WO2025012425A1 - Sel de trométhamine d'acide 4-chloro-5-[4-(2,6-dichlorophényl)sulfonylpipérazin-1-yl]-1-benzofuran-2-carboxylique et diverses formes de celui-ci - Google Patents

Sel de trométhamine d'acide 4-chloro-5-[4-(2,6-dichlorophényl)sulfonylpipérazin-1-yl]-1-benzofuran-2-carboxylique et diverses formes de celui-ci Download PDF

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Publication number
WO2025012425A1
WO2025012425A1 PCT/EP2024/069807 EP2024069807W WO2025012425A1 WO 2025012425 A1 WO2025012425 A1 WO 2025012425A1 EP 2024069807 W EP2024069807 W EP 2024069807W WO 2025012425 A1 WO2025012425 A1 WO 2025012425A1
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Prior art keywords
disease
tromethamine salt
agonist
ray diffraction
diffraction pattern
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Inventor
Raphaël Darteil
Jacky Vonderscher
Diane Sampson
Nicolas PHILIPPON
Joël Vacus
Julien LEROUDIER
Sandra Werner
Françoise Richard-Tiberghien
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Enyo Pharma SA
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Enyo Pharma SA
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Priority to CN202480046191.7A priority Critical patent/CN121646582A/zh
Publication of WO2025012425A1 publication Critical patent/WO2025012425A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2

Definitions

  • the present invention relates to the medicinal field and, more specifically, it relates to a new salt of 4-chloro-5-[4-(2,6-dichlorophenyl)sulfonylpiperazin-l-yl]-l-benzofuran-2-carboxylic acid, its different forms, methods for preparing the same, and uses for treating a number of diseases.
  • EYP001 has been proven to be an efficient FXR agonist and, in particular, for treating diseases or disorders related to the activity of the FXR receptors including hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, lipodystrophy, cholestasis/fibrosis, cholesterol gallstone disease, gastrointestinal disease or condition, hyperglycemia, diabetes mellitus, type 2 diabetes, insulin resistance, metabolic inflexibility, nephropathy, liver diseases, atherosclerosis, cancer, inflammatory disorders, obesity, osteoporosis, skin aging, hair growth regulation and pigmentation disorders, Parkinson's disease and/or Alzheimer's disease.
  • diseases or disorders related to the activity of the FXR receptors including hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, lipodystrophy, cholestasis/fibrosis, cholesterol gallstone disease, gastrointestinal disease or condition, hyperglycemia, diabetes mellitus, type 2 diabetes, insulin resistance, metabolic inflexibility, nephropathy, liver
  • EYP001 While the therapeutic effects of EYP001 free acid have been widely studied, they are limited due to its pharmaceutical properties. To date, EYP001 has been only studied in its free acid forms.
  • EYP001 4-chloro-5-[4-(2,6-dichlorophenyl)sulfonylpiperazin- l-yl]-l-benzofuran-2-carboxylic acid (EYP001). It has better solubility then, for instance, the free acid form of EYP001 and other salts, particularly in the gastrointestinal tract. It also has improved pharmacokinetics properties. As a result, a higher bioavailability and a lower variability can be achieved relative to the free acid form of EYP001.
  • tromethamine salt of 4-chloro-5-[4-(2,6- dichlorophenyl)sulfonylpiperazin-l-yl]-l-benzofuran-2-carboxylic acid (EYP001) in a crystalline form.
  • crystalline form I of the tromethamine salt of EYP001 which presents excellent thermal stability (melting point superior to 180 °C ) and is non-hygroscopic, has been isolated.
  • a tromethamine salt of 4-chloro-5-[4-(2,6- dichlorophenyl)sulfonylpiperazin-l-yl]-l-benzofuran-2-carboxylic acid (EYP001) in a crystalline form (form I), wherein the X-ray diffraction pattern of the crystalline form comprises peaks at the following diffraction angles 2-Theta (29): 15.2° ⁇ 0.2°, 16.0° ⁇ 0.2°, 17.1° ⁇ 0.2°, 18.3° ⁇ 0.2°, 18.7° ⁇ 0.2°, 20.6° ⁇ 0.2°, 22.6° ⁇ 0.2°, and 23.2° ⁇ 0.2°, wherein the X-ray diffraction pattern is obtained with a Cu Ka anode.
  • this crystalline form I of the tromethamine salt of EYP001 is such that the X-ray diffraction pattern thereof comprises peaks at the following diffraction angles 2-Theta (29): 6.3° ⁇ 0.2°, 6.9° ⁇ 0.2°, 8.4° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.0° ⁇ 0.2°, 11.0° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.9° ⁇ 0.2°, 15.2° ⁇ 0.2°, 15.5° ⁇ 0.2°, 16.0° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.1° ⁇ 0.2°, 18.3° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.2° ⁇ 0.2°, 19.9 ° ⁇ 0.2°, 20.6° ⁇ 0.2°, 21.0° ⁇ 0.2°, 21.8° ⁇ 0.2°, 22.6° ⁇ 0.2°, 23.2° ⁇ 0.2°, 23.6° ⁇ 0.2°, 24.6° ⁇ 0.2°, 25.7° ⁇ 0.2°, 27.1° ⁇ 0.2°, 28.5° ⁇ 0.2°, 29.7° ⁇ 0.2°, and
  • the crystalline form I of the tromethamine salt of EYP001 is such that the X-ray diffraction pattern of the crystalline form comprises the following peaks: wherein the X-ray diffraction pattern is obtained with a Cu Ka anode.
  • a crystalline form II of the tromethamine salt of EYP001 which presents excellent thermal stability (melting point: 236 °C) and is non-hygroscopic, has been isolated.
  • a tromethamine salt of 4-chloro-5-[4-(2,6- dichlorophenyl)sulfonylpiperazin-l-yl]-l-benzofuran-2-carboxylic acid (EYP001) in a crystalline form (form II), wherein the X-ray diffraction pattern of the crystalline form comprises peaks at the following diffraction angles 2-Theta (29): 9.0° ⁇ 0.2°, 14.5° ⁇ 0.2°, 15.9° ⁇ 0.2°, 17.9° ⁇ 0.2°, 20.1° ⁇ 0.2°, 21.4° ⁇ 0.2°, and 25.2° ⁇ 0.2°, wherein the X-ray diffraction pattern is obtained with a Cu Ka anode.
  • the crystalline form II of the tromethamine salt of EYP001 is such that the X-ray diffraction pattern thereof comprises peaks at the following diffraction angles 2-Theta (29): 7.0° ⁇ 0.2°, 9.0° ⁇ 0.2°, 11.3° ⁇ 0.2°, 12.3° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14.5° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.3° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.9° ⁇ 0.2°,
  • the crystalline form II of the tromethamine salt of EYP001 is such that the X-ray diffraction pattern of the crystalline form comprises the following peaks: wherein the X-ray diffraction pattern is obtained with a Cu Ka anode.
  • a crystalline form III of the tromethamine salt of EYP001 in a monohydrated form which presents excellent thermal stability (melting point: 237 °C), has been isolated.
  • a tromethamine salt of 4-chloro-5-[4-(2,6- dichlorophenyl)sulfonylpiperazin-l-yl]-l-benzofuran-2-carboxylic acid (EYP001) in a crystalline form (form III), wherein the X-ray diffraction pattern of the crystalline form comprises peaks at the following diffraction angles 2-Theta (29): l l.l° ⁇ 0.2°, 15.7° ⁇ 0.2°, 15.9° ⁇ 0.2°, 17.3° ⁇ 0.2°, 20.9° ⁇ 0.2°, 21.2° ⁇ 0.2°, 21.8° ⁇ 0.2°, and 27.2° ⁇ 0.2°, wherein the X-ray diffraction pattern is obtained with a Cu Ka anode.
  • the crystalline form III of the tromethamine salt of EYP001 is such that the X-ray diffraction pattern thereof comprises peaks at the following diffraction angles 2-Theta (29): 6.3° ⁇ 0.2°, 7.0° ⁇ 0.2°, 8.7° ⁇ 0.2°, 10.5° ⁇ 0.2°, l l.l° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.9° ⁇ 0.2°, 17.3° ⁇ 0.2°, 18.3° ⁇ 0.2°, 20.0° ⁇ 0.2°, 20.9° ⁇ 0.2°, 21.8° ⁇ 0.2°, 22.7° ⁇ 0.2°, 23.2° ⁇ 0.2°, 25.1° ⁇ 0.2°, 25.9° ⁇ 0.2°, 27.2° ⁇ 0.2°, 28.3° ⁇ 0.2°, 29.4° ⁇ 0.2°, 31.8° ⁇ 0.2°, 32.4° ⁇ 0.2°, 35.2° ⁇ 0.2°, 36.0° ⁇ 0.2°, and 37.0° ⁇ 0.2°, wherein the X-ray diffraction pattern is obtained with a Cu Ka anode.
  • the crystalline form III of the tromethamine salt of EYP001 is such that the X-ray diffraction pattern of the crystalline form comprises the following peaks: wherein the X-ray diffraction pattern is obtained with a Cu Ka anode.
  • a further aspect of the invention is a tromethamine salt of EYP001 or a crystalline form of a tromethamine salt of EYP001 as defined herein for use as a drug or a medicine.
  • Another aspect of the invention is a pharmaceutical or veterinary composition
  • a pharmaceutical or veterinary composition comprising a tromethamine salt of EYP001 or a crystalline form of a tromethamine salt of EYP001 as defined herein, and a pharmaceutically acceptable excipient.
  • the pharmaceutical or veterinary composition as defined herein further comprises an additional therapeutic agent, for instance a TLR3 agonist, a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, a RIG-I modulator, a STING agonist, an antiviral agent, such as Bulevirtide, an antibacterial agent, an interferon or a pegylated from thereof, a checkpoint inhibitor such as a PD-1 or PD-L1 agonist, an ERA, an ACE inhibitor, an ARB, a RASS antagonist, a beta-blocker, a diuretic agent, a MRA, a SGLT2 inhibitor, a GLP1 agonist, a SGLT1 inhibitor, FGF19, FGF21, a DPP-4 inhibitor, a PPAR agonist, a THR beta agonist, a FASN, an inhibitor of HSD17bl3 or a combination thereof.
  • an additional therapeutic agent for instance a TLR3 agonist, a
  • Another aspect of the invention is a pharmaceutical or veterinary composition as defined herein for use for the treatment of a disease selected from the group consisting of a chronic liver disease, a gastrointestinal disease, a renal disease, a cardiovascular disease, a metabolic disease, an infection, a cancer, and an autoimmune disease.
  • a disease selected from the group consisting of a chronic liver disease, a gastrointestinal disease, a renal disease, a cardiovascular disease, a metabolic disease, an infection, a cancer, and an autoimmune disease comprising administering to the subject an effective amount of a pharmaceutical or veterinary composition as defined herein.
  • Another aspect of the invention is a use of a pharmaceutical or veterinary composition as defined herein for the manufacture of a drug for treating a disease selected from the group consisting of a chronic liver disease, a gastrointestinal disease, a renal disease, a cardiovascular disease, a metabolic disease, an infection, a cancer, and an autoimmune disease.
  • the disease is an infection, especially a chronic infection, preferably a viral infection, more preferably an infection by hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), herpes simplex virus (HSV), papillomavirus (HPV) (e.g., condylomata acuminate), varicella-zoster virus, cytomegalovirus (CMV), rhinoviruses, hepatitis A virus, hepatitis E virus, Kaposis sarcoma herpesvirus, coronavirus including SARS- Covl, MERS-Cov and SARS-Cov2, retrovirus including HIV, and influenza virus.
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • HDV hepatitis D virus
  • HPV herpes simplex virus
  • HPV papillomavirus
  • HPV papillomavirus
  • CMV papillo
  • the pharmaceutical or veterinary composition for use for the treatment of an infection is to be used in combination with a TLR3 agonist, a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, a RIG-I modulator, a STING agonist, an antiviral agent, such as Bulevirtide, an antibacterial agent, an interferon or a pegylated from thereof, a checkpoint inhibitor such as a PD- 1 or PD- L1 agonist, or a combination thereof.
  • the disease is a renal disease, especially a renal disease comprising renal fibrosis and/or Chronic Kidney Disease (CKD), for instance selected from the group consisting of hypertension, type 2 diabetes, type 1 diabetes, obesity, Non-Alcoholic Steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), metabolic (dysfunction) associated fatty liver disease (MAFLD), ageing, infectious glomerulonephritis, in particular infections such as syphilis, malaria, hepatitis B, hepatitis C or HIV, focal segmental glomerulosclerosis, IgA nephropathy, minimal change glomerulopathy, membranous nephropathy, renal vasculitis, urinary tract obstruction, genetic alterations, autoimmune diseases such as systemic lupus erythematosus (SLE), and drug- or toxin-induced nephropathy such as nephropathy induced by drugs such as captopril, NSA
  • CKD Chronic
  • the disease is Chronic Kidney Disease (CKD).
  • CKD Chronic Kidney Disease
  • the pharmaceutical or veterinary composition for use for the treatment of a renal disease is to be used in combination with an ERA, an ACE inhibitor, an ARB, a RASS antagonist, a betablocker, a diuretic agent, a MRA, a SGLT2 inhibitor, a GLP1 agonist or a combination thereof.
  • the disease is a liver disease, especially a chronic liver disease, preferably primary biliary cirrhosis or primary biliary cholangitis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), metabolic-associated fatty liver disease (MAFLD), alcoholic hepatitis, liver transplant associated graft versus host disease, living donor transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic
  • PBC primary
  • the pharmaceutical or veterinary composition for use for the treatment of a liver disease is to be used in combination with a SGLT2 inhibitor, a GLP1 agonist, a SGLT1 inhibitor, FGF19, FGF21, a DPP-4 inhibitor, a PPAR agonist, a THR beta agonist, a FASN, an inhibitor of HSD17bl3 or a combination thereof.
  • FIG. 1 Overlaid XRPD profiles of EYP001 tromethamine salt (Form I - sample A), tromethamine counter-ion, and EYP001 acid form.
  • Figure 2 XRPD pattern of EYP001 tromethamine salt (Form I - sample A)
  • Figure 3 DSC profile of EYP001 tromethamine salt (Form I - sample A).
  • Figure 4 TGA profile of EYP001 tromethamine salt (Form I - sample A).
  • FIG 6 Overlaid XRPD profiles of EYP001 tromethamine crystalline form I, and EYP001 tromethamine crystalline form II.
  • Figure 7 XRPD pattern of EYP001 tromethamine salt (Form II)
  • Figure 11 Overlaid XRPD profiles of EYP001 tromethamine crystalline form I, and EYP001 tromethamine crystalline form III.
  • Figure 15 DVS isotherm sorption plot at 25 °C of EYP001 tromethamine salt (Form III).
  • Figure 16 Overlaid XRPD profiles of EYP001 tromethamine salt in amorphous form, and in crystalline forms I, II, and III.
  • the term “about” or “around” will be understood by one ordinary skill in the art and will vary to some extent on the context in which it is used. For instance, in a particular context, “about” or “around” may mean up to plus or minus 10% of a particular term.
  • the terms “compound” or “molecule” refer to a tromethamine salt of EYP001 according to the invention including its forms as disclosed herein.
  • treatment refers to any act intended to ameliorate the health status of patients such as therapy, prevention, prophylaxis and retardation of a disease.
  • such terms refer to the amelioration or eradication of the disease, or symptoms associated with it.
  • this term refers to minimizing the spread or worsening of the disease, resulting from the administration of one or more therapeutic agents to a subject with such a disease.
  • the terms “subject”, “individual” or “patient” are interchangeable and refer to an animal, preferably to a mammal, even more preferably to a human, including adult and child.
  • the term “subject” can also refer to non-human animals, in particular mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates, among others.
  • Quantity is used interchangeably herein and may refer to an absolute quantification of a molecule.
  • the term “therapeutic effect” refers to an effect induced by an active ingredient, or a pharmaceutical composition according to the invention, capable to prevent or to delay the appearance or development of a disease or disorder, or to cure or to attenuate the effects of a disease or disorder.
  • the term “effective amount” refers to a quantity of an active ingredient or of a pharmaceutical composition which prevents, removes or reduces the deleterious effects of the disease.
  • the quantity to be administered can be adapted by a person skilled in the art according to the subject to be treated, to the nature of the disease, etc.
  • doses and regimen of administration may be function of the nature, of the stage and of the severity of the disease to be treated, as well as of the weight, the age and the global health of the subject to be treated, as well as of the judgment of the doctor.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” refers to any ingredient except active ingredients that is present in a pharmaceutical composition. Its addition may be aimed to confer a particular consistency or other physical or gustative properties to the final product.
  • a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient must be devoid of any interaction, in particular chemical, with the active ingredients.
  • kits refers especially to a “kit of parts” in the sense that the combination partners as defined herein can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination partners, i.e. simultaneously or at different time points.
  • the parts of the kit of parts can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
  • the ratio of the total amounts of the combination partners to be administered in the combined preparation can be varied.
  • the combination partners can be administered by the same route or by different routes.
  • 4-chloro-5-[4-(2,6-dichlorophenyl)sulfonylpiperazin-l-yl]-l-benzofuran-2-carboxylic acid (IUPAC name; CAS No. 1192171-69-9) is also called herein 4-chloro-5-[4-(2,6- dichlorobenzene-l-sulfonyl)-piperazin-l-yl]-l-benzofuran-2-carboxylic acid or 4-chloro-5-[4- (2,6-dichloro-benzenesulfonyl)-piperazin-l-yl]-benzofuran-2-carboxylic acid, “Vonafexor”, “PLX007”, “EYP001”, or “EYP-001”, and has the following formula:
  • EYP001 free acid was first described by Merck Patent GMBH in Example 136 of WO 2009/127321. It is well understood that EYP001 can be also prepared by other synthesis routes and well-known techniques by one of ordinary skills in the art. EYP001 can even be directly purchased from commercial suppliers.
  • EYP001 free acid has poor solubility, which represents a major obstacle for the development of this drug.
  • a tromethamine salt of EYP001 as provided herein has a number of improved properties compared to the free acid form and even other salts, including better solubility, and leads to better bioavailability than the free acid form.
  • it is suitable for pharmaceutical dosage forms.
  • the tromethamine salt of EYP001 can be prepared according to any methods known by one of ordinary skills in the art for preparing salts of active ingredients.
  • EYP001 can be solubilized in a solvent, preferably a polar solvent, and the counter-ion tromethamine is added.
  • solvents it can be cited, without limitation, water, isopropyl acetate, acetonitrile, isopropyl alcohol, ethanol, methanol, acetone, tetrahydrofuran, and mixtures thereof.
  • the solvent is chosen among tetrahydrofuran, acetonitrile, water, and ethanol.
  • the solvent is a mixture of tetrahydrofuran, water, and ethanol. In a further preferred embodiment, the solvent is tetrahydrofuran. In a further preferred embodiment, the solvent is acetonitrile.
  • the tromethamine salt of EYP001 is prepared by contacting a solution of EYP001 in THF to a solution of tromethamine in water.
  • the tromethamine salt of EYP001 is prepared by contacting a solution of EYP001 in THF to a solution of tromethamine in ethanol/water.
  • a particular embodiment of the invention is therefore a process for preparing a tromethamine salt of 4-chloro-5-[4-(2,6-dichlorophenyl)sulfonylpiperazin-l-yl]-l-benzofuran-2-carboxylic acid comprising the steps of: a) contacting a solution of 4-chloro-5-[4-(2,6-dichlorophenyl)sulfonylpiperazin-l-yl]- l-benzofuran-2-carboxylic acid in THF to a solution of tromethamine in ethanol/water or in water; and ai) isolating the tromethamine salt of 4-chloro-5-[4-(2,6- dichlorophenyl)sulfonylpiperazin-l-yl]-l-benzofuran-2-carboxylic acid obtained in step a).
  • the present invention further provides crystalline forms of a tromethamine salt of EYP001 (Forms I- IV). These crystalline forms present further advantageous physico-chemical properties for pharmaceutical dosage forms.
  • crystalline forms I, II, and III have excellent thermal stabilities (superior to 180 °C), and crystalline forms I and II are non- hygroscopic.
  • the crystalline forms described herein may be identified and/or characterized by various analytical techniques known to one of ordinary skill in the art. Such techniques include, but are not limited to X-ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Dynamic Vapor Sorption (DVS), and/or IR spectrum.
  • XRPD X-ray Powder Diffraction
  • DSC Differential Scanning Calorimetry
  • TGA Thermogravimetric Analysis
  • DVD Dynamic Vapor Sorption
  • IR spectrum IR spectrum
  • the X-ray diffraction pattern of one crystalline form (form I) comprises peaks at the following diffraction angles 2-Theta (26): 15.2° ⁇ 0.2°, 16.0° ⁇ 0.2°, 17.1° ⁇ 0.2°, 18.3° ⁇ 0.2°, 18.7° ⁇ 0.2°, 20.6° ⁇ 0.2°, 22.6° ⁇ 0.2°and 23.2° ⁇ 0.2°, wherein the X-ray diffraction pattern is obtained with a Cu Ka anode.
  • the X-ray diffraction pattern of the crystalline form comprises peaks at the following diffraction angles 2-Theta (26): 6.3° ⁇ 0.2°, 6.9° ⁇ 0.2°, 8.4° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.0° ⁇ 0.2°, 11.0° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.9° ⁇ 0.2°, 15.2° ⁇ 0.2°, 15.5° ⁇ 0.2°, 16.0° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.1° ⁇ 0.2°, 18.3° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.2° ⁇ 0.2°, 19.9 ° ⁇ 0.2°,
  • the X-ray diffraction pattern is obtained with a Cu Ka anode.
  • the X-ray diffraction pattern of the crystalline form, obtained with a Cu Ka anode comprises peaks listed in the following table 1 or by its X-ray diffraction pattern as depicted in Figure 2.
  • the X-ray diffraction pattern of one crystalline form (form II) comprises peaks at the following diffraction angles 2-Theta (29): 9.0° ⁇ 0.2°, 14.5° ⁇ 0.2°, 15.9° ⁇ 0.2°, 17.9° ⁇ 0.2°, 20.1° ⁇ 0.2°, 21.4° ⁇ 0.2°, and 25.2° ⁇ 0.2°, wherein the X-ray diffraction pattern is obtained with a Cu Ka anode.
  • the X-ray diffraction pattern of the crystalline form comprises peaks at the following diffraction angles 2-Theta (29): 7.0° ⁇ 0.2°, 9.0° ⁇ 0.2°, 11.3° ⁇ 0.2°, 12.3° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14.5° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.3° ⁇ 0.2°, 16.6° ⁇ 0.2°,
  • the X-ray diffraction pattern is obtained with a Cu Ka anode.
  • the X-ray diffraction pattern of the crystalline form, obtained with a Cu Ka anode comprises peaks listed in the following table 2 or by its X-ray diffraction pattern as depicted in Figure 7.
  • Table 2 X-Ray Peaks of a crystalline form II of a tromethamine salt of EYP001
  • the X-ray diffraction pattern of one crystalline form (form III) comprises peaks at the following diffraction angles 2-Theta (29): ): l l.l° ⁇ 0.2°, 15.7° ⁇ 0.2°, 15.9° ⁇ 0.2°, 17.3° ⁇ 0.2°, 20.9° ⁇ 0.2°, 21.2° ⁇ 0.2°, 21.8° ⁇ 0.2°, and 27.2° ⁇ 0.2°, wherein the X-ray diffraction pattern is obtained with a Cu Ka anode.
  • the X-ray diffraction pattern of the crystalline form comprises peaks at the following diffraction angles 2-Theta (29): 6.3° ⁇ 0.2°, 7.0° ⁇ 0.2°, 8.7° ⁇ 0.2°, 10.5° ⁇ 0.2°, ll.l° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.9° ⁇ 0.2°, 17.3° ⁇ 0.2°, 18.3° ⁇ 0.2°, 20.0° ⁇ 0.2°, 20.9° ⁇ 0.2°, 21.8° ⁇ 0.2°, 22.7° ⁇ 0.2°, 23.2° ⁇ 0.2°, 25.1° ⁇ 0.2°, 25.9° ⁇ 0.2°, 27.2° ⁇ 0.2°, 28.3° ⁇ 0.2°, 29.4° ⁇ 0.2°, 31.8° ⁇ 0.2°, 32.4° ⁇ 0.2°, 35.2° ⁇ 0.2°, 36.0° ⁇ 0.2°, and 37.0° ⁇ 0.2°, wherein the X-ray diffraction pattern is obtained with a Cu Ka anode. Still more particularly, the X-ray diffraction pattern of the crystalline form, obtained with a
  • an X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed.
  • intensities in an X-ray diffraction pattern may fluctuate depending upon measurement conditions employed and the shape or morphology of the particle together with the crystal size distribution.
  • relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensity should not be taken into account.
  • a measurement error of diffraction angle for a conventional X-ray diffraction pattern is typically circa ⁇ 0.02° (in 2 theta) or less, preferably circa ⁇ 0.01°.
  • the crystal form of the instant invention is not limited to a crystal form that provides an X-ray diffraction pattern completely identical to the X-ray diffraction pattern depicted in Figures 2, 7, and 12 or described in tables 1, 2, and 3, respectively.
  • any crystal form that provides an X-ray diffraction pattern substantially identical to that disclosed in Figure 2 or described in table 1 falls within the scope of the present invention.
  • the ability to ascertain substantial identities of X-ray diffraction patterns is within the purview of one of ordinary skill in the art.
  • Crystalline form(s) of a tromethamine salt of EYP001 may be also characterised by Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), and Dynamic Vapor Sorption (DVS).
  • DSC Differential Scanning Calorimetry
  • TGA Thermogravimetric Analysis
  • DVS Dynamic Vapor Sorption
  • a crystalline form of a tromethamine salt of EYP001 (form I) has a melting point, by Differential Scanning Calorimetry (DSC), superior to 180 °C.
  • a crystalline form of a tromethamine salt of EYP001 (form I) shows no significant mass loss, measured by thermogravimetric analysis (TGA) at the range of 20 °C to 182 °C.
  • TGA thermogravimetric analysis
  • a crystalline form of a tromethamine salt of EYP001 (form I) is non- hygroscopic. More specifically, the Dynamic Vapor Sorption (DVS) analysis of this crystalline form I of the invention shows only 1.3 % water uptake at 25 °C/60 % RH.
  • a crystalline form of a tromethamine salt of EYP001 (form
  • a crystalline form of a tromethamine salt of EYP001 (form II) shows no significant mass loss, measured by thermogravimetric analysis (TGA) with an onset temperature of 220 °C.
  • a crystalline form of a tromethamine salt of EYP001 (form II) is non-hygroscopic. More specifically, the Dynamic Vapor Sorption (DVS) analysis of this crystalline form II of the invention shows only 0.3 % water uptake at 25 °C/60 % RH.
  • a crystalline form of a tromethamine salt of EYP001 (form
  • crystalline form III has a melting point, by Differential Scanning Calorimetry (DSC), of about 237 °C.
  • DSC Differential Scanning Calorimetry
  • a crystalline form of a tromethamine salt of EYP001 (form III) is under a mono-hydrated form. More specifically, the Dynamic Vapor Sorption (DVS) analysis of this crystalline form III of the invention shows that the bulk can be considered as existing under a mono-hydrated form.
  • DSC Differential Scanning Calorimetry
  • Crystalline form(s) of the invention may be prepared by a variety of methods, including for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and spray drying.
  • Techniques for crystallization or recrystallization of a crystalline form from a solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding a supersaturated solvent mixture of the molecule and/or salt, freeze drying the solvent mixture, and addition of anti-solvents (counter-solvents) to the solvent mixture.
  • Crystals of drugs, including polymorphs, methods of preparation, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, S.
  • solvent for crystallization techniques that employ solvent, the choice of solvent(s) is typically dependent upon one or more factors, such as solubility of the compound, crystallization technique, vapor pressure of the solvent, viscosity of the solvent and toxicity. Combinations of solvents may be employed, for example, the compound may be solubilized into a first solvent to afford a solution, followed by the addition of an anti- solvent to decrease the solubility of the compound in the solution and to afford the formation of crystals.
  • An anti-solvent is a solvent in which the compound has a low solubility.
  • the solvent is chosen among water, isopropyl acetate, ethyl acetate, dimethylsulfoxide, heptane, acetonitrile, isopropyl alcohol, methanol, ethanol, acetone, tetrahydrofuran, and mixtures thereof.
  • the solvent is chosen among water, tetrahydrofuran, acetonitrile, and mixtures thereof.
  • the anti-solvent is chosen among ethanol and acetone.
  • An aspect of the invention is a process for preparing a crystalline form of a tromethamine salt of 4-chloro-5-[4-(2,6-dichlorophenyl)sulfonylpiperazin-l-yl]-l-benzofuran-2-carboxylic acid comprising the steps of: a) contacting a solution of 4-chloro-5-[4-(2,6-dichlorophenyl)sulfonylpiperazin-l-yl]-
  • a particular aspect of the invention is a process for preparing a crystalline form of a tromethamine salt of 4-chloro-5-[4-(2,6-dichlorophenyl)sulfonylpiperazin-l-yl]-l-benzofuran-
  • 2-carboxylic acid comprising the steps of: a) contacting a solution of 4-chloro-5-[4-(2,6-dichlorophenyl)sulfonylpiperazin-l-yl]- l-benzofuran-2-carboxylic acid in THF to a solution of tromethamine in water; b) optionally triggering the formation of a crystalline form, and/or optionally improving the crystallinity of the crystalline form, preferably by adding ethanol; and c) isolating the crystalline form obtained in step b) or a).
  • step a) is performed in solution, in particular EYP001 is suspended in THF and tromethamine is suspended in ethanol/water, preferably in water.
  • the 4-chloro-5-[4-(2,6-dichlorophenyl)sulfonylpiperazin-l-yl]-l- benzofuran-2-carboxylic acid:tromethamine stoichiometry in step a) is about 1:1
  • Step b) can be performed for instance by addition of an anti- solvent, such as ethanol, when step a) is performed in solution.
  • Step b) may also be performed by seeding the solution with a crystal of the desired crystalline form and/or applying one or several temperature cycling.
  • step b) is performed by addition of an anti-solvent, such as ethanol, when step a) is performed in solution, or by seeding the solution with a crystal of the desired crystalline form and then by applying one or several temperature cycling. This latter step is designed to improve the crystallinity and thereby the filterability and the chemical purity of the final product.
  • step c) can be performed for instance by evaporation of the reaction solvent, by filtration or by centrifugation.
  • step c) may further include one or several washing steps.
  • Each step, each step part (for instance the first or second part of step b)), and/or each combination of steps (for instance the combination of step b) and step c)) of the process of the invention may be performed once, or may be repeated several times in the process of the invention, independently of the other steps or step parts.
  • the temperature cycling may be performed once, alternatively it can be repeated several times, preferably between 2 and 5 times, more preferably 2 or 3 times. Repetition of the succession of steps (b) allows in particular increasing the crystallinity of the form.
  • a crystalline form obtained by the process is a further aspect of the invention. This may be the crystalline form I.
  • the crystalline form II of the tromethamine salt of EYP001 can be prepared starting from the crystalline form I.
  • a further particular aspect of the invention is a process for preparing crystalline form II of a tromethamine salt of EYP001 comprising the steps of: a) stirring the crystalline form I of a tromethamine salt of EYP001 in THF at a temperature between 40 and 60 °C, preferably about 50 °C, for a few hours, such as between 4 and 18 hours, 4 and 16 hours, 6 and 14 hours, preferably between 8 and 12 hours; b) isolating the solid obtained at step a), washing, and drying; and c) isolating the crystalline form II of the tromethamine salt of EYP001.
  • the crystalline form III of the tromethamine salt of EYP001 can be prepared starting from the amorphous form, which can be obtained by dissolving the crystalline form I of a tromethamine salt of EYP001 in a mixture of THF/water; and freeze-drying the mixture.
  • a further particular aspect of the invention is a process for preparing crystalline form III of a tromethamine salt of EYP001 comprising the steps of: a) adding acetonitrile to the amorphous form of a tromethamine salt of EYP001 to obtain a suspension, left to stand at 4 °C for a few hours, such as between 1 and 6 hours, or 2 and 5 hours, b) isolating the solid obtained at step a) by filtration, washing, and drying; and c) isolating the crystalline form III of the tromethamine salt of EYP001.
  • a further particular aspect of the invention is a process for preparing an amorphous form of a tromethamine salt of EYP001 comprising the steps of: a) dissolving the crystalline form I of a tromethamine salt of EYP001 in a mixture of THF/water; b) freeze-drying the mixture; and c) isolating the amorphous form.
  • compositions comprising a tromethamine salt of EYP001.
  • compositions optionally include at least one pharmaceutically acceptable carrier or excipient.
  • the tromethamine salt of EYP001 therein may be in a crystalline form, for instance in form I, II, or III.
  • the compound or the pharmaceutical or veterinary composition as defined herein may be administered by any conventional route of administration.
  • the compound or the pharmaceutical or veterinary composition can be administered by a topical, enteral, oral, parenteral, intranasal, intravenous, intra-arterial, intramuscular, subcutaneous or intraocular administration and the like.
  • the compound according to the invention or the pharmaceutical or veterinary composition according to the invention is administered by enteral or parenteral route of administration.
  • the compound or the pharmaceutical or veterinary composition is preferably administered by intravenous route of administration.
  • the compound or the pharmaceutical or veterinary composition is preferably administered by oral route of administration.
  • composition comprising the compound of the invention is formulated in accordance with standard pharmaceutical practice (Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York) known by a person skilled in the art.
  • the composition can be formulated into conventional oral dosage forms such as tablets, capsules, powders, granules and liquid preparations such as syrups, elixirs, and concentrated drops.
  • Nontoxic solid carriers or diluents may be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, sucrose, magnesium, carbonate, and the like.
  • binders which are agents which impart cohesive qualities to powdered materials, are also necessary.
  • starch, gelatin, sugars such as lactose or dextrose, and natural or synthetic gums can be used as binders.
  • Disintegrants are also necessary in the tablets to facilitate break-up of the tablet.
  • Disintegrants include starches, clays, celluloses, algins, gums and crosslinked polymers.
  • lubricants and glidants are also included in the tablets to prevent adhesion to the tablet material to surfaces in the manufacturing process and to improve the flow characteristics of the powder material during manufacture.
  • Colloidal silicon dioxide is most commonly used as a glidant and compounds such as talc or stearic acids are most commonly used as lubricants.
  • in a crystalline form as defined herein may be varied over a wide range from 10 to 1,000 mg per adult per day, from 25 to 1,000 mg per adult per day, from 50 to 1,000 mg per adult per day, from 25 to 800 mg per adult per day, from 50 to 800 mg per adult per day, from 50 to 600 mg per adult per day or from 100 to 600 mg per adult per day.
  • the daily dosage of a tromethamine salt is in the range from 1 to 500 mg per day, from 2 to 450 mg per day, from 5 to 450 mg per day, from 10 to 450 mg per day, from 20 to 450 mg per day, from 25 to 450 mg per day, from 50 to 450 mg per day, from 100 to 450 mg per day, from 150 to 450 mg per day, from 25 to 400 mg per day, from 50 to 400 mg per day, from 100 to 400 mg per day, from 150 to 400 mg per day, from 25 to 350 mg per day, from 50 to 350 mg per day, from 100 to 350 mg per day, from 150 to 350 mg per day, from 200 to 450 mg per day, from 200 to 400 mg per day, from 200 to 350 mg per day, from 250 to 450 mg per day, from 250 to 400 mg per day, or from 250 to 350 mg per day.
  • a medicament typically contains from about 5 mg to about 800 mg of a tromethamine salt, e.g., in a crystalline form as defined herein, from about 25 mg to about 800 mg of a tromethamine salt, e.g., in a crystalline form as defined herein, from about 25 mg to about 500 mg of a tromethamine salt, e.g., in a crystalline form as defined herein, from about 10 mg to about 500 mg of a tromethamine salt, e.g., in a crystalline form as defined herein, from about 25 mg to about 450 mg of a tromethamine salt, e.g., in a crystalline form as defined herein, from about 50 mg to about 400 mg of a tromethamine salt, e.g., in a crystalline form as defined herein, or from about 50 mg to about 300 mg of a tromethamine salt, e.g., in a crystalline form as defined herein.
  • a further aspect of the invention is a tromethamine salt, e.g., in a crystalline form as defined herein, for use as a drug or a medicine or a pharmaceutical or veterinary composition, which optionally includes a pharmaceutically acceptable carrier or excipient.
  • the invention further relates to the use of a tromethamine salt, e.g., in a crystalline form as defined herein, as a drug or a medicine.
  • the invention further relates to a method for treating a disease in a subject, wherein a therapeutically effective amount of a tromethamine salt, e.g., in a crystalline form as defined herein, is administered to said subject in need thereof.
  • the invention also relates to the use of a tromethamine salt, e.g., in a crystalline form as defined herein, for the manufacture of a medicine.
  • the invention also relates to a pharmaceutical or veterinary composition comprising a tromethamine salt, e.g., in a crystalline form as defined herein, for use as a drug.
  • the crystalline form may be form I, form II, or form III.
  • a tromethamine salt, e.g., in a crystalline form as defined herein, or the pharmaceutical or veterinary composition comprising it is for use in the treatment of a disease in combination with an additional therapeutic agent.
  • the pharmaceutical or veterinary composition comprising a tromethamine salt, e.g., in a crystalline form as defined herein, further comprises an additional therapeutic agent.
  • the present invention relates to a product or kit comprising a tromethamine salt, e.g., in a crystalline form as defined herein, and an additional therapeutic agent as a combined preparation for simultaneous, separate or sequential use, in particular in the treatment of a disease.
  • the present invention relates to a combined preparation comprising a tromethamine salt, e.g., in a crystalline form as defined herein, and an additional therapeutic agent for simultaneous, separate or sequential use, in particular in the treatment of a disease.
  • the present invention relates to the use of a tromethamine salt, e.g., in a crystalline form as defined herein, or a pharmaceutical or veterinary composition comprising it for the manufacture of a medicine for the treatment of a disease in combination with an additional therapeutic agent.
  • the present invention relates to a method for treating a disease in a subject, wherein a therapeutically effective amount of a tromethamine salt, e.g., in a crystalline form as defined herein, and a therapeutically effective amount of an additional therapeutic agent are administered to said subject in need thereof.
  • the additional therapeutic agent to be used in combination with a tromethamine salt can any of the additional therapeutic agents disclosed below, whatever is the disease to be treated.
  • the crystalline form may be form I, form II, or form III.
  • the additional therapeutic agent can be selected from the group consisting of a TLR3 agonist, a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, a RIG-I modulator, a STING agonist, an antiviral agent, such as Bulevirtide, an antibacterial agent, an interferon or a pegylated from thereof, a checkpoint inhibitor such as a PD-1 or PD-L1 agonist, an ERA, an ACE inhibitor, an ARB, a RASS antagonist, a beta-blocker, a diuretic agent, a MRA, a SGLT2 inhibitor, a GLP1 agonist, a SGLT1 inhibitor, FGF19, FGF21, a DPP-4 inhibitor, a PPAR agonist, a THR beta agonist, a FASN, an inhibitor of HSD17bl3 or a combination thereof.
  • an antiviral agent such as Bulevirtide, an antibacterial agent, an interferon
  • the disease to be treated can be selected from the group consisting of a chronic liver disease, a gastrointestinal disease, a renal disease, a cardiovascular disease, a metabolic disease, an infection, a cancer, and an autoimmune disease.
  • the disease is an infection, especially a chronic infection.
  • the infection can be a viral infection, a bacterial infection, especially a mycobacterial infection, or a protozoan infection.
  • the infection is a viral infection.
  • the additional therapeutic agent can be any drug useful for the treatment of infection and, for instance, a TLR3 agonist, a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, a RIG-I modulator, a STING agonist, an antiviral agent, such as Bulevirtide, an antibacterial agent, an interferon or a pegylated from thereof, a checkpoint inhibitor such as a PD-1 or PD-L1 agonist, or a combination thereof.
  • a TLR3 agonist such as TLR7 agonist, a TLR8 agonist, a TLR9 agonist, a RIG-I modulator, a STING agonist
  • an antiviral agent such as Bulevirtide
  • an antibacterial agent such as an antibacterial agent, an interferon or a pegylated from thereof
  • a checkpoint inhibitor such as a PD-1 or PD-L1 agonist, or a combination thereof.
  • the additional therapeutic agent is a TLR3 agonist, such as Poly I:C (polyribosinic:polyribocytidic acid), polyA:U (poly(adenylic acid- uridylic acid), Poly ICLC (polyinosinic acid-polycytidylic acid-poly-L-lysinecarboxy- methylcellulose complex or Hiltonol), PolyI:polyC12U (polyIC12U, Ampligen or Rintatolimod), Riboxxol (RGIC®50), RIBOXXIM (RGIC®100), APOXXIM, TL-532, ARNAX, IPH3102, MCT-465 and MCT-485.
  • TLR3 agonist such as Poly I:C (polyribosinic:polyribocytidic acid), polyA:U (poly(adenylic acid- uridylic acid), Poly ICLC (polyinosinic acid-polycyt
  • a non-exhaustive list of viral infections includes an infection by hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), herpes simplex virus (HSV), papillomavirus (HPV) (e.g., condylomata acuminate), varicella-zoster virus, cytomegalovirus (CMV), rhinoviruses, hepatitis A virus, hepatitis E virus, Kaposis sarcoma herpesvirus, coronavirus including SARS-Covl, MERS-Cov and SARS-Cov2, retrovirus including HIV, and influenza virus.
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • HDV hepatitis D virus
  • HPV herpes simplex virus
  • HPV papillomavirus
  • HPV papillomavirus
  • CMV papillomavirus
  • rhinoviruses he
  • the viral infection is an infection by hepatitis B virus (HBV), in particular a chronic HBV infection or a chronic HBV hepatitis.
  • HBV hepatitis B virus
  • the additional therapeutic agent to be used in combination for the treatment of HBV is selected from the group consisting of a polymerase inhibitor such as L-nucleosides, deoxyguanosine analogs and nucleoside phosphonates, a nucleoside analog such as lamivudine (Epivir), adefovir (Hepsera), tenofovir (Viread), telbivudine (Tyzeka), entecavir (Baraclude), emtricitabine, and an interferon such as interferon alpha-2a and PEGylated interferon alpha-2a (Pegasys) and interferon alpha-2b (ViraferonPeg ou Introna).
  • a polymerase inhibitor such as L-nucle
  • the viral infection is an infection by hepatitis D virus (HDV), in particular a chronic HDV infection or a chronic HDV hepatitis.
  • HDV hepatitis D virus
  • the additional therapeutic agent to be used in combination for the treatment of HDV infection or HBV and HDV co-infection is selected from the group consisting of: an interferon, for instance an interferon alpha (IFN-a), an interferon lambda or a pegylated form thereof, preferably selected from the group consisting of IFN-a such as IFN-ala, IFN-alb, IFN-a2a, IFN-a2b, and IFN-Z.
  • IFN-a interferon alpha
  • IFN-a interferon lambda
  • pegylated form thereof preferably selected from the group consisting of IFN-a such as IFN-ala, IFN-alb, IFN-a2a, IFN-a2b, and IFN-Z.
  • an antiviral agent specific to HDV for instance a nucleoside analog, a prenylation inhibitor, or a famesyl transferase inhibitor, preferably ribavirin, ritonavir, lonafamib and EBP 921, more preferably ritonavir, lonafarnib or a combination thereof; an antiviral agent specific to HBV, for instance a nucleoside analog such as lamivudine, adefovir, telbivudine, entecavir, tenofovir and emtricitabine; an antiviral agent specific to HBV and HDV, for instance a nucleoside analog such as lamivudine, adefovir, telbivudine, entecavir, tenofovir and emtricitabine; an antiviral agent specific to HBV and HDV, for instance a nucleoside analog such as lamivudine,
  • the disease is a renal disease.
  • the renal disease comprises renal fibrosis, including glomerulosclerosis and/or tubulointerstitial fibrosis.
  • the subject to be treated has a renal fibrosis.
  • the renal fibrosis can be diagnosed based on a kidney biopsy. Alternatively, it can be diagnosed based on an alternative analysis such as magnetic resonance imaging (MRI) or urinary tract proteomics (e.g., CKD273).
  • MRI magnetic resonance imaging
  • CKD273 urinary tract proteomics
  • the renal disease is a chronic kidney disease.
  • the subject has a renal fibrosis and suffers from a chronic kidney disease.
  • Chronic Kidney Disease is defined as the presence of kidney damage (usually detected as urinary albumin excretion of >30 mg/day or equivalent) or decreased kidney function (defined as estimated glomerular filtration rate [eGFR] ⁇ 60 mL/min/1.73 m2) for three or more months, irrespective of the cause.
  • the CKD is a CKD with a stage chosen from Gl, G2, G3a, G3b, G4 or G5, preferably Gl, G2, G3a, G3b, or G4, based upon glomerular filtration rate (eGFR) as indicated in Table A, more preferably G2, G3a, G3b, or G4, still more particularly G2, G3a, or G3b.
  • the subject has a renal fibrosis.
  • the CKD is a CKD with a CKD stage chosen from Al, A2 or A3 based upon albuminuria (ACR).
  • the CKD has a stage selecting from stage 1*, stage 1, stage 2 or stage 3 as defined in Table A.
  • the CKD has a stage selecting from stage 1, stage 2 or stage 3 as defined in Table A.
  • the CKD has a stage selecting from stage 1 or stage 2 as defined in Table A.
  • the subject has a renal fibrosis or CKD and the disease is selected from the group consisting of hypertension, type 2 diabetes, type 1 diabetes, obesity, Non-Alcoholic Steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), metabolic (dysfunction) associated fatty liver disease (MAFLD), ageing, infectious glomerulonephritis, in particular infections such as syphilis, malaria, hepatitis B, hepatitis C or HIV, focal segmental glomerulosclerosis, IgA nephropathy, minimal change glomerulopathy, membranous nephropathy, renal vasculitis, urinary tract obstruction, genetic alterations, autoimmune diseases such as systemic lupus erythematosus (SLE), and drug- or toxin-induced nephropathy such as nephropathy induced by drugs such as captopril, NSAIDs, penicillamine, probenecid, bucillamine, anti-TN
  • the subject has a renal fibrosis or a CKD and the disease is selected from the group consisting of hypertension, type 2 diabetes, type 1 diabetes, obesity, Non-Alcoholic Steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFED), metabolic (dysfunction) associated fatty liver disease (MAFED), ageing, infectious glomerulonephritis, in particular infections such as syphilis, malaria, hepatitis B, hepatitis C or HIV, focal segmental glomerulosclerosis, IgA nephropathy, minimal change glomerulopathy, membranous nephropathy, renal vasculitis, urinary-tract infections, urinary tract obstruction, genetic alterations, autoimmune diseases such as systemic lupus erythematosus (SEE), and drug- or toxin-induced nephropathy such as nephropathy induced by drugs such as captopril, NSAIDs, penicillamine
  • SEE system
  • the subject has a renal fibrosis or a CKD and the disease is a systemic disease affecting the kidney, for instance a disease selected from the group consisting of hypertension, type 2 diabetes, type 1 diabetes, Non-Alcoholic Steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), metabolic (dysfunction) associated fatty liver disease (MAFLD), infectious glomerulonephritis, in particular infections such as syphilis, malaria, hepatitis B, hepatitis C or HIV, renal vasculitis, autoimmune diseases such as systemic lupus erythematosus (SLE), and drug- or toxin-induced nephropathy such as neuphropathy induced by drugs such as captopril, NSAIDs, penicillamine, probenecid, bucillamine, anti-TNF therapy, and tiopronin or by toxins such as inorganic salts (e.g., gold, mercury).
  • a disease selected
  • Thermogravimetric analysis was performed on a TA Instruments TGA Hi-Res 2950 apparatus equipped with an evolved gas analysis furnace. A sample was placed in an opened aluminium basket and analysed according to the following conditions:
  • the dynamic vapor sorption (DVS) analysis (gas water sorption) was performed on a DVS- Intrinsic incubator (SMS Ltd), equipped with DVS-Intrinsic Control Software 1.0.
  • the sample placed in an aluminium basket holder, was submitted to a full-cycle analysis (sorption followed by desorption cycle) under the following conditions:
  • the sample was first pre-dried under a stream of dry air until a stabilized sample mass was observed. Then, the relative humidity was increased by 5 % increments. At each step, the sample mass was allowed to increase until equilibrium is reached (according to a given dm/dt target), and then a new relative humidity rise occurred. Relative humidity was ramped up to 95 %. After equilibration at this point, desorption began in a similar stepwise manner, with sample mass decrease again allowed to stabilize after each incremental humidity decrease.
  • the sample mass recording allowed describing of the whole vapor water sorption/desorption behaviour versus relative humidity.
  • sample EYP001 tromethamine salt (Sample A) was first dried (maintained at 0 % RH) before being submitted to the sorption-desorption cycle. During the preliminary drying phase (sample maintained at 25 °C/0 % RH before starting the vapor water sorption process), the sample lost 0.9 % of its initial mass. This mass loss was roughly consistent with the first mass losses observed by TGA.
  • Figure 5 displays the recorded DVS isotherm plot (water sorption/desorption traces) of the tested sample.
  • Figure 16 presents the XRPD pattern of EYP001 tromethamine salt amorphous form, EYP001 tromethamine crystalline forms I, II, and III. A visual comparison of these patterns clearly shows that an amorphous form of EYP001 tromethamine salt was isolated.
  • a supplemental crystalline form II was obtained starting from the crystalline form I.
  • X-ray diffraction (XRD) analysis was performed on a Briiker D2 Phaser diffractometer, using a copper anti-cathode, a mono-crystalline silicon sample holder and a LynxEye linear detector. Instrument operating conditions for X-ray pattern acquisition were as follows:
  • DSC Differential scanning calorimeter
  • Thermogravimetric analysis was performed on a TA Instruments TGA Hi-Res 2950 apparatus equipped with an evolved gas analysis furnace. A sample was placed in an opened aluminium basket and analysed according to the following conditions:
  • TGA profile of the tromethamine salt (Form II) and TGA detailed integration results are presented in Figure 9 and Table 7, respectively. Upon heating, no mass loss was detected before the beginning of the compound main thermal decomposition (observed with an onset temperature of 220 °C).
  • the dynamic vapor sorption (DVS) analysis (gas water sorption) was performed on a DVS- Intrinsic incubator (SMS Ltd), equipped with DVS-Intrinsic Control Software 1.0.
  • the sample placed in an aluminium basket holder, was submitted to a full-cycle analysis (sorption followed by desorption cycle) under the following conditions:
  • the sample was first pre-dried under a stream of dry air until a stabilized sample mass was observed. Then, the relative humidity was increased by 5 % increments. At each step, the sample mass was allowed to increase until equilibrium is reached (according to a given dm/dt target), and then a new relative humidity rise occurred. Relative humidity was ramped up to 95 %. After equilibration at this point, desorption began in a similar stepwise manner, with sample mass decrease again allowed to stabilize after each incremental humidity decrease.
  • the sample mass recording allowed describing of the whole vapor water sorption/desorption behaviour versus relative humidity.
  • EYP001 tromethamine salt form II sample was first dried (maintained at 0 % RH) before being submitted to the sorption-desorption cycle. During the preliminary drying phase (sample maintained at 25 °C/0 % RH before starting the vapor water sorption process), no significant mass loss was observed.
  • Figure 10 displays the recorded DVS isotherm plot (water sorption/desorption traces) of the tested sample.
  • FaSSIF medium the soluble concentration was assessed after 24 hours of stirring.
  • FeSSIF medium the soluble concentration was assessed after 0.5 hours, 1 hour, 2 hours, and 24 hours of stirring.
  • EYP001 tromethamine salt in all forms displayed a much higher solubility in the pH 4.5 acetate buffer compared to EYP001 free acid, EYP001 Benethamine salt, EYP001 Zinc salt, EYP001 Benzathine salt, and EYP001 Ethylene diamine salt.
  • EYP001 tromethamine salt in all forms showed also a higher solubility compared to EYP001 free acid, EYP001 Piperazine salt, EYP001 Morpholine salt, EYP001 Imidazole salt, EYP001 Benethamine salt, EYP001 Zinc salt, and EYP001 Cyclohexylamine salt (Table 12).
  • EYP001 tromethamine salt in all forms also showed a higher solubility compared to EYP001 free acid and EYP001 Potassium salt (Table 13).
  • Example 3 Pharmacokinetic study
  • EYP001 free acid, EYP001 4,2-aminoethylmorpholine salt, and EYP001 tromethamine salt form I in aqueous formulations (0.5% CMC, 0.25% Tween 80, water) were orally administrated at a dose of 50 mg EqEYP00i/Kg in 3 male rats for each compound.
  • Blood samples were taken at 0.25h, 0.5h, Ih, 2h, 4h, 6h, 8h, 12h, and 24h after oral administration.
  • EYP001 free acid, EYP001 tromethamine salt form II, and EYP001 tromethamine salt form III in aqueous formulations (0.5% CMC, 0.25% Tween 80, water) were orally administrated at a dose of 10 mg EqEYP00i/Kg in 8 male rats for each compound.
  • EYP001 tromethamine salt Form I showed superior exposure (AUC0-24) compared to EYP001 free acid and EYP001 4,2-aminoethylmorpholine salt in Experiment #1.
  • EYP001 tromethamine salt Form II and EYP001 tromethamine salt Form III showed superior exposure (AUC0-24) and higher Cmax compared to EYP001 free acid in Experiment #2 using a higher number of animals. Also, this study clearly demonstrated that the variability of the exposure and the variability of the Cmax were reduced with EYP001 tromethamine salt (including crystalline forms II and III) compared to EYP001 free acid (see CV% in Table 14B).

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Abstract

L'invention concerne un sel de trométhamine de l'acide 4-chloro-5-[4-(2,6-dichlorophényl)sulfonylpipérazin-1-yl]-1-benzofuran-2-carboxylique et ses formes. L'invention concerne également des compositions pharmaceutiques ou vétérinaires comprenant ce sel de trométhamine et leur utilisation pour traiter un certain nombre de maladies.
PCT/EP2024/069807 2023-07-13 2024-07-12 Sel de trométhamine d'acide 4-chloro-5-[4-(2,6-dichlorophényl)sulfonylpipérazin-1-yl]-1-benzofuran-2-carboxylique et diverses formes de celui-ci Pending WO2025012425A1 (fr)

Priority Applications (1)

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CN202480046191.7A CN121646582A (zh) 2023-07-13 2024-07-12 4-氯-5-[4-(2,6-二氯苯基)磺酰基哌嗪-1-基]-1-苯并呋喃-2-甲酸的氨丁三醇盐及其各种形式

Applications Claiming Priority (2)

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EP23306215.7 2023-07-13
EP23306215 2023-07-13

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WO2025012425A1 true WO2025012425A1 (fr) 2025-01-16

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WO2009127321A1 (fr) 2008-04-18 2009-10-22 Merck Patent Gmbh, Dérivés de benzofurane, benzothiophène, benzothiazol en tant que modulateurs de fxr
US20190106749A1 (en) 2017-10-11 2019-04-11 Regeneron Pharmaceuticals, Inc. Inhibition Of HSD17B13 In The Treatment Of Liver Disease In Patients Expressing The PNPLA3 I148M Variation
WO2020172075A1 (fr) * 2019-02-19 2020-08-27 Gilead Sciences, Inc. Formes solides d'agonistes de fxr
US12030861B1 (en) * 2023-07-13 2024-07-09 Enyo Pharma L-lysine salt of 4-chloro-5-[4-(2,6-dichlorophenyl)sulfonylpiperazin-1-yl]-1-benzofuran-2-carboxylic acid and various forms thereof

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WO2009127321A1 (fr) 2008-04-18 2009-10-22 Merck Patent Gmbh, Dérivés de benzofurane, benzothiophène, benzothiazol en tant que modulateurs de fxr
US20190106749A1 (en) 2017-10-11 2019-04-11 Regeneron Pharmaceuticals, Inc. Inhibition Of HSD17B13 In The Treatment Of Liver Disease In Patients Expressing The PNPLA3 I148M Variation
WO2020172075A1 (fr) * 2019-02-19 2020-08-27 Gilead Sciences, Inc. Formes solides d'agonistes de fxr
US12030861B1 (en) * 2023-07-13 2024-07-09 Enyo Pharma L-lysine salt of 4-chloro-5-[4-(2,6-dichlorophenyl)sulfonylpiperazin-1-yl]-1-benzofuran-2-carboxylic acid and various forms thereof

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