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WO2023036820A1 - Utilisations thérapeutiques de 1-[2-(2,4-diméthyl-phénylsulfanyl)phényl]pipérazine - Google Patents

Utilisations thérapeutiques de 1-[2-(2,4-diméthyl-phénylsulfanyl)phényl]pipérazine Download PDF

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Publication number
WO2023036820A1
WO2023036820A1 PCT/EP2022/074860 EP2022074860W WO2023036820A1 WO 2023036820 A1 WO2023036820 A1 WO 2023036820A1 EP 2022074860 W EP2022074860 W EP 2022074860W WO 2023036820 A1 WO2023036820 A1 WO 2023036820A1
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Prior art keywords
piperazine
phenyl
dimethylphenylsulfanyl
pharmaceutically acceptable
acceptable salt
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Inventor
Bjarke Ebert
Roger S. MCINTYRE
Carsten Walter SPANNHUTH
Christoph FREIHERR VON DER GOLTZ
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H Lundbeck AS
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H Lundbeck AS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics

Definitions

  • the present invention relates to novel uses of l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]- piperazine or a pharmaceutically acceptable salt thereof in the treatment of signs and symptoms of post-CO VID-19 syndrome or ongoing symptomatic COVID-19.
  • a candidate treatment for post-COVID-19 syndrome would preferably be capable of improving measures of cognitive function (i.e., objective and subjective), motivation and energy, as well as reducing fatigue.
  • the candidate treatment would preferably target biological systems subserving circadian rhythms, as well as reward and reinforcement brain mechanisms.
  • the profile of the candidate treatment would preferably have effect on inflammatory cytokines and cellular systems.
  • Vortioxetine [l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine] is a multimodal antidepressant that works through modulation of receptor activity and serotonin transporter inhibition. Vortioxetine has been approved for the treatment of major depression globally in more than 80 countries, including the United States (FDA 2013) and European countries (European Commission 2013). l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine (vortioxetine) is thought to work through a combination of two pharmacological modes of action: reuptake inhibition and receptor activity.
  • l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine is a 5-HT3 and 5-HT7 receptor antagonist, 5-HTIB receptor partial agonist, 5-HTIA receptor agonist and inhibitor of the 5-HT transporter.
  • l-[2- (2,4-dimethyl-phenylsulfanyl)phenyl]piperazine enhances levels of the neurotransmitters serotonin, noradrenalin, dopamine, acetylcholine and histamine in specific areas of the brain. All of these activities are considered to be of clinical relevance and potentially involved in the mechanism of action of the compound.
  • vortioxetine was efficacious, safe, and well tolerated in adults and the elderly with Major Depressive Disorder (MDD), in short-term treatment and long-term maintenance treatment.
  • MDD Major Depressive Disorder
  • the approved therapeutic dose range for vortioxetine in adults is 5 to 20 mg/day.
  • Vortioxetine is established as pro-cognitive, as evidenced by significant improvement on both subjective and objective measures and it also improves general functioning in patients with MDD (Christensen MC. et. al., J. Affect. Disord. (2016), 227, 787-94; McIntyre R. S. et. al. J. Clin. Psychiatry (2017), 78, 15-21). Vortioxetine is documented to improve anticipatory and consummatory measures of reward function/anhedonia in patients with MDD (Cao B, et al., Front Psychiatry. (2019), 10, 17).
  • vortioxetine has demonstrated significant improvement on measures of motivation and energy, is not associated with emotional blunting and has preliminary evidence of improving sleep behaviour and circadian rhythms in patients with MDD (Fagiolini A. et. al. J. Affect: Disord. (2021), 283, 472-9, Cao B., et. al. J. Psychopharmacol. (2019), 33, 1388-94).
  • the invention relates to l-[2-(2,4-dimethyl-phenylsulfanyl)- phenyl] piperazine or a pharmaceutically acceptable salt thereof for use in the treatment of signs and symptoms of ongoing symptomatic COVID-19 or post-COVID-19 syndrome in a subject, wherein said signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia.
  • the invention provides a method for the treatment of signs and symptoms of ongoing symptomatic C OVID- 19 or post-COVID-19 syndrome in a subject, wherein said signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia, the method comprising the administration of a therapeutically effective amount of l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine or a pharmaceutically acceptable salt thereof to a patient in need thereof.
  • the invention provides l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]- piperazine or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of signs and symptoms of ongoing symptomatic COVID-19 or post-COVID-19 syndrome in a subject, wherein said signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia.
  • Compound I l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine and pharmaceutically acceptable salts thereof is referred to as Compound I.
  • a particular salt, e.g. the hydrobromide salt is referred to as Compound I HBr.
  • said pharmaceutically acceptable salts are acid addition salts of acids that are non-toxic.
  • Said salts include salts made from organic acids, such as maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline.
  • Said salts may also be made from inorganic salts, such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Particular mention is made of salts made from methanesulfonic acid, maleic acid, fumaric acid, meso-tartaric acid, (+)-tartaric acid, (-)-tartaric acid, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphorous acid and nitric acid. Distinct mention is made of the hydrobromide salt.
  • the invention provides the use of the hydrobromide salt of l-[2-(2,4-dimethylphenylsulphanyl)- phenyl]piperazine.
  • Oral dosage forms, and in particular tablets, are often preferred by the patients and the medical practitioner due to the ease of administration and the consequent better compliance.
  • the active ingredients are crystalline.
  • the invention relates to the use of Compound I in a crystalline form. The crystallinity of Compound I is evidenced by the XRDP shown in e.g WO 2007/144005.
  • the hydrobromide salt of l-[2-(2,4-dimethylphenylsulphanyl)-phenyl]piperazine may exist in several forms, i.e. it is polymorphic.
  • the polymorphic forms have different properties.
  • the beta form Compound I HBr (as defined in WO 2007/144005) is the more stable as demonstrated by the higher DSC melting point and the lower solubility.
  • the beta form has an attractive combination of low hygroscopicity and solubility, which makes this compound particularly suited for making tablets.
  • the invention provides the use of the hydrobromide salt of l-[2-(2,4-dimethylphenylsulphanyl)- phenyl]piperazine with XRDP reflections at approximately 6.89, 9.73, 13,78 and 14.62 (°20) ( ⁇ 0.1), such as at approximately 6.89, 8.48, 9.73, 13.78, 14.62 and 24.73 (°20) ( ⁇ 0.1).
  • Compound I is provided in an oral drop formulation
  • other salts characterised by higher solubility may be preferred.
  • a compound is administered as an oral drop formulation, a few drops of a concentrated, liquid formulation of said drug is measured out and added to a glass of water, juice or the like that the patient drinks.
  • the antidepressant cipramil is provided as an oral drop formulation at 40 mg/ml.
  • the DL lactate salt of Compound I has been found to have a high solubility and therefore to be particularly suited for oral drop formulations.
  • Vortioxetine is available in some countries as an oral drop formulation at 20 mg/mL.
  • the invention provides the use of the DL- lactate salt of l-[2-(2,4-dimethylphenylsulphanyl)-phenyl]piperazine.
  • Compound I is typically administered in daily doses of 1-100 mg, such as 2- 40 mg, such as 2, 5, 10, 15, 20, 25, 30, 35 mg.
  • a daily dose may involve once daily dosing, or dosing two or more times daily.
  • Compound I is conveniently administered as a pharmaceutical composition which may be prepared by conventional methods in the art. Particular mentioning is made of tablets, which may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine.
  • adjuvants or diluents comprise: anhydrous calcium hydrogen phosphate, PVP, PVP-VA copolymers, microcrystalline cellulose, sodium starch glycolate, corn starch, mannitol, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients.
  • Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to desired volume, sterilising the solution and filling it in suitable ampules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.
  • Oral drop formulations typically comprise, in addition to the active ingredient, excipients selected from solvent, buffer, surfactant, surface tension modifier, viscosity modifier, preservative, antioxidant, colourants, tastes masker, and flavour.
  • compositions which may be used in this invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, liquids etc., or parenterally in the form of solutions for injection.
  • suitable route for example orally in the form of tablets, capsules, powders, syrups, liquids etc.
  • parenterally in the form of solutions for injection for example orally in the form of tablets, capsules, powders, syrups, liquids etc.
  • parenterally in the form of solutions for injection for preparing such compositions, methods well known in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients or other additives normally used in the art may be used.
  • Compound I is administered in unit dosage form containing said compound in an amount of about 1 to 50 mg, such as 5, 10, 15 or 20 mg.
  • Tablets comprising Compound I may conveniently be prepared by wet granulation. Using this method, the dry solids (active ingredients, filler, binder etc.) are blended and moistened with water or another wetting agent (e.g. an alcohol) and agglomerates or granules are built up of the moistened solids. Wet massing is continued until a desired homogenous particle size has been achieved whereupon the granulated product is dried.
  • Compound I is typically mixed with lactose monohydrate, corn starch and copovidone in a high shear mixer together with water.
  • these granulates may be sieved in a sieve with a suitable sieve size, and dried. The resulting, dried granulates are then mixed with microcrystalline cellulose, croscarmellose sodium and magnesium stearate, following which the tablets are pressed.
  • wet granulation of Compound I may be achieved using mannitol, corn starch and copovidone, which granulates are mixed with microcrystalline cellulose, sodium starch glycolate and magnesium stearate before tablets are pressed.
  • wet granulation of Compound I may be achieved by using anhydrous calcium hydrogen phosphate, corn starch and copovidone, which granulates are mixed with microcrystalline cellulose, sodium starch glycolate (type A), talc and magnesium stearate before tablets are pressed.
  • Copovidone is a PVP-VA copolymer.
  • tablets comprising Compound I may be obtained by mixing Compound I, mannitol and microcrystalline cellulose in a fluid bed granulation dryer onto which mixture an aqueous solution of hydroxypropyl cellulose is sprayed to give a granulated powder. The obtained granulates are then mixed with microcrystalline cellulose, sodium starch glycolate and magnesium stearate. The obtained mixture can subsequently be pressed into tablets. Typically, the tablets are coated with a suitable coating material.
  • the invention provides l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the treatment of signs and symptoms of ongoing symptomatic CO VID- 19 or post-COVID- 19 syndrome in a subject, wherein said signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia, and wherein said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide salt, lactic acid salt and pyroglutamate salt.
  • the invention provides l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof according to the use above, wherein l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 1-50 mg l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine.
  • the invention provides l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof according to the uses above, wherein l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 5mg, lOmg, 15 or 20mg l-[2-(2,4-dimethylphenylsulfanyl)- phenyl] piperazine.
  • the invention provides l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof according to the uses above, wherein l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a dose of 5 mg/day, lOmg/day, 15mg/day or 20mg/day of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine.
  • the invention provides l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof according to the uses above, wherein l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered as oral tablets or oral drops.
  • the invention provides l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof according to the uses above, wherein said subject is human.
  • the invention provides a method for the treatment of signs and symptoms of ongoing symptomatic CO VID- 19 or post-COVID- 19 syndrome in a subject, wherein said signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia, the method comprising the administration of a therapeutically effective amount of 1- [2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof to a patient in need thereof.
  • said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide salt, lactic acid salt and pyroglutamate salt.
  • l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 1-50 mg l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine.
  • l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 5mg, lOmg, 15mg or 20mg l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine.
  • l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a dose of 5 mg/day, lOmg/day, 15mg/day or 20mg/day of l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine.
  • l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered as oral tablets or oral drops. In an embodiment said subject is human.
  • the invention provides the use of l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]- piperazine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of signs and symptoms of ongoing symptomatic COVID-19 or post-CO VID-19 syndrome in a subject, wherein said signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia.
  • said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide salt, lactic acid salt and pyroglutamate salt.
  • l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 1-50 mg l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine.
  • l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 5mg, lOmg, 15mg or 20mg l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine.
  • l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a dose of 5 mg/day, lOmg/day, 15mg/day or 20mg/day of l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine.
  • l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered as oral tablets or oral drops. In an embodiment said subject is human.
  • the invention relates to l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the treatment of signs and symptoms of ongoing symptomatic CO VID-19 or post-COVID- 19 syndrome in a subject with ongoing symptomatic COVID-19 or post-COVID- 19 syndrome, wherein said signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia.
  • said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide salt, lactic acid salt and pyroglutamate salt.
  • l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 1-50 mg l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine.
  • l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 5mg, lOmg, 15mg or 20mg l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine.
  • l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a dose of 5 mg/day, lOmg/day, 15mg/day or 20mg/day of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine.
  • l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered as oral tablets or oral drops. In an embodiment said subject is human.
  • the invention relates to l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the treatment of signs and symptoms of post-COVID-19 syndrome in a subject with post-COVID-19 syndrome, wherein said signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia.
  • said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide salt, lactic acid salt and pyroglutamate salt.
  • l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 1-50 mg l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine.
  • l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 5mg, lOmg, 15mg or 20mg l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine.
  • l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a dose of 5 mg/day, lOmg/day, 15mg/day or 20mg/day of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine.
  • l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered as oral tablets or oral drops. In an embodiment said subject is human.
  • the invention relates to l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the treatment of signs and symptoms of ongoing symptomatic CO VID- 19 in a subject with ongoing symptomatic COVID-19, wherein said signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia.
  • said signs and symptoms continue for more than 4 weeks, such as more than 5 weeks, such as more than 6 weeks, such as more than 7 weeks, such as more than 8 weeks, such as more than 9 weeks, such as more than 10 weeks, such as more than 11 weeks following the onset of an infection consistent with COVID-19.
  • said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide salt, lactic acid salt and pyroglutamate salt.
  • l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 1-50 mg l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine.
  • l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 5mg, lOmg, 15mg or 20mg l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine.
  • l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a dose of 5 mg/day, lOmg/day, 15mg/day or 20mg/day of l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine.
  • l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered as oral tablets or oral drops. In an embodiment said subject is human.
  • the invention relates to l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the treatment of signs and symptoms of an infection consistent with CO VID-19 infection in a subject, wherein said signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia.
  • said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide salt, lactic acid salt and pyroglutamate salt.
  • l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 1-50 mg l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine.
  • l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 5mg, lOmg, 15mg or 20mg l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine.
  • l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a dose of 5 mg/day, lOmg/day, 15mg/day or 20mg/day of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine.
  • l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered as oral tablets or oral drops. In an embodiment said subject is human.
  • the invention relates to l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the treatment of signs and symptoms that develop during or after an infection consistent with COVID-19 in a subject, wherein said signs and symptoms continue for more than 4 weeks, such as more than 5 weeks, such as more than 6 weeks, such as more than 7 weeks, such as more than 8 weeks, such as more than 9 weeks, such as more than 10 weeks, such as more than 11 weeks, such as more than 12 weeks following the onset of an infection consistent with COVID-19, and wherein said signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia.
  • said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide salt, lactic acid salt and pyroglutamate salt.
  • l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 1-50 mg l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine.
  • l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 5mg, lOmg, 15mg or 20mg l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine.
  • l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a dose of 5 mg/day, lOmg/day, 15mg/day or 20mg/day of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine.
  • l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered as oral tablets or oral drops. In an embodiment said subject is human.
  • the invention relates to l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the treatment of long term signs and symptoms of COVED- 19 infection in a subject, wherein said long term signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia.
  • said long term signs and symptoms continue for more than 4 weeks, such as more than 5 weeks, such as more than 6 weeks, such as more than 7 weeks, such as more than 8 weeks, such as more than 9 weeks, such as more than 10 weeks, such as more than 11 weeks, such as more than 12 weeks following the onset of said COVID-19 infection.
  • said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide salt, lactic acid salt and pyroglutamate salt.
  • l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 1-50 mg l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine.
  • l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 5mg, lOmg, 15mg or 20mg l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine.
  • l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a dose of 5 mg/day, lOmg/day, 15mg/day or 20mg/day of l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine.
  • l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered as oral tablets or oral drops. In an embodiment said subject is human.
  • the baseline-to-endpoint change in Digit Symbol Substitution Test (DSST) score is an increase of about 12 points, such as 11 points, such as 10 points, such as 9 points, such as 8 points, such as about 6 points, after 8 weeks of administration.
  • DSST Digit Symbol Substitution Test
  • the baseline-to-endpoint change in the Trails Making Test (TMT)-A score is a decrease of about 6 seconds, such as 7 seconds, such as 8 seconds, such as 9 seconds, such as 10 seconds, such as 11 seconds, such as about 12 seconds, after 8 weeks of administration.
  • the baseline-to-endpoint change in the Trails Making Test (TMT)-B score is a decrease of about 16 seconds, such as 18 seconds, such as 19 seconds, such as 20 seconds, such as 21 seconds, such as about 22 seconds, after 8 weeks of administration.
  • the baseline-to-endpoint change in the Rey's auditory verbal learning test (RAVLT) score is an increase by 5, such as by 4, such as by 3 words (acquisition) and an increase by 1, such as by 2, such as by 3 words (delayed recall), after 8 weeks of administration.
  • the baseline-to-endpoint change in the Perceived Deficits Questionnaire, 20-item (PDQ-20) score is a reduction in score of about 14, such as 13, such as 12, such as 11, such as 10, such as about 8, after 8 weeks of administration.
  • the baseline-to-endpoint change in the Fatigue Severity Scale is a reduction of about 3 points, such as 4 points, such as 5 points, such as 6 points, such as 7 points, such as about 8 points, after 8 weeks of administration.
  • the baseline-to-endpoint change in the Snaith Hamilton Pleasure Rating Scale is a decrease of about 2 points, such as 3 points, such as about 4 points after 8 weeks of administration.
  • the baseline-to-endpoint change in the Patient Health Questionnaire, 9- item (PHQ-9) score is a reduction of about 5 points, such as 6 points, such as 7 points, such as 8 points, such as about 9 points after 8 weeks of administration.
  • the baseline-to-endpoint change in the Generalized Anxiety Scale, 7-item is a decrease by about 3 points, such as 4 points, such as 5 points, such as 6 points, such as about 7 points after 8 weeks of administration.
  • the baseline-to-endpoint change in the World Health Organization Wellbeing Scale, 5-item is an increase of about 1 point, such as about 2 points, such as about 3 points after 8 weeks of administration.
  • the baseline-to-endpoint change in the EuroQol, 5-dimension, 5-level (EQ-5D-5L) score is an increase of about 18, such as 20, such as 21, such as 22, such as 23, such as 24, such as about 25 after 8 weeks of administration.
  • the baseline-to-endpoint change in the Sheehan Disability Scale (SDS) is a reduction of about 6 points, such as 7 points, such as 8 points, such as 9 points, such as about 10 points after 8 weeks of administration.
  • the baseline-to-endpoint reduction in the Post-Covid Functional Scale corresponds to a statistically significant improvement after 8 weeks of administration.
  • the baseline-to-endpoint change in the fMRI and Monetary Incentive Delay (MID) Task is a statistically significant change in brain activation after 8 weeks of administration.
  • the baseline-to-endpoint change in the Stanford Expectations of Treatment Scale is an improvement in positive and/or in negative expectancy of more than 1 point, such as of 2 points, such as of 3 points after 8 weeks of administration.
  • the baseline-to-endpoint change in the Behavioural Activation Scale is an improvement of 3 points, such as 4 points, such as 5 points, such as 6 points after 8 weeks of administration.
  • the baseline-to-endpoint change in the International Physical Activity Questionnaire (IPAQ) score is an improvement of about 4 points, such as 5 points, such as 6 points, such as about 7 points after 8 weeks of administration.
  • the Digit Symbol Substitution Test was initiated over a century ago as an experimental tool to understand human associative learning. Its clinical utility, owing to its brevity and high discriminant validity, was first recognized in the 1940s, and now the DSST is among the most commonly used tests in clinical neuropsychology.
  • the DSST is a paper-and- pencil cognitive test presented on a single sheet of paper that requires a subject to match symbols to numbers according to a key located on the top of the page. The subject copies the symbol into spaces below a row of numbers.
  • the DSST is perhaps the most commonly used test in all of neuropsychology, owing to several inherent properties: brevity, reliability, and the minimal impact of language, culture, and education on test performance. DSST offers a practical and effective method to monitor cognitive functions over time in clinical practice.
  • Trails Making Test (TMT)-A/B: The Trail Making Test is commonly used as a diagnostic tool in clinical settings. Poor performance is known to be associated with many types of brain impairment.
  • the test is a neuropsychological test of visual attention and task switching. It consists of two parts in which the subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy.
  • the test can provide information about visual search speed, scanning, speed of processing, mental flexibility, as well as executive functioning.
  • the test can be used to assess change in cognitive function.
  • the Perceived Deficits Questionnaire -- Depression (PDQ) is a brief patient-rated scale to assess subjective cognitive dysfunction in people with depression.
  • the PDQ-D is a 20-item questionnaire that generates a total score and 4 subscale scores (attention/concentration, retrospective memory, prospective memory, and planning/organization).
  • a 5-item version (PDQ-D-5) is also available.
  • the PDQ-D was originally developed as a scale for use in patients with multiple sclerosis. It has since been adapted and validated for use in patients with major depressive disorder. The test can be used to assess change in subjective cognitive functioning.
  • the Fatigue Severity Scale is a 9-item scale which measures the severity of fatigue and its effect on a person's activities and lifestyle in patients with a variety of disorders. It was originally devised for people with Multiple Sclerosis or systemic lupus erythematosus. The test can be used to assess change in severity and impact of fatigue.
  • Snaith Hamilton Pleasure Rating Scale SHAPS: The Snaith-Hamilton Pleasure Scale (SHAPS) is a self-administered, paper-and-pencil questionnaire with 14 items assessing four domains of pleasure response/hedonic experience: interest/pass-times, social interaction, sensory experience, and food/drink. The test can be used to assess change in four domains of pleasure response/hedonic experience: interest/pastimes, social interaction, sensory experience, and food/drink.
  • Patient Health Questionnaire, 9-item is an instrument that is widely used in diagnosing and determining the severity of depression.
  • the PHQ-9 asks patients to rate, on a four-point scale ranging from “not at all” to “most days,” the frequency with which they have experienced certain depression symptoms m the preceding 2 weeks.
  • the test can be used to assess change across self-rated depressive symptoms.
  • GAD-7 Generalized Anxiety Scale, 7-item
  • GAD-7 The Generalised Anxiety Disorder Assessment (GAD-7) is a seven-item instrument that is used to measure or assess the severity of generalised anxiety disorder (GAD). Each item asks the individual to rate the severity of his or her symptoms over the past two weeks. The test can be used to assess change across self-rated general anxiety symptoms.
  • WHO-5 World Health Organization Well being Scale, 5-item
  • WHO-5 The World Health Organization- Five Well-Being Index (WHO-5) is a short self-reported measure of current mental wellbeing. The test can be used to assess change in subjective well-being.
  • Sheehan Disability Scale The SDS (Table 1) is a five-item, self-rated questionnaire designed to measure the extent to which a patient's disability due to an illness or health problem interferes with work/school, social life/leisure activities, and family life/home responsibilities. The test can be used to assess change in functional impairment due to disability.
  • Rey auditory verbal learning test
  • RAVLT The Rey Auditory Verbal Learning Test (RAVLT) is a neuropsychological assessment designed to evaluate verbal memory in patients.
  • the RAVLT can be used to evaluate the nature and severity of memory dysfunction and to track changes in memory function over time.
  • the test can be used to assess change in verbal memory.
  • the EQ-5D-5L is a generic health status measure developed by the EuroQol Group for measurement of quality of daily life, providing descriptions of five dimensions of health status: mobility, self-care, usual activities, pain/ discomfort and anxiety/depression. The test can be used to assess change in quality of daily life across 5 dimensions (mobility, capacity for self-care, conduct of usual activities, pain/discomfort and anxiety/depression).
  • PCFS Post-Covid Functional Scale
  • the PCFS Scale can be used both at the time of hospital discharge, and to monitor functional status post discharge.
  • the scale has been designed to cover the entire range of functional limitations. The test can be used to assess change in functional status over time following COVID-19 infection.
  • fMRI and Monetary Incentive Delay (MID) Task MID is a tool for studying the different stages of reward-based learning, from reward anticipation to its delivery.
  • Stanford Expectations of Treatment Scale may be used in clinical trials to improve statistical sensitivity for detecting treatment differences or in clinical settings to identify patients with poor treatment expectancies.
  • Montgomery- Asberg Depression Rating Scale is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders.
  • CCSRS Columbia-Suicide Severity Rating Scale
  • BAS Behavioral Activation Scale
  • BAS Behavioral Activation Scale
  • BAS is a 24-item self-report questionnaire designed to measure two motivational systems: the behavioral inhibition system (BIS), which corresponds to motivation to avoid aversive outcomes, and the behavioral activation system (BAS), which corresponds to motivation to approach goal-oriented outcomes.
  • RPE Perceived Exertion Scale
  • IPAQ International Physical Activity Questionnaire
  • the CogState Identification Test measures attention using a choice reaction time paradigm.
  • the outcome measure is speed of performance.
  • the CogState Detection Test measures processing speed using a simple reaction time paradigm.
  • the outcome measure is speed of performance.
  • the CogState DSST is a processing speed test that is based on the well-established digit symbol coding paradigm.
  • the outcome measure is total number of correct responses in matching the symbols with the appropriate digits.
  • the CogState One Card Learning Test measures visual memory using a pattern separation paradigm. Outcome measures is accuracy of performance.
  • Acute COVID- 19 means signs and symptoms of COVID- 19 for up to 4 weeks following an infection consistent with COVID-19.
  • CO VID-19 that develop during or after an infection consistent with COVID-19, and continue from 4 to 12 weeks following an infection consistent with COVID-19 (e.g. continue from 4 to 12 weeks after the start of acute COVID 19).
  • the term ‘Subacute COVID-19’ is also intended to indicate signs and symptoms of CO VID-19 from 4 to 12 weeks following an infection consistent with COVID-19, such as from 4 to 12 weeks following the onset of an infection consistent with CO VID- 19.
  • post-CO VID 19 syndrome means: signs and symptoms that develop during or after an infection consistent with COVID- 19, and continue for more than 12 weeks following an infection consistent with COVID-19, (e.g. continue 12 weeks or more after the start of acute COVID 19), and are not explained by an alternative diagnosis.
  • chronic COVID-19 is also intended to indicate signs and symptoms of COVID-19 extending beyond 12 weeks following an infection consistent with COVID-19, such as 12 weeks following the onset of an infection consistent with COVID- 19.
  • An infection consistent with COVID- 19 may be established or confirmed for example by a documented history of SARS-CoV-2 infection with typical symptoms and/or a positive SARS-CoV-2 test (PCR, antigen or antibody) at some point during the course of illness or (in the case of antibodies) also after the acute course of illness.
  • PCR positive SARS-CoV-2 test
  • the onset or start of an infection consistent with COVID-19 may for example be at the onset or start of the typical symptoms of an infection consistent with COVID-19 and/or upon receipt of a positive SARS-CoV-2 test (PCR, antigen or antibody).
  • a positive SARS-CoV-2 test PCR, antigen or antibody
  • long CO VID or “long COVID-19” may be used to describe signs and symptoms that continue or develop after acute CO VID-19. It includes both “ongoing symptomatic COVID-19” (from 4 to 12 weeks after the start of acute COVID 19) and “post-CO VID-19 syndrome” (12 weeks or more after the start of acute COVID 19).
  • the definitions of the above terms are suggested by the NICE guidelines (NICE guideline December 2020: COVID 19 rapid guideline: managing the long-term effects of COVID-19 (NG188)).
  • ‘Signs and symptoms’ of ‘Ongoing symptomatic COVID-19’ may for example be cognitive impairment (e.g. “brain fog”), fatigue, apathy, depression, anxiety, anhedonia, insomnia, anergia, loss of appetite, dyspnea, cough, headaches, and/or chest pain.
  • ‘Signs and symptoms’ of post-CO VID 19 syndrome may for example be cognitive impairment (e.g. “brain fog”), fatigue, apathy, depression, anxiety, anhedonia, insomnia, anergia, loss of appetite, dyspnea, cough, headaches and chest pain.
  • Cognitive deficits ‘Cognitive deficits’, ‘cognitive disturbances’ or ‘cognitive impairment’ as used herein, as a sign and symptom of post-COVID-19 syndrome, ongoing symptomatic COVID-19 or long CO VID include a decline in cognitive functions or cognitive domains, e.g. working memory, attention and vigilance, verbal learning and memory, visual learning and memory, reasoning and problem solving e.g. executive function, speed of processing and/or social cognition.
  • cognitive deficits or cognitive impairment may indicate deficits in attention, disorganized thinking, slow thinking, difficulty in understanding, poor concentration, impairment of problem solving, poor memory, difficulties in expressing thoughts and/or difficulties in integrating thoughts, feelings and behavior, or difficulties in extinction of irrelevant thoughts.
  • it includes “brain fog”.
  • the terms "cognitive deficits”, “cognitive disturbances” and “cognitive impairment” are intended to indicate the same and are used interchangeably.
  • ‘Depression’ as used herein, as a sign and symptom of post-COVID-19 syndrome, ongoing symptomatic COVID-19 or long CO VID, may be characterized by depressive symptoms as defined by DSM-5, e.g. depressed mood, loss of interest/pleasure, weight loss or gain, insomnia or hypersomnia, fatigue or loss of energy, feeling worthless or excessive/inappropriate guilt, and/or decreased concentration.
  • the symptoms may be measured by e.g. MADRS and/or PHQ-9.
  • ’Anhedonia’ as used herein, as a sign and symptom of post-CO VID-19 syndrome, ongoing symptomatic COVID-19 or long CO VID, may be characterized for example by a loss of interest and lack of reactivity to pleasurable stimuli.
  • ’Anxiety’ as used herein, as a sign and symptom of post-COVID-19 syndrome, ongoing symptomatic COVID-19 or long CO VID, may be characterized by symptoms defined by DSM- 5, such as the presence of excessive anxiety and worry, edginess or restlessness, fatigue, impaired concentration, irritability and/or difficulty in sleeping.
  • the symptoms of GAD may be measured by e.g. GAD-7.
  • a “therapeutically effective amount” of a compound as used herein means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of said compound.
  • An amount adequate to accomplish this is defined as "a therapeutically effective amount”.
  • Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician.
  • treatment means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder.
  • the term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications.
  • prophylactic (preventive) and therapeutic (curative) treatment are two separate aspects of the invention.
  • the patient to be treated is preferably a mammal, in particular a human being.
  • All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent permitted by law), regardless of any separately provided incorporation of particular documents made elsewhere herein.
  • vortioxetine in the treatment of cognitive impairment is investigated in a randomized, double-blinded, placebo-controlled clinical trial in persons with post-CO VID- 19 syndrome. Furthermore, the effect of vortioxetine in the treatment of depression, anxiety, fatigue /or anhedonia in persons with post-COVID-19 syndrome is investigated.
  • Approximately 200 subjects are enrolled in a placebo-controlled clinical trial, i.e., approximately 100 subjects are allocated to vortioxetine (10-20 mg) and approximately. 100 subjects are allocated to placebo.
  • Participants receiving vortioxetine will be provided 10 mg/day on days 1-14 of the treatment period, andwill be titrated to 20 mg/day at the start of week 3 (day 15) based on study clinician judgment. For the remaining 6 weeks, the dose of vortioxetine will be 20 mg/day, unless adjudicated otherwise by a study clinician.
  • Baseline-to-endpoint i.e., Week 8
  • DSST Digit Symbol Substitution Test
  • SHAPS Snaith Hamilton Pleasure Rating Scale
  • PCFS Post-Covid Functional Scale
  • MID Monetary Incentive Delay
  • the CogState Online Cognitive Battery employed in the present trial will consist of four tests:
  • Pre-existing conditions that may cause cognitive impairment, or symptoms similar to those seen in post-COVID-19 syndrome (e.g., major neurocognitive disorder, schizophrenia, chronic fatigue syndrome [CFS]/ encephalitis meningitis [EM]), as assessed by Mini International Neuropsychiatric Interview (MINI) 7.0.2.
  • major neurocognitive disorder e.g., schizophrenia, chronic fatigue syndrome [CFS]/ encephalitis meningitis [EM]
  • MINI Mini International Neuropsychiatric Interview
  • Medications approved and/or employed off-label for cognitive dysfunction e.g., psychostimulants.
  • Electroconvulsive therapy in the last 6 months.
  • MAOIs Monoamine Oxidase Inhibitors
  • Participants will be pre-screened via telephone, email, or an online form to determine if they meet above noted inclusion and exclusion criteria.
  • Participants will undergo the various assessments listed in Table 1. In addition, participants will have their blood drawn and may be invited to participate in an optional fMRI scan (see details below). Participants will also be assessed by a study physician and provided a prescription for vortioxetine. Some physician visits may be conducted remotely/ online through a secure platform.
  • Week 2 (Visit 2): Participants will complete items listed in Table 1, Week 2 (Visit 2).
  • Week 4 (Visit 3): Participants will complete items listed in Table 1, Week 4 (Visit 3).
  • This visit may be completed remotely/online.
  • Week 8 (Visit 4): Participants will complete items listed in Week 8 (Visit 4) will be completed. The study physician will also discuss transition of care (see below) and/or medication continuation. Participants will also have their blood drawn and may be asked to participate in the optional fMRI scan.
  • Optional Post-Study Clinical visit with physician if patient discontinuing with medication andas needed. If a participant chooses to continue with the medication, he/she will be asked to follow up with his/her most responsible physician (MRP) for ongoing care and this post-study visit would not be needed.
  • MRP most responsible physician
  • a BAS: Behavioural Activation Scale; CSSRS: Columbia-Suicide Severity Rating Scale; DSST: Digit Symbol Substitution Test; EQ-5D-5L: 5-Level EQ-5D version; fMRI: functional magnetic resonance imaging; FSS: Fatigue Severity Scale; GAD-7: Generalized Anxiety Disorder, 7-item; IPAQ: International Physical Activity Questionnaire; MADRS: Montgomery -Asberg Depression Rating Scale; MID: Monetary Incentive Delay; M I N I: MiniInternational Neuropsychiatric Interview; MoCA: Montreal Cognitive Assessment; PCFS: Post-Covid Functional Scale; PDQ-20: Perceived Deficits Questionnaire, 20-item; PHQ-9: Patient Health Questionnaire, 9-item; RAVLT: Rey's auditory verbal learning test; RPE: Borg Rating of Perceived Exertion Scale; SDS: Sheehan Disability Scale; SETS: Stanford Expectations of Treatment Scale

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Abstract

L'invention concerne des utilisations thérapeutiques de 1-[2-(2,4-diméthyl-phénylsulfanyl)phényl]pipérazine ou un sel pharmaceutiquement acceptable de celle-ci dans le traitement de signes et de symptômes du syndrome post-COVID-19 ou du COVID19 symptomatique en cours.
PCT/EP2022/074860 2021-09-10 2022-09-07 Utilisations thérapeutiques de 1-[2-(2,4-diméthyl-phénylsulfanyl)phényl]pipérazine Ceased WO2023036820A1 (fr)

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