO-d6): 10.73 (2H, br. s, NH2 +), 8.76 (1H, t, J= 4.8 Hz, NH), 8.28 (1Η, d, J = 9.0 Hz, AiH), 7.61 (1H, d, J= 2.2 Hz, AiH), 7.52 (1H, dd, J = 9.0, 2.2 Hz, ArH), 7.47 (2Η, t, J = 7.7 Hz, ArH), 7.25 (1Η, t, J = 7.4 Hz, ArH), 7.18 (2Η, d, J = 8.0 Hz, ArH), 3.68 (2Η, d, J= 4.8 Hz, CH2), 2.87 (4Η, q, J= 7.3 Hz, 2xCH2), 2.69 (3Η, s, CH3), 1.17 (6Η, t, J= 7.3 Hz, 2xCH3).
13C NMR (125 MHz, DMSO-d6): 170.43, 168.58, 157.56, 155.61, 152.68, 146.55, 131.24, 130.35, 125.16, 124.47, 123.67, 122.39, 119.81, 119.42, 112.20, 42.97, 41.16, 21.56, 11.33. The X-ray powder pattern is shown in Fig. 11, the DSC record is shown in Fig. 12, Tt = 183°C. Example 7
Preparation of the crystalline dicyclohexylammomum salt of roxadustat of form I
Roxadustat (0.10 g, form A), which had been dissolved in a minimal quantity of THF (1.3 ml), was dosed into a flask and subsequently, dicyclohexylamine (1.3 equivalents, 0.073 ml) was added. The solution was left to crystallize under stirring for 20 h at 25°C. The crystalline product was aspirated on frit, washed with a minimal quantity of THF (2 x 1 ml) and dried at 45°C for 24 h in vacuum. The product was obtained in the yield of 0.14 g (92%). Ratio of APLdicyclohexylamine = 1:1, contents of solvents: 1 molar equivalent of THF, determined by means of NMR.
1H-NMR (500 MHz, DMSO-d6): 8.77 (1H, br. s, NH), 8.29 (1Η, d, J = 8.9 Hz, ArH), 7.61 (1Η, s, ArH), 7.52 (1Η, d, J= 8.9 Hz, ArH), 7.47 (2Η, t, J= 7.7 Hz, ArH), 7.25 (1Η, t, J= 7.4 Hz, ArH), 7.18 (2Η, d, J = 8.0 Hz, ArH), 3.68 (2Η, d, J = 4.7 Hz, CH2), 2.99 (2Η, m, 2xCH), 2.69 (3Η, s, CH3), 1.99 (4Η, m, 2xCH2), 1.73 (4Η, m, 2xCH2), 1.59 (2Η, m, CH?), 1.28 (8Η, m, 4xCH2), 1.09 (2Η, m, CH2).
13C NMR (125 MHz, DMSO-d6): 169.73, 168.59, 157.55, 155.61, 152.68, 146.55, 131.23, 130.35, 125.17, 124.47, 123.67, 122.39, 119.83, 119.42, 112.21, 51.86, 42.99, 29.43, 25.00, 24.08, 21.56.
The X-ray powder pattern is shown in Fig. 13, the DSC record of the THF solvate of the dicyclohexylammonium salt of roxadustat is shown in Fig. 14, Tt= 190°C.
Example 8
Preparation of the crystalline dicyclohexylammonium salt of roxadustat of form H
Roxadustat (0.20 g, form A), which had been dissolved in a minimal quantity of THF (2.6 ml), was dosed into a flask and subsequently, dicyclohexylamine (1.3 equivalents, 0.146 ml) was added. The solution was left to crystallize under stirring for 18 h at 25°C. The crystalline product was aspirated on frit, washed with a minimal quantity of THF (2 ml), water (2 ml), vacuum-dried for 12 h at the temperature of 45°C and subsequently for 24 h at 80°C. The dicyclohexylammonium salt, form II was obtained with the purity of 99.5% in the yield of 0.30 g (99%). The NMR record was equal to form I. Ratio of roxadustat:dicyclohexylamine = 1:1, contents of residual solvents: 0.13 molar equivalents of THF, determined by means of NMR.
The X-ray powder pattern is shown in Fig. 15, the DSC record is shown in Fig. 16, Tt = 189°C. Example 9
Preparation of the crystalline ammonium salt of roxadustat of form I
Roxadustat (1.0 g, form A) was suspended in a mixture of solvents (acetomtrile:water=35:65) at the temperature of 50°C. An aqueous solution of ammonia (25%, 0.44 ml) was added to the mixture by dripping. The solution was further stirred at the temperature of 25°C for 20 h and then concentrated to 1/2 of the original volume. The yellow suspension was filtered and washed with a minimal quantity of water. An IR measurement confirmed formation of a salt. 7.4% content of water was determined by means of thermogravimetry (theoretical dihydrate: 8.9%). The ratio of roxadustat: ammonia = approx. 1 :1 was determined by means of NMR.
1H-NMR (500 MHz, DMSO-d6): 8.77 (IH, br. s, NH), 8.46 (4Η, br. s, NH4+), 8.28 (IH, d, J = 9.0 Hz, ArH), 7.61 (1Η, d, J= 2.2 Hz, ArH), 7.52 (1Η, dd, J= 9.0, 2.2 Hz, ArH), 7.47 (2Η, t, J= 7.7 Hz, ArH), 7.25 (1Η, t, J= 7.4 Hz, ArH), 7.17 (2Η, d, J= 8.0 Hz, ArH), 3.64 (2Η, d, J = 3.8 Hz, CH2), 2.68 (3Η, s, CH3).
13C NMR (125 MHz, DMSO-d6): 169.90, 168.52, 157.54, 155.63, 152.69, 146.53, 131.23, 130.36, 125.17, 124.47, 123.69, 122.38, 119.85, 119.42, 112.21, 43.12, 21.58.
The X-ray powder pattern is shown in Fig. 17, the DSC record is shown in Fig. 18, Tt = 159°C.
Example 10
Preparation of the crystalline ammonium salt of roxadustat of form II
Roxadustat (0.50 g, form A), which had been dissolved in a minimal quantity of THF (5.5 ml), was dosed into a flask and subsequently, aqueous ammonia (25% solution, 1.5 equivalents, 0.16 ml) was added. The product precipitated immediately after the addition. The mixture was stirred for 2 h at the temperature of 25°C. The crystalline product was aspirated on frit, washed with a minimal quantity of THF (2 x 2,5 ml) and dried at the temperature of 45 °C for 18 h in vacuum. Form II was obtained in the yield of 0.35 g (66%). Ratio of roxadustat:ammonia = approx. 1:1, contents of solvents: 0.08 molar equivalents of THF, determined by means of NMR. The NMR record corresponded to Example 9.
The X-ray powder pattern is shown in Fig. 19, the DSC record is shown in Fig. 20, Tt = 164°C. Example 11
Preparation of the crystalline lithium salt of roxadustat of form I
Roxadustat (1.0 g, form A), which had been dissolved in a mixture of ethanol and tetrahydrofuran in the ratio of 8:3 (total volume 30 ml), was dosed into a flask at the temperature of 80°C and subsequently, aqueous LiOH was added (1.5 equivalents, 0.102 g of LiOH dissolved in 3 ml of water). Then, the solution was left to freely cool down to the room temperature (25°C) and at this temperature it was stirred for another 48 hours. The crystalline product was aspirated on frit, washed with a minimal quantity cooled ethanol and dried freely at the temperature of 25°C. The product was obtained in the form of beige powder in the yield of 0.367 g (34%). An IR measurement confirmed formation of a salt.
The X-ray powder pattern is shown in Fig. 21, the DSC record is shown in Fig. 22, Tt = 125°C.
Example 12
Preparation of the crystalline lithium salt of roxadustat of form II
Roxadustat (1.0 g, form A), which had been dissolved in a mixture of acetone and tetrahydrofuran in the ratio of 8:2 (total volume 27 ml), was dosed into a flask at the temperature of 85°C and subsequently, aqueous LiOH was added (1.5 equivalents, 0.102 g of LiOH dissolved in 5 ml of water). Then, the solution was left to freely cool down to the room temperature (25 °C) and at this temperature it was stirred for another 48 hours. The crystalline product was aspirated on frit, washed with a minimal quantity of acetone and dried freely at the temperature of 25°C. The product was obtained in the form of beige powder in the yield of 0.484 g (47%). An IR measurement confirmed formation of a salt. 13.3% of water were measured by means of TGA.
The X-ray powder pattern is shown in Fig. 23, the DSC record is shown in Fig. 24, Tt = 226°C.
Example 13
Preparation of the crystalline lithium salt of roxadustat of form III
The lithium salt of roxadustat (0.1 g, form II from the previous example) was dried at 60°C in vacuum (200 mbar) for 22 hours. The product was obtained in the form of beige powder in the yield of 0.09 g (90%). 4.2% of water were measured by means of TGA. The X-ray powder pattern is shown in Fig. 25, the DSC record is shown in Fig. 26, Tt = 227°C.
Example 14
Preparation of the crystalline potassium salt of roxadustat of form I
Roxadustat (1.0 g, form A), which had been dissolved in acetone (66 ml) was dosed into a flask at the temperature of 50°C and subsequently, aqueous KOH was added (approx. 1.5 equivalents, 0.2 g of KOH dissolved in 6 ml of water). The product precipitated immediately after the addition. Then, the suspension was stirred at the temperature of 50°C for 17 h and for another 3 h at the temperature of 25°C. The crystalline product was aspirated on frit, washed with a minimal quantity of acetone and dried at a temperature of 35-40°C for 1 h in vacuum. The product in the form of yellow powder was obtained in the yield of 0.87 g (78%), chemical purity 99.5% (measured with UHPLC). The content of potassium was determined to be 8.6% by titration (10% theoretically). An IR measurement confirmed formation of a salt.
The X-ray powder pattern is shown in Fig. 27, the DSC record is shown in Fig. 28, Tt = 63°C.
Example 15
Preparation of the crystalline potassium salt of roxadustat of form II
The mother liquor of Example 11 (containing 3.80 g of the potassium salt of roxadustat) was concentrated on a vacuum evaporator and ethanol was added by dripping to the obtained aqueous solution. The final mixture was concentrated on a rotary vacuum evaporator and the suspension was filtered and washed with ethanol. The product in the form of green powder was obtained in the yield of 3.78 g (99%), chemical purity 99.0% (measured with UHPLC). The X-ray powder pattern is shown in Fig. 29, the DSC record is shown in Fig. 30, Tt = 288°C.
Example 16
Preparation of the crystalline potassium salt of roxadustat of form III
A potassium salt of roxadustat (0.15 g, form I), which had been dissolved in a methanolrwater mixture in the ratio of 9: 1 (5.55 ml), was dosed into a flask at the reflux temperature. Then, the solution was left to freely cool down to the room temperature (25 °C) and at this temperature it was further stirred for another 22 h. Then, the suspension was filtered through frit and washed with a minimal quantity of methanol. The obtained product in the form of intensively yellow powder was dried in vacuum for 2h (200 mbar) at the temperature of 45°C and the amount of
0.68 g of the product was obtained. TGA proved the presence of 8.8% of water.
The X-ray powder pattern is shown in Fig. 31, the DSC record is shown in Fig. 32, Tt =
308.3°C.
Example 17
Preparation of the crystalline potassium salt of roxadustat of form IV
A potassium salt of roxadustat (0.15 g, form I), which had been dissolved in an ethanol: water mixture in the ratio of 6:1 (5.8 ml), was dosed into a flask at the reflux temperature. Then, the solution was left to freely cool down to the room temperature (25°C) and at this temperature it was further stirred for another 22 h. Then, the suspension was filtered through frit and washed with a minimal quantity of ethanol. The obtained product in the form of yellowish powder was dried in vacuum for 2h (200 mbar) at the temperature of 45°C and the amount of 0.6 g of the product was obtained. TGA proved the presence of 8% of water.
The X-ray powder pattern is shown in Fig. 33, the DSC record is shown in Fig. 34, Tt = 120.5°C.
Example 18
Preparation of the crystalline hemi-calcium salt of roxadustat of form I
1.0 g of the sodium salt of roxadustat, which had been dissolved in methanol (125 ml), was dosed into a flask at the temperature of 55°C and subsequently, a solution of calcium chloride (0.35 g of CaCl2 in 3.3 ml of methanol) was added by dripping. The suspension was stirred, then filtered and the clear mother liquor was left to crystallize at the temperature of 25°C for 13 days. The product was isolated by filtration, washed with water and subsequently dried for 17 h at the temperature of 30°C in vacuum. The crystalline product was obtained in the form of greyish yellow powder in the yield of 0.25 g (26%). An IR measurement confirmed formation of a salt.
The X-ray powder pattern is shown in Fig. 35, the DSC record is shown in Fig. 36, Tt= 96°C. Example 19
Preparation of the crystalline hemi-calcium salt of roxadustat of form II
0.040 g of a sodium salt of roxadustat, which had been dissolved in methanol (5 ml), was dosed into a vial at the temperature of 50°C and subsequently, a solution of calcium chloride (0,008 g of CaCk in 0.3 ml of methanol) was added by dripping. The suspension was stirred for 48 h at the laboratory temperature and subsequently filtered. The crystalline product was obtained in the form of beige powder in the yield of 0.038 g. An IR measurement confirmed formation of a salt. The X-ray powder pattern is shown in Fig. 37.
Example 20
Preparation of the crystalline hemi-calcium salt of roxadustat of form III
The sodium salt of roxadustat (10 g) was dissolved at 50°C in a methanohwater mixture with the ratio of 1:1 (280 ml). During 45 min, a solution of calcium chloride (CaCl2-2H20, 0.6 equivalents, 2.36 g) in a methanohwater mixture with the ratio of 1:1 (100 ml) was added to this solution by dripping at the temperature of 50°C. The mixture was subsequently slowly cooled down to the laboratory temperature and stirred for 22 h. The product was isolated by filtration and washed with 100 ml of a methanol: water mixture with the ratio of 1 :1 and dried in a vacuum drier at the temperature of 45°C for 20 h. The crystalline product in the form of fine yellowish green powder was obtained in the yield of 6.4 g, chemical purity 99.74% (measured with UHPLC).
The X-ray powder pattern is shown in Fig. 38.
Example 21 Preparation of the crystalline hemi-calcium salt of roxadustat of form IV
1.0 g of the sodium salt of roxadustat, which had been dissolved in water (20 ml), was dosed into a flask at the temperature of 55°C and subsequently, a solution of calcium chloride (1.96 g of CaCl2 in 7 ml of water; 5 equivalents) was added by dripping during 45 minutes. The suspension was stirred at the room temperature (25°C) for 48 h. The product was isolated by filtration, washed thoroughly with water and subsequently dried for 22 h at the temperature of 45°C in vacuum (200 mbar). The crystalline product was obtained in the yield of 1.0 g (100%). A TGA measurement confirmed the presence of 12.4% of water.
The X-ray powder pattern is shown in Fig. 39. Example 22
Preparation of the amorphous hemi-calcium salt of roxadustat
1.0 g of the sodium salt of roxadustat, which had been dissolved in methanol (125 ml), was dosed into a flask at the temperature of 55°C and subsequently, a solution of calcium chloride (0.35 g of CaCl2 in 3.3 ml of methanol) was added by dripping. The product precipitated immediately after the addition. Then, the suspension was stirred at the temperature of 50°C for 17 h and for another 17 h at the temperature of 25°C. The product was aspirated on frit and dried at the temperature of 35°C in vacuum. The amorphous product was obtained in the form of fine yellowish powder in the yield of 0.46 g (46%). An IR measurement confirmed formation of a salt.
The X-ray powder pattern is shown in Fig. 40, the DSC record is shown in Fig. 41, Tg = 205°C.
Example 23
Preparation of the crystalline hemi-magnesium salt of roxadustat
1.0 g of the sodium salt of roxadustat, which had been dissolved in methanol (125 ml), was dosed into a flask at the temperature of 55°C and subsequently, a solution of magnesium chloride (0.64 g of MgCl2-6H20 in 3.3 ml of methanol) was added by dripping. Then, the suspension was stirred at the temperature of 50°C for 17 h and for another 17 h at the temperature of 25°C. The product was aspirated on frit and dried at the temperature of 35°C in vacuum. The product was obtained in the form of fine white powder in the yield of 0.81 g (84%). An IR measurement confirmed formation of a salt.
The X-ray powder pattern is shown in Fig. 42, the DSC record is shown in Fig. 43, Tt= 85°C. Example 24
Preparation of the amorphous hemi-magnesium salt of roxadustat
1.0 g of the sodium salt of roxadustat, which had been dissolved in methanol (125 ml), was dosed into a flask at the temperature of 55°C and subsequently, a solution of magnesium chloride (0.64 g of MgCl2-6H20 in 3.3 ml of methanol) was added by dripping. Further, the suspension was stirred at the temperature of 50°C for 17 h and for another 17 h at the temperature of 25°C. Then, the suspension was filtered and the clear mother liquor was left to crystallize at the temperature of 25°C for 7 days. Filtration provided the product in the form of fine brownish yellow powder in the yield of 0.18 g (19%). An IR measurement confirmed formation of a salt.
The X-ray powder pattern is shown in Fig. 44, the DSC record is shown in Fig. 45, Tg = 62°C. Example 25
Preparation of the crystalline iron (III) salt of roxadustat
0.040 g of a sodium salt of roxadustat, which had been dissolved in methanol (5 ml), was dosed into a vial at the temperature of 50°C and subsequently, a solution of iron (III) chloride (0.35 equivalents, 200 μl of 0.2M FeCl3 in MeTHF) and 0.1 ml of water were added by dripping. Further, the suspension was stirred at the temperature of 50°C for 1 h and for another 48 h at the temperature of 25°C. Then, the suspension was filtered and the crystalline product was dried in vacuum at the temperature of 25°C for at least 0.5 h. The product was obtained in the form of reddish black powder in the yield of 0.013 g (31%). An IR measurement confirmed formation of a salt.
The X-ray powder pattern is shown in Fig. 46, the DSC record is shown in Fig. 47, Tt = 183°C.
Example 26
Preparation of the amorphous hemi-iron (II) salt of roxadustat
0.040 g of a sodium salt of roxadustat, which had been dissolved in methanol (5 ml), was dosed into a vial at the temperature of 50°C and subsequently, a solution of iron (II) chloride (0.6 equivalents, 0,009 g FeCl2 in 0.4 ml of methanol and 0.1 ml of water) was added by dripping. Further, the suspension was stirred at the temperature of 50°C for 1 h and for another 48 h at the temperature of 25°C. Then, the suspension was filtered and the product was dried in vacuum at the temperature of 25°C for at least 0.5 h. The product was obtained in the form of black powder in the yield of 0.029 g (67%). An IR measurement confirmed formation of a salt.
The X-ray powder pattern is shown in Fig. 48, the DSC record is shown in Fig. 49, Tg = 60°C Example 27
Preparation of crystalline napsylate of roxadustat of form I
0.50 g of roxadustat of form A and 0.47 g of 2-naphtalenesulfonic acid (1.1 equivalents) were dosed into a flask. Subsequently, THF (15 ml) was added and the mixture was stirred for 0.5 h at the temperature of 50°C and the mixture was further stirred for another 17 h at the temperature of 25°C. Then, the suspension was filtered, washed with a minimal quantity of THF and the product was dried in vacuum at the temperature of 40°C for at least 0.5 h. The product was obtained in the form of white powder in the yield of 0.56 g (70%). An IR measurement confirmed formation of a salt. Ratio of roxadustat:2-naphtalenesulfonic acid = 1:1, contents of solvents: 0.45 molar equivalents ofTHF, determined by means ofNMR.
lH-NMR (500 MHz, DMSO-d6): 9.15 (1H, t, J= 6.1 Hz, NH), 8.32 (1H, d, J= 9.1 Hz, AiH), 8.15 (1H, s, ArH), 7.98 (1Η, m, ArH), 7.91 (1Η, m, ArH), 7.87 (1Η, d, J= 8.6 Hz, ArH), 7.72 (1H, dd, J = 8.5, 1.6 Hz, ArH), 7.64 (1Η, d, J = 2.3 Hz, ArH), 7.56 (1Η, dd, J = 9.1, 2.3 Hz, ArH), 7.53 (2Η, m, ArH), 7.49 (2Η, t, J = 8.0 Hz, ArH), 111 (1H, t, J = 7.5 Hz, ArH), 7.20 (2Η, d, J= 8.0 Hz, ArH), 4.06 (2Η, d, J= 6.1 Hz, CH2), 2.72 (3Η, s, CH3).
13C NMR (125 MHz, DMSO-d6): 170.76, 169.85, 157.80, 155.51, 152.91, 146.83, 145.62, 132.67, 132.12, 131.41, 130.38, 128.43, 127.42, 127.26, 126.38, 126.25, 125.28, 124.55, 123.98, 123.97, 123.57, 122.56, 119.48, 119.41, 112.17, 40.61, 21.44.
The X-ray powder pattern is shown in Fig. 50, the DSC record is shown in Fig. 51, Tt = 147°C.
Example 28
Preparation of crystalline napsylate of roxadustat of form II
70 mg of roxadustat napsylate of form I from the previous experiment were dosed into a Petri dish and dried in a vacuum drier at the temperature of 80°C for 24 h. This way, the solvent was removed from the sample (determined by means of NMR) and form II was prepared.
The X-ray powder pattern of roxadustat napsylate of form II is shown in Fig. 52, the DSC record is shown in Fig. 53; this is a non-solvated form with the melting point of 142°C.
Example 29
Preparation of crystalline besylate of roxadustat
0.50 g of roxadustat of form A and 0.25 g of benzenesulfonic acid (1.1 equivalents) were dosed into a flask. Subsequently, THF (15 ml) was added and the mixture was stirred for 0.5 h at the temperature of 50°C and another 48 h at the temperature of 25°C. Then, the suspension was filtered, washed with a minimal quantity of THF and the product was dried in vacuum at the temperature of 45°C for 20 h. The product was obtained in the form of white powder in the yield of 0.64 g (88%). An IR measurement confirmed formation of a salt. Ratio of roxadustatbenzenesulfonic acid = 1:1, determined by means of NMR.
1H-NMR (500 MHz, DMSO-d6): 9.14 (1H, t, J= 6.1 Hz, NH), 8.32 (1H, d, J= 9.2 Hz, ArH), 7.64 (1H, d, J = 2.2 Hz, ArH), 7.61 (2Η, dd, J = 7.6, 2.1 Hz, ArH), 7.55 (1H, dd, J= 9.2, 2.2 Hz, ArH), 7.49 (2Η, t, J = 7.5 Hz, ArH), 7.33 (3Η, m, ArH), 7.27 (1Η, t, J = 7.5 Hz, ArH), 7.19 (2Η, d, J= 7.8 Hz, ArH), 4.06 (2Η, d, J= 6.1 Hz, CH2), 2.72 (3Η, s, CH3).
13C NMR (125 MHz, DMSO-d6): 170.75, 169.80, 157.79, 155.50, 152.89, 148.19, 146.83, 131.39, 130.37, 128.42, 127.62, 125.44, 125.27, 124.55, 123.57, 122.46, 119.48, 119.39, 112.15, 40.61, 21.41.
The X-ray powder pattern is shown in Fig. 54, the DSC record is shown in Fig. 55, Tt = 155°C.
Example 30
Preparation of crystalline tosylate of roxadustat of form I 0.200 g of roxadustat of form A and 0.108 g of p-toluenesulfonic acid (1.1 equivalents) were dosed into a flask. Subsequently, THF (6 ml) was added and the mixture was stirred for 0.5 h at the temperature of 50°C and another 17 h at the temperature of 25°C. Then, the suspension was filtered and washed with a minimal quantity of THF. The product was obtained in the form of white powder in the yield of 0.205 g (69%). An IR measurement confirmed formation of a salt. Ratio of roxadustat:p-toluenesulfonic acid = 1 :1, contents of solvents: 0.6 molar equivalents of THF, determined by means of NMR.
1H-NMR (500 MHz, DMSO-d6): 9.15 (1H, t, J= 6.2 Hz, NH), 8.32 (1Η, d, J= 9.1 Hz, ArH), 7.64 (1Η, d, J = 2.2 Hz, ArH), 7.55 (1Η, dd, J = 9.0, 2.2 Hz, ArH), 7.49 (2Η, t, J= 7.5 Hz, ArH), 7.48 (2Η, d, J = 7.9 Hz, ArH), 7.27 (1Η, t, J = 7.3 Hz, ArH), 7.19 (2Η, d, J= 7.9 Hz, ArH), 7.13 (2Η, d, J = 7.9 Hz, ArH), 4.06 (2Η, d, J = 6.2 Hz, CH2), 2.72 (3Η, s, CH3), 2.30 (3Η, s, CH3).
13C NMR (125 MHz, DMSO-d6): 170.75, 169.85, 157.80, 155.51, 152.90, 146.83, 145.74, 137.54, 131.41, 130.38, 128.01, 125.46, 125.28, 124.55, 123.56, 122.46, 119.48, 119.41,0020112.17, 40.61, 21.44, 20.75.
The X-ray powder pattern is shown in Fig. 56, the DSC record is shown in Fig. 57; this is a solvate with the melting point of 150°C. Example 31
Preparation of crystalline tosylate of roxadustat of form II
70 mg of roxadustat tosylate of form I from the previous experiment were dosed into a Petri dish and dried in a vacuum drier at the temperature of 80°C for 24 h. This way, the solvent was removed from the sample (determined by means of NMR) and form II was prepared.
The X-ray powder pattern of roxadustat tosylate of form II is shown in Fig. 58, the DSC record is shown in Fig. 59; this is a non-solvated form with the melting point of 149°C.
Example 32
Preparation of crystalline tosylate of roxadustat of form III
50 mg of roxadustat tosylate of form I was loaded to the temperature of 188°C. Form III was prepared this way.
The X-ray powder pattern of roxadustat tosylate of form III is shown in Fig. 60, the DSC record is shown in Fig. 61; this is a non-solvated form with the melting point of 183°C.
Example 33
Preparation of crystalline 3-ethyl-l-methyl-lH-imidazol-3-ium roxadustat
1.0 g of roxadustat of form A was dosed into a flask and dissolved in 30 ml of THF. Subsequently, during 20 minutes, a solution of 3 -ethyl- 1 -methyl- lH-imidazol-3-ium acetate in dichloromethane (30 ml) was added by dripping and the mixture was stirred for 22 h at the room temperature (25°C). After evaporation of approximately a half of the reaction mixture volume, the suspension was filtered and washed with a minimal quantity of THF. The product was obtained in the form of white powder in the yield of 0.59 g (51%) and with 99.8% purity (determined by means of UHPLC). An IR measurement confirmed formation of a salt. Ratio of roxadustate: 3 -ethyl- 1 -methyl- lH-imidazol-3-ium = 2:1, contents of solvents: 0.05 molar equivalents of THF and 0.05 molar equivalents of dichloromethane, determined by means of NMR.
1H-NMR (500 MHz, DMSO-d6): 9.16 (0.5H, s, AiH), 8.90 (1H, t, J= 4.8 Hz, NH), 8.29 (1H, d, J = 9.2 Hz, ArH), 7.77 (0.5 H, t, J = 1.8 Hz, ArH), 7.69 (0.5 Η, t, J = 1.8 Hz, AiH), 7.61 (1H, d, J= 2.3 Hz, ArH), 7.52 (1Η, dd, J= 9.0, 2.4 Hz, ArH), 7.48 (2Η, -t, J = 7.4 Hz, ArH), 7.25 (1Η, ~t, J= 7.4 Hz, ArH), 7.18 (2Η, ~d, J= 8.6 Hz, ArH), 4.18 (1Η, q, J= 7.2 Hz, CH2), 3.84 (1.5H, s, CH3), 3.81 (2Η, d, J= 5.2 Hz, CH2), 2.69 (3Η, s, CH3), 1.40 (1.5Η, t, CH3). 13C NMR (125 MHz, DMSO-d6): 169.95, 169.06, 157.64, 155.60, 152.75, 146.67, 136.32, 131.30, 130.37, 125.21, 124.50, 123.64, 123.57, 122.40, 121.97, 119.71, 119.46, 112.18, 44.10, 42.13, 35.68, 21.53, 15.11.
A TGA measurement confirmed the presence of 2,2% of water.
The X-ray powder pattern of 3 -ethyl- 1 -methyl- lH-imidazol-3-ium roxadustat is shown in Fig. 62, the DSC record is shown in Fig. 63; this is a crystalline form with the melting point of 160°C.
Example 34
Preparation of a crystalline form of the caffeine cocrystal of roxadustat of form I
Roxadustat (0.060 g, purity 99.55%) and caffeine (0.0363 g, 1.1 equiv.) were dosed into a flask and then suspended in acetone (5 ml). The reaction mixture was heated up to reflux, which caused its caused its complete dissolution. The mixture was stirred for 2 h without the access of light, subsequently it was left to freely cool down to the laboratory temperature and it was continuously inoculated with form I until the seeds ceased to dissolved (45°C). Crystals started to be separated at 37°C. The mixture was stirred for 22 hours at the room temperature (25°C). Then, the crystals were aspirated on frit, washed with acetone (2x1 ml) and freely air- dried. This way, the amount of 0.054 g (58%) of the product was obtained with the purity of 99.87%. Ratio of roxadustat:caffeine = 1:1, determined by means of NMR.
1H-NMR (500 MHz, DMSO-d6): 13.31 (1H, s, COOH), 9.11 (1H, t, J= 6.4 Hz, NH), 8.29 (1H, d, J = 9.1 Hz, ArH), 7.99 (1Η, s, ArH), 7.62 (1Η, d, J= 2.2 Hz, ArH), 7.53 (1Η, dd, J = 9.1, 2.2 Hz, ArH), 7.48 (2Η, t, J= 7.9 Hz, ArH), 7.25 (1Η, t, J = 7.4 Hz, ArH), 7.18 (2Η, d, J = 7.9 Hz, ArH), 4.05 (2Η, d, J= 6.1 Hz, CH2), 3.87 (3Η, s, CH3), 3.40 (3Η, s, CH3), 3.21 (3Η, s, CH3), 2.70 (3Η, s, CH3) 13C NMR (125 MHz, DMSO-d6): 170.80, 169.95, 157.83, 155.55, 154.59, 152.84, 151.08, 148.14, 146.94, 142.81, 131.44, 130.42, 125.28, 124.59, 123.51, 122.45, 119.53, 119.49, 112.16, 106.65, 40.66, 33.15, 29.40, 27.50, 21.53.
A TGA measurement did not confirm the presence of water or other solvents.
The X-ray powder pattern of the caffeine cocrystal of roxadustat of form I is shown in Fig. 64, the DSC record is shown in Fig. 65; this is a crystalline form with the melting point of 177.2°C. Example 35
Preparation of a crystalline form of the caffeine cocrystal of roxadustat of form II
Roxadustat (10 g, purity 99.55%) and caffeine (6.06 g, 1.1 equiv.) were dosed into a flask and then suspended in acetone (120 ml). The reaction mixture was stirred for 22 hours without the access of light at the room temperature (25 °C). Then, the crystals were aspirated on frit, washed with acetone (5 ml) and dried at 45°C in vacuum (200 mbar) for 18 hours. This way, the amount of 14.46 g (93%) of the product was obtained with the purity of 99.78%. Ratio of roxadustatxaffeine = 1:1, determined by means of NMR. A TGA measurement did not confirm the presence of water or other solvents. The X-ray powder pattern of the caffeine cocrystal of roxadustat of form II is shown in Fig. 66, the DSC record is shown in Fig. 67; this is a crystalline form with the melting point of 178°C.
Example 36
Preparation of a crystalline form of the caffeine cocrystal of roxadustat of form III
Roxadustat (500 g, purity 99.34%) and caffeine (303 mg, 1.1 equiv.) were dosed into a flask and then suspended in acetonitrile (5 ml). The reaction mixture was stirred for 22 hours without the access of light at the room temperature (25°C). Then, the crystals were aspirated on frit, washed with acetonitrile (1 ml) and dried at 45 °C in vacuum (200 mbar) for 18 hours. This way, the amount of 715 mg (92%) of the product was obtained with the purity of 99.64%. Ratio of roxadustat: caffeine = 1:1, determined by means of NMR. A TGA measurement did not confirm the presence of water or other solvents.
The X-ray powder pattern of the caffeine cocrystal of roxadustat of form III is shown in Fig. 68, the DSC record is shown in Fig. 69; this is a crystalline form with the melting point of 175.3°C.

Claims

1. A salt of roxadustat with a coformer in a solid form wherein the coformer is selected from the group consisting of meglumine, N,N'-dibenzylethylenediamine, tert- butylamine, diethylamine, dicyclohexylamine, ammonia, lithium, potassium hydroxide, calcium salt, magnesium salt, iron (III) salt, iron (II) salt, 2- naphtalenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 3-ethyl-l- memyl-lH-imidazol-3-ium and caffeine.
2. A salt of roxadustat with a coformer according to claim 1, the coformer being meglumine, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 3.3; 11.8; 16.8; 22.8; 25.1 and 27.7 ± 0.2° 2- theta.
3. The salt of roxadustat with a coformer according to claim 2, characterized by a differential scanning calorimetric curve with the melting point at 181°C.
4. A salt of roxadustat with a coformer according to claim 1 in the form of crystalline modification I, the coformer being NN-dibenzylethylenediamine, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 5.0; 10.9; 13.3; 18.1; 19.8; 23.8 and 26,1 ± 0.2° 2-theta.
5. The salt of roxadustat with a coformer according to claim 4, characterized by a differential scanning calorimetric curve with the melting point at 126°C.
6. A salt of roxadustat with a coformer according to claim 1 in the form of crystalline modification II, the coformer being N,N-dibenzylemylenediamine, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 7.1; 9.9; 17.1; 19.9; 24.1 and 26.5 ± 0.2° 2-theta.
7. The salt of roxadustat with a coformer according to claim 6, characterized by a differential scanning calorimetric curve with the melting point at 115°C.
8. A salt of roxadustat with a coformer according to claim 1 in the form of crystalline modification I, the coformer being potassium hydroxide, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 2.6; 5.2; 10.8; 18.1; 20.8 and 24.4 ± 0.2° 2-theta.
9. The salt of roxadustat with a coformer according to claim 8, characterized by a differential scanning calorimetric curve with the melting point at 63 °C.
10. A salt of roxadustat with a coformer according to claim 1 in the form of crystalline modification II, the coformer being potassium hydroxide, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 3.0; 11.0; 13.8; 18.2; 22.4 and 27.8 ± 0.2° 2-theta.
11. The salt of roxadustat with a coformer according to claim 10, characterized by a differential scanning calorimetric curve with the melting point at 288°C.
12. A salt of roxadustat with a coformer according to claim 1 in the form of crystalline modification III, the coformer being potassium, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 5.0; 9.9; 13.0; 19.5 and 24.8 ± 0.2° 2-theta.
13. The salt of roxadustat with a coformer according to claim 12, characterized by a differential scanning calorimetric curve with the melting point at 308,3°C.
14. A salt of roxadustat with a coformer according to claim 1 in the form of crystalline modification IV, the coformer being potassium, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 4.9; 7.3; 11.9; 19.8 and 22.7 ± 0.2° 2-theta.
15. The salt of roxadustat with a coformer according to claim 14, characterized by a differential scarining calorimetric curve with the melting point at 120.5°C.
16. A salt of roxadustat with a coformer according to claim 1 in the form of crystalline modification I, the coformer being a calcium salt, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 3.0; 11.5; 12.9; 16.6; 20.1; 23.7 and 26.3 ± 0.2° 2-theta.
17. The salt of roxadustat with a coformer according to claim 16, characterized by a differential scanning calorimetric curve with the melting point at 96°C.
18. A salt of roxadustat with a coformer according to claim 1 in the form of crystalline modification II, the coformer being a calcium salt, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 2.9; 12.1; 16.6; 20.6 and 25.9 ± 0.2° 2-theta.
19. A salt of roxadustat with a coformer according to claim 1 in the form of crystalline modification III, the coformer being a calcium salt, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 3.5; 9.5; 21.5; 27.0 and 28.8 ± 0.2° 2-theta.
20. A salt of roxadustat with a coformer according to claim 1 in the form of crystalline modification IV, the coformer being calcium, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 3.9; 11.6; 16.4; 19.3; 22.5 and 27.7 ± 0.2° 2-theta.
21. A salt of roxadustat with a coformer according to claim 1 in the form of crystalline modification I, the coformer being p-toluenesulfonic acid, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 5.7; 11.7; 15.8; 18.4; 21.9 and 26.0 ± 0.2° 2-theta.
22. The salt of roxadustat with a coformer according to claim 21, characterized by a differential scanning calorimetric curve with the melting point at 150°C.
23. A salt of roxadustat with a coformer according to claim 1 in the form of crystalline modification II, the coformer being p-toluenesulfonic acid, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 5.8; 9.9; 14.1; 19.8; 22.0 and 26.8 ± 0.2° 2-theta.
24. The salt of roxadustat with a coformer according to claim 23, characterized by a differential scanning calorimetric curve with the melting point at 149°C.
25. A salt of roxadustat with a coformer according to claim 1 in the form of crystalline modification III, the coformer being />-toluenesulfonic acid, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 6.3; 10.9; 12.9; 17.3; 19.3 and 25.4 ± 0,2° 2-theta.
26. The salt of roxadustat with a coformer according to claim 25, characterized by a differential scanning calorimetric curve with the melting point at 183°C.
27. A cocrystal of roxadustat with a coformer according to claim 1 in the form of crystalline modification I, the coformer being caffeine, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 8.2; 10.1; 13.1; 16.7; 19.7 and 26.0 ± 0.2° 2-theta.
28. The cocrystal of roxadustat with a coformer according to claim 27, characterized by a differential scanning calorimetric curve with the melting point at 177.2°C.
29. A cocrystal of roxadustat with a coformer according to claim 1 in the form of crystalline modification II, the coformer being caffeine, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 7.8; 10.1; 12.8; 15.7; 19.4 and 26.0 ± 0.2° 2-theta.
30. The cocrystal of roxadustat with a coformer according to claim 29, characterized by a differential scanning calorimetric curve with the melting point at 178°C.
31. A cocrystal of roxadustat with a coformer according to claim 1 in the form of crystalline modification III, the coformer being caffeine, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuKα radiation: 10.0; 11.8; 16.8; 20.1 and 26.6 ± 0.2° 2-theta.
32. The cocrystal of roxadustat with a coformer according to claim 31, characterized by a differential scanning calorimetric curve with the melting point at 175.3°C.
33. A method for preparing a salt of roxadustat with a coformer defined in claims 2 to 15 or 21 to 26, characterized in that roxadustat free acid is dissolved or suspended in a suitable solvent and subsequently, a coformer is added that is selected from the group consisting of meglumine, N,N'-dibenzylethylenediamine, potassium hydroxide, p- toluenesulfonic acid and caffeine.
34. A method for preparing salt of roxadustat with a coformer defined in claims 16 to 20, characterized in that the sodium salt of roxadustat is dissolved in a suitable solvent and subsequently, a coformer is added, which is calcium chloride.
35. A method of preparing according to claim 33 or 34, characterized in that a suitable solvent is a solvent selected from the group consisting of aliphatic C1-C4 alcohols, ketones, ethers, nitriles, water or their mixture, preferably tetrahydrofuran, methanol, acetone, acetonitrile, water or their mixture.
36. Use of a salt of roxadustat with a coformer defined in claims 1 to 32 for the preparation of a pharmaceutical composition.
37. A pharmaceutical composition, characterized in that it comprises a salt of roxadustat with a coformer defined in claims 1 to 32 and at least one pharmaceutically acceptable excipient.
Abstract
The solution relates to solid forms of roxadustat with the systematic name of (4-hydroxy-l- methyl-7-phenoxyisoquinoline-3-carbonyl)glycine of formula I, methods of their preparation and use in a drug form. These solid forms of roxadustat of formula I are prepared by a reaction of roxadustat free acid with suitable coformers (inorganic or organic acids, bases, neutral molecules, or salts or ion pairs) in a suitable solvent or mixtures of solvents, the coformer is selected from the group consisting of meglumine, N,N'-dibenzylethylenediamine, tert- butylamine, diethylamine, dicyclohexylamine, ammonia, lithium, potassium hydroxide, calcium salt, magnesium salt, iron (III) salt, iron (II) salt, 2-naphtalenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 3-ethyl-l-methyl-lH-imidazol-3-ium acetate and caffeine.
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PCT/CZ2018/000039 2017-08-30 2018-08-30 Solid forms of roxadustat WO2019042485A1 (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111205224A (en) * 2020-04-22 2020-05-29 南京佰麦生物技术有限公司 Crystal form of roxasistat hydrate, and preparation method and application thereof
WO2021077994A1 (en) 2019-10-22 2021-04-29 苏州科睿思制药有限公司 Crystal form of hypoxia-inducible factor-prolyl hydroxylase inhibitor
CN113956200A (en) * 2021-12-16 2022-01-21 南京威凯尔生物医药科技有限公司 Crystallization process of roxasistat bulk drug with controlled particle size
WO2022150623A1 (en) * 2021-01-08 2022-07-14 Akebia Therapeutics, Inc. Compounds and composition for the treatment of anemia

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004108681A1 (en) 2003-06-06 2004-12-16 Fibrogen, Inc. Nitrogen-containing heteroaryl compounds and their use in increasing endogenous erythropoietin
WO2014014835A2 (en) 2012-07-16 2014-01-23 Fibrogen, Inc. Crystalline forms of a prolyl hydroxylase inhibitor
CN103694172A (en) * 2013-12-26 2014-04-02 辽宁亿灵科创生物医药科技有限公司 Derivative of aza-aryl compound
WO2014197660A1 (en) 2013-06-06 2014-12-11 Fibrogen, Inc. Pharmaceutical formulations of a hif hydroxylase inhibitor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004108681A1 (en) 2003-06-06 2004-12-16 Fibrogen, Inc. Nitrogen-containing heteroaryl compounds and their use in increasing endogenous erythropoietin
WO2014014835A2 (en) 2012-07-16 2014-01-23 Fibrogen, Inc. Crystalline forms of a prolyl hydroxylase inhibitor
WO2014197660A1 (en) 2013-06-06 2014-12-11 Fibrogen, Inc. Pharmaceutical formulations of a hif hydroxylase inhibitor
CN103694172A (en) * 2013-12-26 2014-04-02 辽宁亿灵科创生物医药科技有限公司 Derivative of aza-aryl compound

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 808118-40-3

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021077994A1 (en) 2019-10-22 2021-04-29 苏州科睿思制药有限公司 Crystal form of hypoxia-inducible factor-prolyl hydroxylase inhibitor
CN113015722A (en) * 2019-10-22 2021-06-22 苏州科睿思制药有限公司 Crystal form of hypoxia-inducible factor prolyl hydroxylase inhibitor
CN113015722B (en) * 2019-10-22 2022-02-11 苏州科睿思制药有限公司 Crystal form of hypoxia-inducible factor prolyl hydroxylase inhibitor
CN111205224A (en) * 2020-04-22 2020-05-29 南京佰麦生物技术有限公司 Crystal form of roxasistat hydrate, and preparation method and application thereof
WO2022150623A1 (en) * 2021-01-08 2022-07-14 Akebia Therapeutics, Inc. Compounds and composition for the treatment of anemia
CN113956200A (en) * 2021-12-16 2022-01-21 南京威凯尔生物医药科技有限公司 Crystallization process of roxasistat bulk drug with controlled particle size

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