WO2024105168A1 - Nouvelles combinaisons utiles pour les traitements de la sla - Google Patents

Nouvelles combinaisons utiles pour les traitements de la sla Download PDF

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WO2024105168A1
WO2024105168A1 PCT/EP2023/082064 EP2023082064W WO2024105168A1 WO 2024105168 A1 WO2024105168 A1 WO 2024105168A1 EP 2023082064 W EP2023082064 W EP 2023082064W WO 2024105168 A1 WO2024105168 A1 WO 2024105168A1
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acid
pharmaceutically acceptable
acceptable salts
compound
formula
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PCT/EP2023/082064
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English (en)
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Pierre MINIOU
Emmanuelle ABGUEGEN
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Inflectis Bioscience
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    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to compounds and combinations that have potential therapeutic applications in treating Amyotrophic Lateral Sclerosis (ALS).
  • the invention provides combined therapies that are capable of exhibiting a curative and/or protective effect against ALS and/or its symptoms.
  • ALS is the most common type of motor neuron disease. It is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntarily muscles. Early symptoms include stiff muscles and muscle twitch, gradually increasing weakness and muscle wasting.
  • Limb-onset ALS begins with weakness in the arms or legs, while bulbar-onset ALS begins with difficulty speaking or swallowing. ALS eventually causes paralysis and early death, usually from respiratory failure.
  • WO 2021/126320 suggests a method of treating ALS symptoms with a combination of a bile acid, such as inter alliae taurursodiol (TURSO), and a phenylbutyrate compound, including 4-phenylbutyric acid (4-PBA).
  • a bile acid such as inter alliae taurursodiol (TURSO)
  • a phenylbutyrate compound including 4-phenylbutyric acid (4-PBA).
  • This combination of two compounds was designed to reduce neuronal death by mitigating endoplasmic reticulum stress and mitochondrial dysfunction and have been investigated in a randomized Phase 2 study in ALS patients (S. Paganoni et al. 2020 NEJM 383:10) where it showed encouraging results.
  • the bile acid taurousodeoxycholic acid (TUDCA) has also been investigated alone in a randomized Phase 2 study in ALS patients (Elia et al. 2016 Eur J Neurol.
  • the compound 2-(2,6-dichlorobenzylidene)hydrazinecarboximidamide also referred to as guanabenz, is an agonist of the alpha-2 adrenergic receptor that is used as an antihypertensive drug.
  • guanabenz is an agonist of the alpha-2 adrenergic receptor that is used as an antihypertensive drug.
  • Guanabenz has been investigated in a randomized Phase 2 study in ALS patients (E.D. Bella et al. 2017 BMJ Open 7, e015434). It showed encouraging results, however, the incidence of hypotension in this study discouraged further development in this indication (E.D. Bella et al. 2021 Brain awab167).
  • a first object of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising: i. a benzylideneguanidine compound of formula (I): and the (Z) and (E) isomers thereof, or a tautomer thereof, or pharmaceutically acceptable salts thereof, wherein:
  • R1 , R2, R3, R4, R5 are independently hydrogen, deuterium, halogen, haloalkyl, alkyl, alkoxy, hydroxyl, aryl, or aryloxy, and ii. a bile acid, or pharmaceutically acceptable salts thereof, wherein the ingredients i and ii are formulated in the same or in separate formulations.
  • the compounds of formula (I) are independently hydrogen, deuterium, halogen, haloalkyl, alkyl, alkoxy, hydroxyl, aryl, or aryloxy, and ii. a bile acid, or pharmaceutically acceptable salts thereof, wherein the ingredients i and ii are formulated in the same or in separate formulations.
  • alkyl includes both saturated straight chain and branched alkyl groups which may be substituted (mono- or poly-) or unsubstituted.
  • the alkyl group is a C1-20 alkyl group, more preferably a C1-15, more preferably still a C1-12 alkyl group, more preferably still, a C1-6 alkyl group, more preferably a C1-3 alkyl group.
  • Particularly preferred alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl.
  • the alkyl group is unsubstituted.
  • aryl refers to a C6-12 aromatic group which may be substituted (mono- or poly-) or unsubstituted. Typical examples include phenyl and naphthyl etc. Suitable substituents include, for example, one or more R 10 groups.
  • the compound of formula (I) may be chosen from : and the (Z) and (E) isomers thereof, or a tautomer thereof, or pharmaceutically acceptable salts thereof.
  • compounds of formula (I) as defined above advantageously exhibit no activity toward the adrenergic a2A receptor.
  • the loss in alpha-2 adrenergic activity renders the compounds therapeutically useful in the treatment of neurodegenerative diseases, including ALS.
  • the absence of alpha-2 adrenergic activity means that compounds of formula (I) can be administered at a dosage suitable to treat ALS, without any significant effect on blood pressure.
  • Compounds of formula (I) may be thus different from guanabenz, if needed.
  • the compound of formula (I) may be 2-(2- chlorobenzylidene)hydrazinecarboximidamide of formula (I’) (also named IFB-088 or icerguastat): or the (Z) and (E) isomers thereof, or a tautomer thereof, or pharmaceutically acceptable salts thereof.
  • Suitable bile acids are disclosed in WO 2021/126320 and WO 2014/158547.
  • the bile acid may be chosen from the group consisting in taurousodeoxycholic acid (TUDCA), taurursodiol (TURSO), ursodeoxycholic acid (UDCA), chenodeoxycholic acid, cholic acid, hyodeoxycholic acid, lithocholic acid, and glycoursodeoxycholic acid, or pharmaceutically acceptable salts thereof.
  • taurousodeoxycholic acid (TUDCA)
  • TURSO taurursodiol
  • UDCA ursodeoxycholic acid
  • cholic acid cholic acid
  • hyodeoxycholic acid hyodeoxycholic acid
  • lithocholic acid and glycoursodeoxycholic acid, or pharmaceutically acceptable salts thereof.
  • TURSO is the taurine conjugate form of UDCA.
  • bile acid may be taurousodeoxycholic acid (TUDCA) of formula:
  • TUDCA is FDA approved for the treatment of biliary cirrhosis.
  • compositions of the invention may comprise:
  • compositions of the invention may comprise one or more further active ingredients.
  • compositions of the invention may further comprise iii. a phenylbutyrate compound.
  • Suitable phenylbutyrate compounds are disclosed in WO2021/126320 and WO 2014/158547.
  • the phenylbutyrate compound may be chosen from the group consisting in 4-phenylbutyric acid (4-PBA), Glyceryl Tri-(4-phenylbutyrate), phenyl acetic acid, 2-(4- Methoxyphenoxy) acetic acid (2-POAA-OMe), 2-(4-Nitrophenoxy) acetic acid (2-POAA- N02), 2-(2-Naphthyloxy) acetic acid (2-NOAA), and pharmaceutically acceptable salts thereof, preferably 4-phenylbutyric acid (4-PBA) of formula:
  • 4-PBA is FDA approved for the treatment of urea cycle disorders.
  • compositions of the invention may comprise:
  • the combinations of ingredients i, ii, and optional iii is referred to as “the combinations of the inventions, whether formulated together or separately, and/or whether administered simultaneously, separately or sequentially.
  • the compounds of the combinations of the invention can be present as salts or esters, in particular pharmaceutically and veterinarily acceptable salts or esters.
  • Pharmaceutically acceptable salts of the compounds of the invention include suitable acid addition or base salts thereof. A review of suitable pharmaceutical salts may be found in Berge et al, J Pharm Sci, 66, 1 -19 (1977). Salts are formed, for example with strong inorganic acids such as mineral acids, e.g.
  • hydrohalic acids such as hydrochloride, hydrobromide and hydroiodide, sulfuric acid, phosphoric acid sulphate, bisulphate, hemisulphate, thiocyanate, persulphate and sulphonic acids; with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (Ci-C4)-alkyl- or aryl-sulfonic acids which are un
  • Preferred salts include, for example, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic sulphonic acids such as methanesulphonate, ethanesulphonate, 2-hydroxyethane sulphonate, camphorsulphonate, 2-naphthalenesulphonate, benzenesulphonate, p- chlorobenzenesulphonate and
  • Esters are formed either using organic acids or alcohols/hydroxides, depending on the functional group being esterified.
  • Organic acids include carboxylic acids, such as alkanecarboxylic acids of 1 to 12 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acid, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (Ci-C4)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-toluen
  • Suitable hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide.
  • Alcohols include alkanealcohols of 1 - 12 carbon atoms which may be unsubstituted or substituted, e.g. by a halogen).
  • the invention includes, where appropriate all enantiomers, diastereoisomers and tautomers of the compounds of the invention.
  • the person skilled in the art will recognise compounds that possess optical properties (one or more chiral carbon atoms) or tautomeric characteristics.
  • the corresponding enantiomers and/or tautomers may be isolated/prepared by methods known in the art. Enantiomers are characterised by the absolute configuration of their chiral centres and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Such conventions are well known in the art (e.g. see ‘Advanced Organic Chemistry’, 3 rd edition, ed. March, J., John Wiley and Sons, New York, 1985).
  • a tautomer form of compound (I) of formula (I’”) is :
  • Compounds of the invention containing a chiral centre may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well- known techniques and an individual enantiomer may be used alone.
  • geometric forms of compound 1 of formula (I’”) are:
  • the present invention contemplates the use of all the individual stereoisomers and geometric isomers of those inhibitor agents, and mixtures thereof.
  • the terms used in the claims encompass these forms, provided said forms retain the appropriate functional activity (though not necessarily to the same degree).
  • the present invention also includes all suitable isotopic variations of the agent or a pharmaceutically acceptable salt thereof.
  • An isotopic variation of an agent of the present invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into the agent and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 0, 35 S, 18 F and 36 CI, respectively.
  • isotopic variations of the agent and pharmaceutically acceptable salts thereof are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • the invention includes compounds of general formula (I) where any hydrogen atom has been replaced by a deuterium atom. Isotopic variations of the agent of the present invention and pharmaceutically acceptable salts thereof of this invention can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents.
  • the compounds or physiologically acceptable salts, esters or other physiologically functional derivatives thereof, described herein may be presented as a pharmaceutical formulation, comprising the compounds or physiologically acceptable salt, ester or other physiologically functional derivative thereof, together with one or more pharmaceutically acceptable carriers therefore and optionally other therapeutic and/or prophylactic ingredients.
  • the carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the pharmaceutical compositions may be for human or animal usage in human and veterinary medicine.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).
  • suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like.
  • suitable diluents include ethanol, glycerol and water.
  • compositions may comprise as, or in addition to, the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s), buffer(s), flavouring agent(s), surface active agent(s), thickener(s), preservative(s) (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
  • suitable binder(s) lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s), buffer(s), flavouring agent(s), surface active agent(s), thickener(s), preservative(s) (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
  • binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose and polyethylene glycol.
  • suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition.
  • preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid.
  • Antioxidants and suspending agents may be also used.
  • compositions include those suitable for oral, topical (including dermal, buccal, ocular and sublingual), rectal or parenteral (including subcutaneous, intradermal, intramuscular and intravenous), nasal, intra-ocularly and pulmonary administration e.g., by inhalation.
  • the formulation may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association an active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • compositions suitable for oral administration wherein the carrier is a solid are most preferably presented as unit dose formulations such as boluses, capsules or tablets each containing a predetermined amount of active compound.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine an active compound in a free-flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, lubricating agent, surface-active agent or dispersing agent.
  • Moulded tablets may be made by moulding an active compound with an inert liquid diluent. Tablets may be optionally coated and, if uncoated, may optionally be scored.
  • Capsules may be prepared by filling an active compound, either alone or in admixture with one or more accessory ingredients, into the capsule shells and then sealing them in the usual manner.
  • Cachets are analogous to capsules wherein an active compound together with any accessory ingredient(s) is sealed in a rice paper envelope.
  • An active compound may also be formulated as dispersible granules, which may for example be suspended in water before administration, or sprinkled on food. The granules may be packaged, e.g., in a sachet.
  • Formulations suitable for oral administration wherein the carrier is a liquid may be presented as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil- in-water liquid emulsion.
  • Formulations for oral administration in the present invention may be presented as: discrete units such as capsules, gellules, drops, cachets, pills or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution, emulsion or a suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; or as a bolus etc.
  • the term “acceptable carrier” includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, glycerol stearate stearic acid, silicone fluid, talc waxes, oils and colloidal silica.
  • Flavouring agents such as peppermint, oil of Wintergreen, cherry flavouring and the like can also be used. It may be desirable to
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent.
  • compositions suitable for oral administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.
  • Formulations for oral administration include controlled release dosage forms, e.g., tablets wherein an active compound is formulated in an appropriate release - controlling matrix, or is coated with a suitable release - controlling film. Such formulations may be particularly convenient for prophylactic use.
  • compositions of the present invention may also be in form of suppositories, pessaries, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions or dusting powders.
  • compositions suitable for parenteral administration include sterile solutions or suspensions of an active compound in aqueous or oleaginous vehicles.
  • Injectable preparations may be adapted for bolus injection or continuous infusion. Such preparations are conveniently presented in unit dose or multi-dose containers which are sealed after introduction of the formulation until required for use.
  • an active compound may be in powder form which is constituted with a suitable vehicle, such as sterile, pyrogen-free water, before use.
  • An active compound may also be formulated as long-acting depot preparations, which may be administered by intramuscular injection or by implantation, e.g., subcutaneously or intramuscularly.
  • Depot preparations may include, for example, suitable polymeric or hydrophobic materials, or ion-exchange resins. Such long-acting formulations are particularly convenient for prophylactic use.
  • Formulations suitable for pulmonary administration via the buccal cavity are presented such that particles containing an active compound and desirably having a diameter in the range of 0.5 to 7 microns are delivered in the bronchial tree of the recipient.
  • such formulations are in the form of finely comminuted powders which may conveniently be presented either in a pierceable capsule, suitably of, for example, gelatin, for use in an inhalation device, or alternatively as a self-propelling formulation comprising an active compound, a suitable liquid or gaseous propellant and optionally other ingredients such as a surfactant and/or a solid diluent.
  • Suitable liquid propellants include propane and the chlorofluorocarbons
  • suitable gaseous propellants include carbon dioxide.
  • Self- propelling formulations may also be employed wherein an active compound is dispensed in the form of droplets of solution or suspension.
  • Such self-propelling formulations are analogous to those known in the art and may be prepared by established procedures. Suitably they are presented in a container provided with either a manually-operable or automatically functioning valve having the desired spray characteristics; advantageously the valve is of a metered type delivering a fixed volume, for example, 25 to 100 microlitres, upon each operation thereof.
  • an active compound may be in the form of a solution or suspension for use in an atomizer or nebuliser whereby an accelerated airstream or ultrasonic agitation is employed to produce a fine droplet mist for inhalation.
  • Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, 0.1 M and preferably 0.05 M phosphate buffer or 0.8%-0.9% saline. Additionally, such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.
  • a process for the preparation of a pharmaceutical or veterinary composition as described above comprising bringing the active compound(s) into association with the carrier, for example by admixture.
  • the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • the invention extends to methods for preparing a pharmaceutical composition comprising bringing a compound of general formula (I) and a bile acid, or pharmaceutically acceptable salts thereof in conjunction or association with a pharmaceutically or veterinarily acceptable carrier or vehicle.
  • the Applicant has demonstrated that the combinations of the invention have potential therapeutic applications in treating and/or preventing a neurodegenerative disorder, such as ALS, and/or symptoms thereof.
  • the present invention thus also relates to a method for treating and/or preventing a neurodegenerative disease or one or more symptoms thereof comprising administering in a patient suffering from said neurodegenerative disease the combination of the invention.
  • the present invention thus also provides for a method for treating and/or preventing a neurodegenerative disease or one or more symptoms thereof comprising administering in a human subject suffering from said neurodegenerative disease i. a benzylideneguanidine compound of formula (I): and the (Z) and (E) isomers thereof, or a tautomer thereof, or pharmaceutically acceptable salts thereof, wherein:
  • R1 , R2, R3, R4, R5 are independently hydrogen, deuterium, halogen, haloalkyl, alkyl, alkoxy, hydroxyl, aryl, or aryloxy, and ii. a bile acid, or pharmaceutically acceptable salts thereof. in a simultaneous, separate and/or sequenced fashion.
  • the compound of formula (I) may be chosen from:
  • the method of the invention may further comprise administering a phenyl butyrate compound, such as 4-phenylbutyric acid (4-PBA), Glyceryl Tri-(4-phenyibutyrate), phenyl acetic acid, 2-(4- Methoxyphenoxy) acetic acid (2-POAA- OMe), 2-(4-Nitrophenoxy) acetic acid (2-POAA- N02), 2-(2-Naphthyloxy) acetic acid (2- NOAA), or pharmaceutically acceptable salts thereof.
  • a phenyl butyrate compound such as 4-phenylbutyric acid (4-PBA), Glyceryl Tri-(4-phenyibutyrate), phenyl acetic acid, 2-(4- Methoxyphenoxy) acetic acid (2-POAA- OMe), 2-(4-Nitrophenoxy) acetic acid (2-POAA- N02), 2-(2-Naphthyloxy) acetic acid (2- NOAA), or
  • the method of the invention comprises administering 2-(2-chlorobenzylidene)hydrazinecarboximidamide or the (Z) and (E) isomers thereof, or a tautomer thereof, or pharmaceutically acceptable salts thereof.
  • TUDCA TUDCA
  • 4-PBA 4-PBA
  • Another aspect of the invention relates to the use of a composition or combination of the invention in the preparation of a medicament for treating and/or preventing a neurodegenerative disorder, such ALS, and/or symptoms thereof.
  • preparation of a medicament includes the use of one or more of the above described ingredients i and ii, and optionally iii are formulated in the same or in separate formulations.
  • composition or combination of the invention for use for treating and/or preventing a neurodegenerative disorder, such ALS, and/or symptoms thereof.
  • terapéuticaally effective amount refers to that amount of the compound being administered which will treat or prevent to some extent a neurodegenerative disorder.
  • the neurodegenerative disease is typically selected from Alzheimer's Disease (AD), Huntington's Disease (HD), Parkinson's Disease (PD), Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP), Amyotrophic Lateral Sclerosis (ALS), Primary Lateral Sclerosis (PLS), Progressive Muscular Atrophy (PMA), Pick's Disease, Creutzfeldt-Jakob's Disease, dementia, Multi-Infarct Dementia, Dementia with Lewy Bodies (DLB), Mixed dementia, Frontotemporal dementia (FTD), FrontoTemporal Lobar Degeneration (FTLD), corticobasal degeneration (CBD) and TDP43-proteinopathies (E.M.J de Boer 2021 J Neurol Neurosurg Psychiatry. 92(1 ): 86-95).
  • AD Alzheimer's Disease
  • HD Huntington's Disease
  • PD Parkinson's Disease
  • MSA Multiple System Atrophy
  • PSP Progressive Supranuclear Palsy
  • ALS
  • the neurodegenerative disease is Amyotrophic Lateral Sclerosis (ALS), or any of its various forms, such as bulbar-onset ALS.
  • ALS Amyotrophic Lateral Sclerosis
  • the neurodegenerative disease is Primary Lateral Sclerosis (PLS) or Progressive Muscular Atrophy (PMA).
  • PLS Primary Lateral Sclerosis
  • PMA Progressive Muscular Atrophy
  • the methods of evaluating the ALS patient’s response to the treatment, and/or evaluating ALS disease progression and/or prevention are chosen from ALS Functional Rating Scale (ALSFRS or ALSFRS-R), ALS-Milano-Torino functional Staging (ALS-MITOS) score, King’s College score, respiratory function, muscle strength, quality of life, weight, speech analysis, cognitive or behavioral function, biomarkers assessment (NF-I, NF-H, TDP-43%), among others.
  • ALS Functional Rating Scale ALSFRS or ALSFRS-R
  • ALS-MITOS ALS-Milano-Torino functional Staging
  • ALS irritable bowel syndrome
  • muscle strength deterioration e.g. weakness in the legs, feet, hands or ankles
  • deficient fine motor skill e.g. weakness in the legs, feet, hands or ankles
  • deficient swallowing e.g. slurred speech
  • deficient breathing e.g. slurred speech
  • untimely crying laughing or yawning
  • thinking or behavioral changes deficient respiratory muscle function, pulmonary dysfunction.
  • ALS symptoms also include trouble walking or doing usual daily activities, tripping and falling.
  • the deficient respiratory muscle function in the human subject is assessed by evaluation of the subject’s vital capacity (VC), maximum mid-expiratory flow rate (MMERF), forced vital capacity (FVC), slow vital capacity (SVC) and/or forced expiratory volume in 1 second (FEVi) , or a combination thereof.
  • VC vital capacity
  • MMERF maximum mid-expiratory flow rate
  • FVC forced vital capacity
  • SVC slow vital capacity
  • FEVi forced expiratory volume in 1 second
  • FEVi forced expiratory volume in 1 second
  • the term “treating” includes abrogating, substantially inhibiting, slowing or reversing the progression of a neurodegenerative disease, substantially ameliorating clinical symptoms of a disease or disorder or substantially improving the survival of a patient.
  • preventing » refers to preventing or delaying the onset of a neurodegenerative disorder, such ALS, and/or of the appearance of the symptoms thereof.
  • the method of the invention may typically include delaying the onset of ALS or its symptoms, ameliorating the condition of the ALS patient, slowing the progression of ALS or its symptoms, prolonging survival of the ALS patient, in particular prolonging the tracheostomy-free survival of the patient, and/or reducing the deterioration of ALS and the symptoms thereof.
  • Tracheostomy-free survival is defined as the time without tracheostomy or permanent noninvasive positive pressure ventilation (NIPPV), or up to death.
  • Permanent NIPPV is often arbitrarily defined within the context of ALS clinical trials as the use of NIPPV for longer than 22 or 23 h a day.
  • the combinations of the present invention may be adapted for oral, rectal, nasal, intrabronchial, topical or parenteral (including subcutaneous, intramuscular, intravenous, intraarterial and intradermal), intraperitoneal or intrathecal administration.
  • the formulation is an orally administered formulation.
  • the formulations may conveniently be presented in unit dosage form, i.e., in the form of discrete portions containing a unit dose, or a multiple or sub-unit of a unit dose.
  • the formulations may be in the form of tablets and sustained release capsules, and may be prepared by any method well known in the art of pharmacy.
  • a person of ordinary skill in the art can easily determine an appropriate dose of one of the instant compositions to administer to a subject.
  • a physician will determine the actual dosage for each active ingredient i, ii or iii which will be most suitable for an individual patient and it will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.
  • the dosages disclosed herein are exemplary of the average case. There can of course be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • an effective amount of a combination of the invention may be administered to target a particular condition or disease.
  • this dosage amount will further be modified according to the type of administration of the compound.
  • parenteral administration of a combination of the invention is preferred.
  • the precise amount thereof which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.
  • the combinations of this invention may also be administered to the patient, in a manner such that the concentration of drug is sufficient to achieve one or more of the therapeutic indications disclosed herein.
  • the compounds of this invention which may have good bioavailability, may be tested in one of several biological assays to determine the concentration of a compound which is required to have a given pharmacological effect.
  • Figure 1 shows the effect on cytoprotection of 2-(2-chlorobenzylidene) hydrazinecarboximidamide and 4-PBA and their combinations.
  • Figure 2 shows the effect on cytoprotection of 2-(2-chlorobenzylidene) hydrazinecarboximidamide and TUDCA and their combinations.
  • Figure 3 illustrates the effects of 2-(2-chlorobenzylidene)hydrazinecarboximidamide and AMX0035 on (A) the survival of SOD1 transgenic motoneurons and (B) on cytoplasmic TDP43 localisation in SOD1 transgenic motoneurons following glutamate intoxication.
  • the reactants and commercial compounds were purchased from Acros Organics or Sigma- Aldrich.
  • cytoprotective effect of phenyl-methylidene guanidine compounds of the invention in combination with a bile acid and/or a phenylbutyrate compound has been assessed by evaluating the viability of Hela cells stressed with tunicamycin and treated with the compounds and their combinations.
  • HeLa cells were seeded in 96 well plate with 2500 cells/well in complete growth medium (EMEM, 2mM glutamine, 10%FBS, Penicillin/Streptomycin 1X) and incubated at 37°C / 5% CO2. The next day, tunicamycin (1 pg/mL) and phenyl-methylidene guanidine compound (10, 7.5, 5, 2.5pM) were added on the cell monolayer with or without TUDCA and/or 4-PBA. The cells were incubated for 48h and the cell viability was assessed by measuring the reduction of WST-8 into formazan.
  • complete growth medium EMEM, 2mM glutamine, 10%FBS, Penicillin/Streptomycin 1X
  • 2-(2-chlorobenzylidene)hydrazinecarboximidamide combined with 4-PBA does not decrease cytoprotection to tunicamycin provided by 2-(2- chlorobenzylidene)hydrazinecarboximidamide alone, thus demonstrating that 4-PBA is not detrimental to the activity of 2-(2-chlorobenzylidene)hydrazinecarboximidamide.
  • TDP-43 was identified as a key component of the insoluble and ubiquitinated cytoplasmic inclusions in the brains of patients suffering from ALS and frontotemporal lobar degeneration (FTLD or FTLD-TDP) diseases. Strikingly, -97% of the ALS cases and ⁇ 45% of all FTLD cases (called: FTLD-TDP) involve TDP- 43’s.
  • MNs Spinal cord motor neurons
  • SOD1 G93A transgenic rat were cultured as described by Boussicault et al., 2020 and Wang et al. 2013. Briefly, pregnant female rats of 14 days gestation were killed using a deep anesthesia with CO2 chamber and a cervical dislocation. Then, fetuses (E14) were removed from the uterus and immediately placed in ice-cold L15 Leibovitz medium with a 2 % penicillin (10,000 U/mL) and streptomycin (10 mg/mL) solution (PS) and 1 % bovine serum albumin (BSA). Spinal cords were removed and placed in ice-cold medium of Leibovitz (L15).
  • DMEM Dulbecco’s modified Eagle’s medium
  • FCS fetal calf serum
  • the supernatant was discarded, and the pellet was resuspended in a defined culture medium consisting of Neurobasal medium with a 2 % solution of B27 supplement, 2 mM of L-glutamine, 2 % of PS solution, and 10 ng/mL of brain-derived neurotrophic factor (BDNF).
  • Viable cells were counted in a Neubauer cytometer, using the trypan blue exclusion test. The cells were seeded at a density of 20,000 per well in 96-well plates precoated with poly-L-lysine and were cultured at 37 °C in an air (95 %)-CO2 (5 %) incubator. The medium was changed every 2 days. The motor neurons were injured with glutamate after 13 days of culture.
  • MAP-2 mouse monoclonal antibody anti microtubule-associated-protein 2
  • TDP-43 a rabbit polyclonal antibody anti-nuclear TAR DNA-binding protein 43 (TDP-43).
  • the antibody TDP-43 was revealed with Alexa Fluor 568 goat anti-rabbit.
  • the cytoplasmic TDP-43 mislocalisation following glutamate intoxication is believed to underlie/contribute to motor neurons degeneration in ALS patients.
  • 100nM of 2-(2- chlorobenzylidene)hydrazinecarboximidamide significantly decreased the cytoplasmic TDP-43 localization in primary rat motoneurons from SOD1 G93A transgenic rats stressed by 5 microM glutamate ( Figure 3B).
  • the combination 100pM PBA + 10pM TUDCA did not significantly decrease the cytoplasmic TDP-43 localization in primary rat motoneurons from SOD1 G93A transgenic rats.

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Abstract

La présente invention concerne le traitement de troubles neurodégénératifs et propose de nouveaux traitements contre de tels troubles, en particulier la SLA. L'invention concerne également de nouvelles combinaisons utiles pour traiter de tels troubles.
PCT/EP2023/082064 2022-11-18 2023-11-16 Nouvelles combinaisons utiles pour les traitements de la sla WO2024105168A1 (fr)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014158547A1 (fr) 2013-03-24 2014-10-02 Amylyx Pharmaceuticals Inc. Compositions pour améliorer la viabilité de cellules et procédés pour leur utilisation
EP2943467A1 (fr) 2013-01-10 2015-11-18 Medical Research Council Dérivés de benzylidèneguanidine et leur utilisation thérapeutique pour le traitement de maladies liées à un mauvais repliement de protéines
WO2016001390A1 (fr) 2014-07-02 2016-01-07 Inflectis Bioscience Dérivés d'o-alkyl-benzylidèneguanidine et leur utilisation thérapeutique pour le traitement de troubles associés à une accumulation de protéines mal repliées
WO2016001389A1 (fr) 2014-07-02 2016-01-07 Inflectis Bioscience Nouvelles utilisations thérapeutiques de dérivés de la benzylidène-guanidine dans le traitement de protéopathies
WO2017021216A1 (fr) 2015-07-31 2017-02-09 Inflectis Bioscience Procédé de traitement de cancer avec une combinaison de dérivés de benzylidèneguanidine et d'agent chimiothérapeutique
US20190038774A1 (en) * 2015-01-26 2019-02-07 The Research Institute At Nationwide Children's Hospital Compounds, compositions, and methods for using hla-f
WO2021126320A1 (fr) 2019-12-16 2021-06-24 Amylyx Pharmaceuticals Inc. Traitement de la sclérose latérale amyotrophique
WO2022125988A1 (fr) * 2020-12-10 2022-06-16 Mayo Foundation For Medical Education And Research DÉGRADATION DE PKCβ1 POUR TRAITER LE CANCER

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2943467A1 (fr) 2013-01-10 2015-11-18 Medical Research Council Dérivés de benzylidèneguanidine et leur utilisation thérapeutique pour le traitement de maladies liées à un mauvais repliement de protéines
WO2014158547A1 (fr) 2013-03-24 2014-10-02 Amylyx Pharmaceuticals Inc. Compositions pour améliorer la viabilité de cellules et procédés pour leur utilisation
EP2978419B1 (fr) * 2013-03-24 2020-04-15 Amylyx Pharmaceuticals Inc. Compositions pour améliorer la viabilité de cellules et procédés pour leur utilisation
WO2016001390A1 (fr) 2014-07-02 2016-01-07 Inflectis Bioscience Dérivés d'o-alkyl-benzylidèneguanidine et leur utilisation thérapeutique pour le traitement de troubles associés à une accumulation de protéines mal repliées
WO2016001389A1 (fr) 2014-07-02 2016-01-07 Inflectis Bioscience Nouvelles utilisations thérapeutiques de dérivés de la benzylidène-guanidine dans le traitement de protéopathies
US20170152220A1 (en) * 2014-07-02 2017-06-01 Inflectis Bioscience O-alkyl-benzylideneguanidine derivatives and therapeutic use for the treatment of disorders associated an accumulation of misfolded proteins
US20190038774A1 (en) * 2015-01-26 2019-02-07 The Research Institute At Nationwide Children's Hospital Compounds, compositions, and methods for using hla-f
WO2017021216A1 (fr) 2015-07-31 2017-02-09 Inflectis Bioscience Procédé de traitement de cancer avec une combinaison de dérivés de benzylidèneguanidine et d'agent chimiothérapeutique
WO2021126320A1 (fr) 2019-12-16 2021-06-24 Amylyx Pharmaceuticals Inc. Traitement de la sclérose latérale amyotrophique
WO2022125988A1 (fr) * 2020-12-10 2022-06-16 Mayo Foundation For Medical Education And Research DÉGRADATION DE PKCβ1 POUR TRAITER LE CANCER

Non-Patent Citations (16)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical Excipients", 1994
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING CO.
BERGE ET AL., J PHARM SCI, vol. 66, 1977, pages 1 - 19
D. TRIBOUILLARD-TANVIER ET AL., PLOS ONE, vol. 3, 2008, pages e1981
DEEPIKA K. ET AL.: "Geometrical Isomerism in Guanabenz Free Base Synthesis, Characterization, Crystal Structure and Theoretical Studies", CRYSTAL GROWTH & DESIGN, 2019
E.D. BELLA ET AL., BMJ OPEN, vol. 7, 2017, pages e015434
E.D. BELLA ET AL., BRAIN AWAB, 2021, pages 167
E.M.J DE BOER, J NEUROL NEUROSURG PSYCHIATRY, vol. 92, no. 1, 2021, pages 86 - 95
ELIA ET AL., EUR J NEUROL., vol. 23, 2016, pages 45 - 52
I. DAS ET AL., SCIENCE, 2015
KAREEM KHALAF ET AL: "Tauroursodeoxycholic acid: a potential therapeutic tool in neurodegenerative diseases", TRANSLATIONAL NEURODEGENERATION, BIOMED CENTRAL LTD, LONDON, UK, vol. 11, no. 1, 4 June 2022 (2022-06-04), pages 1 - 17, XP021303691, DOI: 10.1186/S40035-022-00307-Z *
OCHOA CRISTHIAAN D ET AL: "ROS signaling and ER stress in cardiovascular disease", MOLECULAR ASPECTS OF MEDICINE, PERGAMON PRESS, OXFORD, GB, vol. 63, 22 March 2018 (2018-03-22), pages 18 - 29, XP085474923, ISSN: 0098-2997, DOI: 10.1016/J.MAM.2018.03.002 *
P. TSAYTLER, P. ET AL., SCIENCE, vol. 332, 2011, pages 91 - 94
S. PAGANONI ET AL., NEJM, vol. 383, 2020, pages 10
XIE ET AL.: "LC-MSIMS determination of guanabenz ElZ isomers and its applications to in vitro and in vivo DMPK profiling studies", J PHARMA BIOMED ANALYSIS, 2021, pages 205
ZUCCHI ET AL., ECLINICALMEDICINE, vol. 65, 2023, pages 102256

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