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WO2025104452A1 - Compounds for use in treatment - Google Patents

Compounds for use in treatment Download PDF

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Publication number
WO2025104452A1
WO2025104452A1 PCT/GB2024/052912 GB2024052912W WO2025104452A1 WO 2025104452 A1 WO2025104452 A1 WO 2025104452A1 GB 2024052912 W GB2024052912 W GB 2024052912W WO 2025104452 A1 WO2025104452 A1 WO 2025104452A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
use according
groups
optionally substituted
Prior art date
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Pending
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PCT/GB2024/052912
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French (fr)
Inventor
Luke SLADE
Jonathan David REES
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Mitorx Therapeutics Ltd
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Mitorx Therapeutics Ltd
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Publication date
Application filed by Mitorx Therapeutics Ltd filed Critical Mitorx Therapeutics Ltd
Publication of WO2025104452A1 publication Critical patent/WO2025104452A1/en
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Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • 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 comprising a mitochondrial targeting group linked to a group capable of releasing hydrogen sulphide for use in the treatment of Charcot-Marie-Tooth disease type 2A (CMT2A).
  • CMT2A Charcot-Marie-Tooth disease type 2A
  • the first mitochondria-targeted H2S donor AP39 was reported [Szczesny et al, 2014], The compound is taken up inside the mitochondria because of its lipophilicity and the positive charge of decyl-TPP + .
  • AP39 also showed an increase of intracellular levels of H2S mainly inside the mitochondria in a concentration-dependent manner, an increase in ATP production in endothelial cells, as well as an increase of protein persulfidation inside the mitochondria.
  • AP39 is hygroscopic, has poor aqueous solubility, potential toxicity issues and has not been developed as a drug.
  • Coenzyme Q10 (CoQ10) or ubiquinone, exerts redox and antioxidant effects due to the presence of 1 ,4-benzoquinone ring.
  • CoQ10 also has the ability to interact with other redox carriers in the mitochondrial electron transport chain [Escribano-Lopez et al, 2019], To obtain analogues, with the same antioxidant properties but with a better bioavailability, idebenone was developed by Takeda Chemical Industries (Osaka Japan) and launched in the market as a medicine against age-related brain dysfunction, in 1986 [Sugiyama and Fujita, 1985], No research has been performed to use the mitochondrial targeting properties of idebenone and derivatives to target H2S donors to the mitochondria.
  • a number of idebenone derivatives have been made as antioxidants: A number of idebenone derivatives have also been made as donors of the gasotransmitter nitric oxide:
  • Coenzyme Q Functionalized CdTe/ZnS Quantum Dots for Reactive Oxygen Species (ROS) Imaging Li-Xia Qin et al., Chem. Eur. J. 2011 , 17, 5262-5271 discloses CoQ derivatived QDs as probes to image redox coenzyme function in vitro and in vivo.
  • CMT2A Charcot-Marie-Tooth disease type 2A
  • CMT2A Charcot-Marie-Tooth disease type 2A
  • CMT2A is primarily caused by mutations in the MFN2 gene, which encodes a protein called Mitofusin 2. This protein plays a critical role in mitochondrial fusion and maintaining the health of nerve cells. Mutations in MFN2 disrupt mitochondrial dynamics, leading to nerve cell dysfunction and degeneration. [Zuchner, S., et al (2004), Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nature Genetics, 36(5), 449-451] Individuals with CMT2A typically experience progressive muscle weakness and atrophy, often starting in the lower limbs and later affecting the upper limbs. Sensory loss may also be present. Symptoms may appear in childhood or adulthood, and the severity of the condition can vary among affected individuals. [Chung, K. W., et al (2006), Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations, Brain, 129(8), 2103-2118]
  • MFN2 mitochondrial
  • MFN2 mutations lead to mitochondrial fragmentation and impaired mitochondrial transport along axons, resulting in energy deficits within nerve cells.
  • the progressive nerve damage in CMT2A is due to the loss of axonal integrity and subsequent axonal degeneration. [Baloh, R. Het al (2007), Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations, The Journal of Neuroscience, 27(2), 422-430]
  • the present invention provides active compounds, specifically, mitochondrially targeted hhS donors, as described herein.
  • active specifically includes both compounds with intrinsic activity (drugs) as well as prodrugs of such compounds, which prodrugs may themselves exhibit little or no intrinsic activity.
  • a compound comprising a mitochondrial targeting group linked to a group capable of releasing hydrogen sulfide, or a pharmaceutically acceptable salt thereof, for use in the prevention, management and/or treatment of Charcot-Marie-Tooth disease type 2A (CMT2A).
  • CMT2A Charcot-Marie-Tooth disease type 2A
  • a pharmaceutical composition comprising a compound comprising a mitochondrial targeting group linked to a group capable of releasing hydrogen sulfide, or a pharmaceutically acceptable salt thereof, for use in the prevention, management and/or treatment of Charcot-Marie-Tooth disease type 2A (CMT2A), wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier, excipient, or diluent.
  • CMT2A Charcot-Marie-Tooth disease type 2A
  • a compound comprising a mitochondrial targeting group linked to a group capable of releasing hydrogen sulfide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the prevention, management and/or treatment of Charcot-Marie-Tooth disease type 2A (CMT2A).
  • CMT2A Charcot-Marie-Tooth disease type 2A
  • a method of prevention, management and/or treatment of Charcot-Marie-Tooth disease type 2A (CMT2A) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound comprising a mitochondrial targeting group linked to a group capable of releasing hydrogen sulfide.
  • CMT2A Charcot-Marie-Tooth disease type 2A
  • CMT2A Charcot-Marie-Tooth disease type 2A
  • the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound comprising a mitochondrial targeting group linked to a group capable of releasing hydrogen sulfide, ora pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier, excipient, or diluent.
  • said compounds and the compounds as further defined herein may provide effective treatments for CMT2A by targeting mitochondria through the mitochondrial targeting groups described herein and releasing hydrogen sulphide, from the group capable of releasing hydrogen sulfide as described herein, in the mitochondria to produce the desired physiological effects.
  • Another aspect of the present invention pertains to methods of donating H2S, comprising contacting a cell with an effective amount of an active compound, as described herein, whether in vitro or in vivo.
  • kits comprising (a) the active compound, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the active compound, for use in the prevention, management and/or treatment of Charcot-Marie-Tooth disease type 2A (CMT2A).
  • CMT2A Charcot-Marie-Tooth disease type 2A
  • Another aspect of the present invention pertains to compounds obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • Another aspect of the present invention pertains to compounds obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • Another aspect of the present invention pertains to novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.
  • Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein.
  • One of ordinary skill in the art is readily able to determine whether or not a candidate compound counteracts mitochondrial dysfunction and CMT2A in particular.
  • a candidate compound counteracts mitochondrial dysfunction and CMT2A in particular.
  • one assay which may conveniently be used in order to assess the level of mitochondrial dysfunction offered by a particular compound is described in the examples below.
  • a sample of cells may be grown in vitro and an active compound brought into contact with said cells, and the effect of the compound on those cells observed.
  • effect the morphological status of the cells (e.g., alive or dead, etc.) may be determined.
  • the active compound is found to exert an influence on the cells, this may be used as a prognostic or diagnostic marker of the efficacy of the compound in methods of treating a patient carrying cells of the same cellular type.
  • the invention provides compounds for use in methods of prevention, management and/or treatment of Charcot-Marie-Tooth disease type 2A (CMT2A), comprising administering to a subject in need thereof a therapeutically-effective amount of an active compound, preferably in the form of a pharmaceutical composition.
  • CMT2A Charcot-Marie-Tooth disease type 2A
  • the invention suitably provides compounds for use in the treatment of Charcot-Marie-Tooth disease type 2A (CMT2A), comprising administering to a subject in need thereof a therapeutically-effective amount of an active compound, preferably in the form of a pharmaceutical composition.
  • CMT2A Charcot-Marie-Tooth disease type 2A
  • treatment pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, and cure of the condition.
  • Treatment as a prophylactic measure i.e., prophylaxis is also included.
  • terapéuticaally-effective amount pertains to that amount of an active compound, or a material, composition or dosage form comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio.
  • treatment includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously.
  • treatments and therapies include, but are not limited to small molecules, gene therapy, cell therapy, antibody therapy.
  • Active compounds may also be used, as described above, in combination therapies, that is, in conjunction with other agents, for example, steroids.
  • the active compound or pharmaceutical composition comprising the active compound may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or topically (i.e., at the site of desired action).
  • Routes of administration include, but are not limited to, oral (e.g, by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc,); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g,, by nasal spray); ocular (e.g,, by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g,, via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular,
  • the subject may be an animal, a mammal, a placental mammal, a marsupial, a monotreme a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey an ape or a human.
  • the subject may be any of its forms of development, for example, a spore, a seed, an egg, a larva, a
  • the subject is a human.
  • the active compound While it is possible for the active compound to be used (e.g., administered) alone, it is often preferable to present it as a formulation.
  • compositions comprising a compound, as described herein, and a carrier.
  • the composition is a pharmaceutical composition (e.g., formulation, preparation, medicament) comprising a compound, as described herein, and a pharmaceutically acceptable carrier.
  • the composition is a pharmaceutical composition comprising at least one compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.
  • pharmaceutically acceptable carriers diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.
  • the composition further comprises other active agents, for example, other therapeutic or prophylactic agents.
  • Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts. See, for example, Handbook of Pharmaceutical Additives, 2nd Edition (eds. M. Ash and I. Ash), 2001 (Synapse Information Resources, Inc., Endicott, New York, USA), Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 2nd edition, 1994.
  • Another aspect of the present invention pertains to methods of making a pharmaceutical composition
  • a pharmaceutical composition comprising admixing at least one active compound, as defined above, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the active compound.
  • pharmaceutically acceptable refers to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Each carrier, diluent, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • the formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing Into association the active compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.
  • carriers e.g., liquid carriers, finely divided solid carrier, etc.
  • the formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof.
  • Formulations may suitably be in the form of liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, lozenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols.
  • solutions e.g., aqueous, non-aqueous
  • suspensions e.g., aqueous, non-aqueous
  • Formulations may suitably be provided as a patch, adhesive plaster, bandage, dressing, or the like which is impregnated with one or more active compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation, and absorption enhancers. Formulations may also suitably be provided in the form of a depot or reservoir.
  • the active compound may be dissolved in, suspended in, or admixed with one or more other pharmaceutically acceptable ingredients.
  • the active compound may be presented in a liposome or other microparticulate which is designed to target the active compound, for example, to blood components or one or more organs.
  • Formulations suitable for oral administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.
  • Formulations suitable for buccal administration include mouthwashes, lozenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • Lozenges typically comprise the active compound in a flavored basis, usually sucrose and acacia or tragacanth.
  • Pastilles typically comprise the active compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia.
  • Mouthwashes typically comprise the active compound in a suitable liquid carrier.
  • Formulations suitable for sublingual administration include tablets, lozenges, pastilles, capsules, and pills.
  • Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in- oil), mouthwashes, lozenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • solutions e.g., aqueous, non-aqueous
  • suspensions e.g., aqueous, non-aqueous
  • emulsions e.g., oil-in-water, water-in- oil
  • mouthwashes e.g., lozenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • Formulations suitable for non-oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.
  • solutions e.g., aqueous, non-aqueous
  • suspensions e.g., aqueous, non-aqueous
  • emulsions e.g., oil-in-water, water-in-oil
  • suppositories e.g., pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.
  • Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.
  • Tablets may be made by conventional means, e.g., compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross- linked povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl p-hydroxybenzoate, propyl
  • Molded tablets may be made by molding 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 compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile.
  • Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the stomach.
  • Ointments are typically prepared from the active compound and a paraffinic or a water-miscible ointment base.
  • Creams are typically prepared from the active compound and an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane- 1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
  • the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax
  • the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for intranasal administration, where the carrier is a liquid include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the active compound.
  • Formulations suitable for intranasal administration, where the carrier is a solid include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Formulations suitable for pulmonary administration include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
  • a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
  • Formulations suitable for ocular administration include eye drops wherein the active compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active compound.
  • Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-iiquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.
  • a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-iiquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active compound, such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous or non- aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the active compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate).
  • Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient.
  • excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like.
  • suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
  • the concentration of the active compound in the liquid is from about 1 ng/ml to about 10 pg/ml, for example from about 10 ng/ml to about 1 pg/ml.
  • the formulations may be presented in unit- dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • appropriate dosages of the active compounds, and compositions comprising the active compounds can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects.
  • the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient.
  • the amount of compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
  • Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.
  • kits comprising (a) the active ingredient, preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the active compound, etc.
  • the written instructions may also include a list of indications for which the active ingredient is a suitable treatment.
  • the compound for use as described herein comprises a mitochondrial targeting group linked to a group capable of releasing hydrogen sulfide.
  • Said mitochondrial targeting group and group capable of releasing hydrogen sulfide are suitably as further defined herein.
  • the mitochondrial targeting group and group capable of releasing hydrogen sulfide are linked in the compound.
  • the mitochondrial targeting group and the group capable of releasing hydrogen sulfide are linked by a linker group.
  • the compound for use of the first aspect is of the formula (I):
  • MTG-L-S wherein MTG represents the mitochondrial targeting group; wherein L is a linker group; and wherein S is the group capable of releasing hydrogen sulfide.
  • the linker group L suitably joins the mitochondrial targeting group and the group capable of releasing hydrogen sulfide.
  • Suitably L covalently joins said groups.
  • L suitably comprises a group B which is an optionally substituted alkyl chain, optionally substituted alkenyl chain, or optionally substituted alkynyl chain.
  • B is an unsubstituted C1-20 alkyl chain, suitably a C6-14 alkyl chain, suitably a C8-12 alkyl chain.
  • the linker group L comprises a group Y which is an optionally substituted 5 or 6 membered cycloalkyl or aryl ring.
  • Y is an optionally substituted phenyl group and wherein groups Z and A are attached para to each other on the phenyl group (i.e. in a 1 ,4 arrangement).
  • the Y group may be optionally substituted with one or more of C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkylthio, hydroxy, amino, nitro, thiol, chloro, fluoro, bromo, CF3, CHF2 or CH2F groups.
  • Y is an unsubstituted phenyl group and groups Z and A are attached para to each other on the phenyl group.
  • L has the formula (II):
  • the group capable of releasing hydrogen sulfide is selected from a thiocarbamoyl group, a 5-thioxo-5H-1 ,2-dithiol-3-yl group, a 5-thioxo-5H-1 ,2-dithiol-4-yl group, a 5- oxo-5H-1 ,2-dithiol-3-yl group, a 5-oxo-5H-1 ,2-dithiol-4-yl group, a 5-hydroxyimino-5H-1 ,2-dithiol-3-yl group, a 5-hydroxyimino-5H-1 ,2-dithiol-4-yl group, a phosphinodithioate group or a phosphinodithioic acid group.
  • the group capable of releasing hydrogen sulfide may be selected from: wherein X is S, O or N-OH and R 4 , R 5 and R 6 are independently selected from H or C1-7 alkyl groups.
  • the S group is selected from: wherein X is S or O.
  • S group is selected from:
  • the mitochondrial targeting group is a lipophilic cation, a mitochondrial targeting peptide or a 1 ,4-benzoquinone.
  • the MTG is a lipophilic cation selected from a phosphonium cation, an arsonium cation, an ammonium cation, flupritine, MKT-077, a pyridinium ceramide, a quinolium, a liposomal cation, a sorbitol guanidine, a cyclic guanidine or a rhodamine.
  • Flupritine and MKT-077 are described in Zimmer et al. (Br J Pharmacol, 1998, 123(6), 1 154-8) and Modica-Napolitano et al (Cancer Res., 1996, 56, 544-550).
  • the compound will contain a counterion to the cation, in order for the compound to be charge- balanced.
  • Any suitable counterion known in the art may be used, for example a chloride or bromide anion.
  • the MTG is a phosphonium cation.
  • the phosphonium cation MTG has the formula (HI): wherein X 1 , X 2 and X 3 are each independently C1-12 alkyl, C6-10 aryl, or C1-12 alkylene-Ce-io aryl, wherein the alkyl and alkylene groups and moieties are optionally substituted by one or more, for example one, two or three, of the following groups: halogen atoms, hydroxyl, C1-12 alkoxy or halo- C1- 12 alkoxy groups, and wherein each aryl group or moiety is unsubstituted or substituted by one, two or three halogen atoms, hydroxyl, C1-12 alkoxy or halo- C1-12 alkoxy groups.
  • each alkyl or alkylene group or moiety is unsubstituted or substituted by one or more, such as 1 or 2, halogen atoms.
  • the alkyl and/or alkylene group or moiety is unsubstituted.
  • X 1 , X 2 and X 3 are each a C6-10 aryl group, for example a phenyl group.
  • X 1 , X 2 and X 3 are the same.
  • the mitochondrial targeting group is suitably a triphenylphosphonium cation: Ph 3 P + -.
  • the compound suitably comprises a counterion, for example chloride or bromide anion.
  • the MTG is a mitochondrial targeting peptide.
  • Suitable mitochondrial targeting peptides are as described in Horton et al (Chemistry and Biology 15, 375-382) and Hoye et al (Accounts of Chemical Research, 41 , 1 , 87-97).
  • the MTG is a 1 ,4-benzoquinone or a 1 ,4-naphthoquinone.
  • the MTG suitably has the formula (IV): wherein R 1 and R 2 are independently selected from H, halogen, a C1-6 alkyl group, a C1-6 alkoxy group or together form a cycloalkyl or aryl ring; and wherein R 3 is H, halogen, a C1-6 alkyl group or a C1-6 alkoxy group.
  • R 1 and R 2 are independently selected from H, a C1-6 alkyl group, a C1-6 alkoxy group or together form a cycloalkyl or aryl ring.
  • R 1 and R 2 are independently selected from a C1-6 alkyl group, a C1-6 alkoxy group or together form a cycloalkyl or aryl ring.
  • R 3 is a C1-6 alkyl group or a C1-6 alkoxy group.
  • B is an unsubstituted C1-20 alkyl group
  • Y is an optionally substituted phenyl group and wherein groups Z and A are attached para to each other on the phenyl group; and wherein the S group is selected from: wherein X is S, O or N-OH and R 4 , R 5 and R 6 are independently selected from H or C1-7 alkyl groups.
  • the MTG group is selected from:
  • Ph 3 P + -; the S group is selected from: wherein X is S or O.
  • the compound is selected from:
  • the compound is selected from:
  • the compound is selected from:
  • the compound is selected from:
  • carbo refers to compounds and/or groups which have only carbon and hydrogen atoms.
  • hetero refers to compounds and/or groups which have at least one heteroatom, for example, multivalent heteroatoms (which are also suitable as ring heteroatoms) such as boron, silicon, nitrogen, phosphorus, oxygen, and sulfur, and monovalent heteroatoms, such as fluorine, chlorine, bromine, and iodine.
  • multivalent heteroatoms which are also suitable as ring heteroatoms
  • monovalent heteroatoms such as fluorine, chlorine, bromine, and iodine.
  • saturated refers to compounds and/or groups which do not have any carbon-carbon double bonds or carbon-carbon triple bonds.
  • unsaturated as used herein, pertains to compounds and/or groups which have at ieast one carbon-carbon double bond or carbon-carbon triple bond.
  • aliphatic refers to compounds and/or groups which are linear or branched, but not cyclic (also known as “acyclic” or “open-chain” groups).
  • cyclic refers to compounds and/or groups which have one ring, or two or more rings (e.g., spiro, fused, bridged).
  • ring refers to a closed ring of from 3 to 10 covalently linked atoms, more preferably 3 to 8 covalently linked atoms.
  • aromatic ring refers to a closed ring of from 3 to 10 covalently linked atoms, more preferably 5 to 8 covalently linked atoms, which ring is aromatic.
  • heterocyclic ring refers to a closed ring of from 3 to 10 covalently linked atoms, more preferably 3 to 8 covalently linked atoms, wherein at least one of the ring atoms is a multivalent ring heteroatom, for example, nitrogen, phosphorus, silicon, oxygen, and sulfur, though more commonly nitrogen, oxygen, and sulfur.
  • alicyclic refers to compounds and/or groups which have one ring, or two or more rings (e.g., spiro, fused, bridged), wherein said ring(s) are not aromatic.
  • aromatic refers to compounds and/or groups which have one ring, or two or more rings (e.g., fused), wherein at least one of said ring(s) is aromatic.
  • heterocyclic refers to cyclic compounds and/or groups which have one heterocyclic ring, or two or more heterocyclic rings (e.g., spiro, fused, bridged), wherein said ring(s) may be alicyclic or aromatic.
  • heterocyclic refers to cyclic compounds and/or groups which have one heterocyclic ring, or two or more heterocyclic rings (e.g., fused), wherein said ring(s) is aromatic. Substituents
  • substituted refers to a parent group which bears one or more substituents.
  • substituted is used herein in the conventional sense and refers to a chemical moiety which is covalently attached to, appended to, or if appropriate, fused to, a parent group.
  • substituents are well known, and methods for their formation and introduction into a variety of parent groups are also well known.
  • the substituent(s), often referred to herein as R are independently selected from: halo; hydroxy; ether (e.g., Cualkoxy); formyl; acyl (e.g., C1-7alkylacyl , C5-20arylacyl); acylhalide; carboxy; ester; acyloxy; amido; acylamido; thioamido; tetrazolyl; amino; nitro; nitroso; azido; cyano; isocyano; cyanato; isocyanato; thiocyano; isothiocyano; sulfhydryl; thioether (e.g., C1- Talkylthio); sulfonic acid; sulfonate; sulfone; sulfonyloxy; sulfinyloxy; sulfamino; sulfonamino; sulfinamino; sulfin
  • substituent(s), often referred to herein as R are independently selected from:
  • the substituent(s), often referred to herein as R are independently selected from: hydroxy; ether (e.g., C1-7alkoxy); ester; amido; amino; and, C1-7alkyl (including, e.g., C1-7haloalkyl, C1-7hydroxyalkyl, C1-7carboxyalkyl, C1-7aminoalkyl, C5-20aryl-C1-7alkyl).
  • substituent(s), often referred to herein as R are independently selected from:
  • C1-20alkyl refers to a monovalent moiety obtained by removing a hydrogen atom from a C1-7hydrocarbon compound having from 1 to 20 carbon atoms, which may be aliphatic or alicyclic, or a combination thereof, and which may be saturated, partially unsaturated, or fully unsaturated.
  • Examples of (unsubstituted) saturated linear C 1.20aIky I groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl (amyl), n-octyl, n-nonyl and n-decyl.
  • Examples of (unsubstituted) saturated branched C1-7alkyl groups include, but are not limited to, iso - propyl, iso-butyl, sec-butyl, tert-butyl, and neo-pentyl.
  • saturated alicyclic (also carbocyclic) C1-7alkyl groups include, but are not limited to, unsubstituted groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornane, as well as substituted groups (e.g., groups which comprise such groups), such as methylcyclopropyl, dimethylcyclopropyl, methylcyclobutyl, dimethylcyclobutyl, methylcyclopentyl, dimethylcyclopentyl, methylcyclohexyl, dimethylcyclohexyl, cyclopropylmethyl and cyclohexylmethyl.
  • Examples of (unsubstituted) unsaturated C1-20alkyl groups which have one or more carbon-carbon triple bonds include, but are not limited to, ethynyl (ethinyl) and 2-propynyl (propargyl).
  • Examples of unsaturated alicyclic (also carbocyclic) C1-7alkyl groups which have one or more carbon- carbon double bonds include, but are not limited to, unsubstituted groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl, as well as substituted groups (e.g., groups which comprise such groups) such as cyclopropenylmethyl and cyclohexenylmethyl.
  • substituted C3-20-cycloalkyl groups include, but are not limited to, those with one or more other rings fused thereto, for example, those derived from: indene (C9), indan (2, 3- dihydro-1 H-indene) (C9), tetraline (1 ,2,3,4-tetrahydronaphthalene (C10), adamantane (C10), decalin (decahydronaphthalene) (C12), fluorene (C13), phenalene (C13).
  • 2H-inden-2-yl is a C5cycloalkyl group with a substituent (phenyl) fused thereto.
  • C3-20heterocyclyl refers to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a C3-20heterocyclic compound, said compound having one ring, or two or more rings (e.g., spiro, fused, bridged), and having from 3 to 20 ring atoms, of which from 1 to 10 are ring heteroatoms, and wherein at least one of said ring(s) is a heterocyclic ring.
  • each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms.
  • the prefixes denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms.
  • C5- eheterocyclyl as used herein, pertains to a heterocyclyl group having 5 or 6 ring atoms.
  • groups of heterocyclyl groups include C3-20heterocyclyl, Ca-yheterocyclyl, C5-7heterocyclyL
  • non-aromatic monocyclic heterocyclyl groups include, but are not limited to, those derived from:
  • N-i aziridine (C3), azetidine (C4), pyrrolidine (tetrahydropyrrole) (C5), pyrroline (e.g., 3-pyrroline, 2,5- dihydropyrrole) (C5), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C5), piperidine (C6), dihydropyridine (C6), tetrahydropyridine (C6), azepine (C7); O1: oxirane (C3), oxetane (C4), oxolane (tetrahydrofuran) (C5), oxole (dihydrofuran) (C5), oxane (tetrahydropyran) (C6), dihydropyran (C6), pyran (C6), oxepin (C7); S-i: thiirane (C3), thietane (C4)
  • substituted (non-aromatic) monocyclic heterocyclyl groups include saccharides, in cyclic form, for example, furanoses (C5), such as arabinofuranose, lyxofuranose, ribofuranose, and xylofuranse, and pyranoses (C6), such as allopyranose, altropyranose, glucopyranose, mannopyranose, guiopyranose, idopyranose, galactopyranose, and talopyranose.
  • C5-20aryl refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of a C5-20aromatic compound, said compound having one ring, or two or more rings (e.g., fused), and having from 5 to 20 ring atoms, and wherein at least one of said ring(s) is an aromatic ring.
  • each ring has from 5 to 7 ring atoms.
  • the prefixes denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms.
  • C5-6aryl as used herein, pertains to an aryl group having 5 or 6 ring atoms. Examples of groups of aryl groups include C3-20aryl, C5-7aryl, C5-6aryl.
  • the ring atoms may be all carbon atoms, as in "carboaryl groups” (e.g.,C5-20carboaryl).
  • carboaryl groups include, but are not limited to, those derived from benzene (i.e., phenyl) (C6), naphthalene (C10), azulene (C10), anthracene (C14), phenanthrene (C14), naphthacene (C18), and pyrene (C16).
  • aryl groups which comprise fused rings include, but are not limited to, groups derived from indene (Cs), isoindene (Cs), and fluorene (C13).
  • the ring atoms may include one or more heteroatoms, including but not limited to oxygen, nitrogen, and sulfur, as in “heteroaryl groups.”
  • the group may conveniently be referred to as a “C5-20heteroaryl” group, wherein “C5-20” denotes ring atoms, whether carbon atoms or heteroatoms.
  • each ring has from 5 to 7 ring atoms, of which from 0 to 4 are ring heteroatoms.
  • Examples of monocyclic heteroaryl groups include, but are not limited to, those derived from: N 1: pyrrole (azole) (C5), pyridine (azine) (C6); Oi: furan (oxole) (C5); Si: thiophene (thiole) (C5); N1O1: oxazole (C5), isoxazole (C5), isoxazine (C6); N2O1: oxadiazole (furazan) (C5); N3O1: oxatriazole (C5);
  • N1S1 thiazole (C5), isothiazole (C5); N2: imidazole (1 ,3-diazole) (C5), pyrazole (1 ,2-diazole) (C5), pyridazine(1 ,2-diazine) (C6), pyrimidine (1 ,3-diazine) (C6) (e.g., cytosine, thymine, uracil), pyrazine (1 ,4-diazine) (C6); N3: triazole (C5), triazine (C6); and, Na: tetrazole (C5).
  • heterocyclic groups include, but are not limited to: Cgheterocyclic groups (with 2 fused rings) derived from benzofuran (O1), isobenzofuran (O 1), indole (N1), isoindole (N1), purine (Na) (e.g., adenine, guanine), benzimidazole (N2), benzoxazole (N1O1), benzisoxazole (N1O1), benzodioxoie (O2), benzofurazan (N2O1), benzotriazole (N3), benzothiofuran (Si), benzothiazole (N1S1), benzothiadiazole (N2S); Cioheterocyclic groups (with 2 fused rings) derived from benzodioxan (O2), quinoline (N1), isoquinoline (N1), benzoxazin
  • Heterocyclic groups which have a nitrogen ring atom in the form of an -NH- group may be N-substituted, that is, as -NR-.
  • pyrrole may be N-methyl substituted, to give N-methypyrrole.
  • N-substitutents include, but are not limited to C1-7alkyl, C3- 2oheterocyclyl, C5-20aryl, and acyl groups.
  • quinoline may be substituted to give quinoline N-oxide; pyridine to give pyridine N- oxide; benzofurazan to give benzofurazan N-oxide (also known as benzofuroxan).
  • Monocyclic examples of such groups include, but are not limited to, those derived from: C5: cyclopentanone, cyclopentenone, cyclopentadienone; C6: cyclohexanone, cyclohexenone, cyclohexadienone; Oi: furanone (C5), pyrone (C6); N1: pyrrolidone (pyrrolidinone) (C5), piperidinone (piperidone) (C6), piperidinedionefC6); N2: imidazolidone (imidazolidinone) (C5), pyrazolone (pyrazolinone) (C5), piperazinone (C6), piperazinedione (C6), pyridazinone (C6), pyrimidinone (C6) (e.g., cytosine), pyrimidinedione (C6) (e.g., thymine, uracil), barbituric acid (C6); N
  • Polycyclic examples of such groups include, but are not limited to, those derived from: C9: indenedione; Ni: oxindole (C9); O1: benzopyrone (e.g., coumarin, isocoumarin, chromone) (C10); N1O1: benzoxazolinone (C9), benzoxazolinone (C10); N2: quinazolinedione (C10); Na: purinone (C9) (e.g., guanine).
  • C9 indenedione
  • Ni oxindole
  • O1 benzopyrone (e.g., coumarin, isocoumarin, chromone)
  • N1O1 benzoxazolinone
  • C10 benzoxazolinone
  • N2 quinazolinedione
  • Na purinone (C9) (e.g., guanine).
  • Halo -F, -Cl, -Br, and -I.
  • Civalkoxy -OR, wherein R is a C1-7alkyl group.
  • C1-7alkoxy groups include, but are not limited to, -OCHs (methoxy), -OCH2CH3 (ethoxy) and -OC(CHs)3 (tert-butoxy).
  • Oxo (keto, -one): O.
  • imino (imine): NR, wherein R is an imino substituent, for example, hydrogen, Ci-ralkyl group, a C3- 2oheterocyclyl group, or a C5-20aryl group, preferably hydrogen or a Ci-yalkyl group.
  • R is an acyl substituent, for example, a C1-20alkyl group (also referred to as C1-20alkylacyl or C1-20alkanoyl), a C3-20heterocyclyl group (also referred to as C3- 2oheterocyclylacyl), or a C5-20aryl group (also referred to as Gs-soaryiacyl), preferably a C1-20aikyl group.
  • acyl substituent for example, a C1-20alkyl group (also referred to as C1-20alkylacyl or C1-20alkanoyl), a C3-20heterocyclyl group (also referred to as C3- 2oheterocyclylacyl), or a C5-20aryl group (also referred to as Gs-soaryiacyl), preferably a C1-20aikyl group.
  • R is an acyloxy substituent, for example, a C1.7alk.yl group, a C3-20heterocyclyl group, or a C5-20aryl group, preferably a Ci-yalkyl group.
  • Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide): -C( ; O)NR 1 R 2 , wherein R 1 and R 2 are independently amino substituents, as defined for amino groups.
  • R 1 and R 2 are independently amino substituents, for example, hydrogen, a Cualkyi group (also referred to as C1-7alkyiamino or di-C1-7alkylamino), a C3-20heterocyclyl group, or a C5-20aryl group, preferably H or a C1-7alkyl group, or, in the case of a "cyclic" amino group, R 1 and R 2 , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms.
  • R 1 and R 2 are independently amino substituents, for example, hydrogen, a Cualkyi group (also referred to as C1-7alkyiamino or di-C1-7alkylamino), a C3-20heterocyclyl group, or a C5-20aryl group, preferably H or a C1-7alkyl group, or, in the case of a "cyclic" amino group, R 1 and R 2 ,
  • amino groups include, but are not limited to, -NH2, -NHCH3, - NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, and -NHPh.
  • cyclic amino groups include, but are not limited to, aziridine, azetidino, piperidino, piperazine, morpholino, and thiomorpholino.
  • C1-7alkylthio groups include, but are not limited to, -SCH3 and -SCH2CH3.
  • Sulfonic acid (sulfo): -S( O)2OH.
  • R is a sulfonate substituent, for example, a C1- 7alkyl group, a C3-20heterocyclyl group, or a C5-20aryl group, preferably a Ci-yalkyl group.
  • Sulfone (sulfonyl): -S( O)2R, wherein R is a sulfone substituent, for example, a C1-7alkyl group, a C3-20heterocyclyl group, or a C5-20aryl group, preferably a C1-7alkyl group.
  • R is a sulfone substituent, for example, a C1-7alkyl group, a C3-20heterocyclyl group, or a C5-20aryl group, preferably a C1-7alkyl group.
  • R is a sulfonyloxy substituent, for example, a C1-7alkyl group, a C3- 2oheterocyclyl group, or a C5-20aryi group, preferably a C1-7alkyi group.
  • R is a sulfinyloxy substituent, for example, a C1-7alkyl group, a C3- 2oheterocyciyl group, or a C5-20aryl group, preferably a C1-7aikyl group.
  • R 1 is an amino substituent, as defined for amino groups, and R is a sulfonamino substituent, for example, a Cualkyl group, a C 3 -2oheterocyclyl group, or a C5-20aryl group, preferably a C1-7alkyl group.
  • R 1 is an amino substituent, as defined for amino groups, and R is a sulfinamino substituent, for example, a C1-7alkyl group, a C 3 -2oheterocyclyl group, or a C5-20aryl group, preferably a C1-7alkyl group.
  • R 1 and R 2 are independently amino substituents, as defined for amino groups.
  • a C1-20alkyl group may be substituted with, for example, hydroxy (also referred to as a C1-20hydroxyalkyl group), C1-20alkoxy (also referred to as a C1-7alkoxyalkyl group), amino (also referred to as a C1-20aminoalkyl group), halo (also referred to as a C1-20haloalkyl group), carboxy (also referred to as a C1-20carboxyalkyl group), and C5-20aryl (also referred to as a Co ⁇ oaryl-C1-7alkyl group).
  • hydroxy also referred to as a C1-20hydroxyalkyl group
  • C1-20alkoxy also referred to as a C1-7alkoxyalkyl group
  • amino also referred to as a C1-20aminoalkyl group
  • halo also referred to as a C1-20haloalkyl group
  • carboxy also referred to as a C1-20carboxy
  • a C5-20aryl group may be substituted with, for example, hydroxy (also referred to as a C5- 2ohydroxyaryl group), halo (also referred to as a Cs-2ohaloaryl group), amino (also referred to as a C5- 2oaminoaryl group, e.g., as in aniline), C1-7alkyl (also referred to as a C1-7alkyl”C5-20aryl group, e.g., as in toluene), and C1-7alkoxy (also referred to as a C1-7alkoxy-C5-20aryl group, e.g., as in anisole).
  • hydroxy also referred to as a C5- 2ohydroxyaryl group
  • halo also referred to as a Cs-2ohaloaryl group
  • amino also referred to as a C5- 2oaminoaryl group, e.g., as in aniline
  • C1-7alkyl also
  • C1-20haloalkyl group refers to a C1-20alkyi group in which at least one hydrogen atom (e.g., 1 , 2, 3) has been replaced with a halogen atom (e.g., F, Cl, Br, I). If more than one hydrogen atom has been replaced with a halogen atom, the halogen atoms may independently be the same or different.
  • Every hydrogen atom may be replaced with a halogen atom, in which case the group may conveniently be referred to as a C1-20perhaloalkyl group.”
  • C1-7haioaikyl groups include, but are not limited to, -CF3, -CHF2, -CH2F, -CCI3, -CBrs, - CH2CH2F, -CH2CHF2, and -CH2CF3.
  • C1-20hydroxyalkyl The term "C1-7hydroxyalkyl group,” as used herein, pertains to a C1-20alkyl group in which at least one hydrogen atom has been replaced with a hydroxy group.
  • C1- ?hydroxyalkyl groups include, but are not limited to, -GH2OH,-CH2CH2OH, and -CH(OH)CH2OH.
  • C1-20carboxyaikyi The term "C1-20carboxyaikyl group,” as used herein, pertains to a C1-20alkyl group in which at least one hydrogen atom has been replaced with a carboxy group.
  • Examples of C1- 2ocarboxyalkyl groups include, but are not limited to, -GH2COOH and -CH2CH2COOH.
  • C1-20aminoalkyl The term "C1-20aminoalkyl group,” as used herein, pertains to a C1-20alkyl group in which at least one hydrogen atom has been replaced with an amino group. Examples of C1- 2oaminoalkyl groups include, but are not limited to, -CH2NH2,-CH2CH2NH2, and -CH2CH2N(CH3)2.
  • C1-20alkyl-C5-20aryl The term "C1-20alkyl-C5-20aryl,” as used herein, describes certain C5-20aryl groups which have been substituted with a C1-20alkyl group.
  • C5-20aryl-C1-20alkyl The term "C5-20aryl-C1-20alkyl,” as used herein, describers certain C1-20alkyl groups which have been substituted with a Cs-2oaryl group.
  • C5-20haloaryl The term "C5-20haloaryl,” as used herein, describes certain C5-20aryl groups which have been substituted with one or more halo groups.
  • halophenyl e.g., fluorophenyl, chlorophenyl, bromophenyl, or iodophenyl, whether ortho-, meta-, or para-substituted
  • dihalophenyl e.g., fluorophenyl, chlorophenyl, bromophenyl, or iodophenyl, whether ortho-, meta-, or para-substituted
  • dihalophenyl e.g., fluorophenyl, chlorophenyl, bromophenyl, or iodophenyl, whether ortho-, meta-, or para-substituted
  • dihalophenyl e.g., fluorophenyl, chlorophenyl, bromophenyl, or iodophenyl, whether ortho-, meta-, or para-substituted
  • dihalophenyl e.g., trihalophenyl
  • Some substituents are bidentate, that is, have two points for covalent attachment.
  • a bidentate group may be covalently bound to two different atoms on two different groups, thereby acting as a linker therebetween.
  • a bidentate group may be covalently bound to two different atoms on the same group, thereby forming, together with the two atoms to which it is attached (and any intervening atoms, if present) a cyclic or ring structure. In this way, the bidentate substituent may give rise to a heterocyclic group/compound and/or an aromatic group/compound.
  • the ring has from 3 to 8 ring atoms, which ring atoms are carbon or divalent heteroatoms (e.g., boron, silicon, nitrogen, phosphorus, oxygen, and sulfur, typically nitrogen, oxygen, and sulfur), and wherein the bonds between said ring atoms are single or double bonds, as permitted by the valencies of the ring atoms.
  • the bidentate group is covalently bound to vicinal atoms, that is, adjacent atoms, in the parent group.
  • C1-20alkylene refers to a bidentate moiety obtained by removing two hydrogen atoms, either both from the same carbon atom, or one from each of two different carbon atoms, of a C1-20hydrocarbon compound having from 1 to 20 carbon atoms, which may be aliphatic or alicyclic, or a combination thereof, and which may be saturated, partially unsaturated, or fully unsaturated.
  • linear saturated C1-20alkylene groups include, but are not limited to, -(Chhjn- where n is an integer from 1 to 20, for example, -CH2- (methylene), -CH2CH2- (ethylene), -CH2CH2CH2- (propylene), and -CH2CH2CH2CH2-(butylene).
  • Examples of branched saturated C1-20alkylene groups include, but are not limited to, -CH(CH 3 )-, - CH(CH 3 )CH 2 -, -CH(CH3)CH 2 CH2-, -CH(CH 3 )CH2CH2CH2-, -CH 2 CH(CH3)CH2-, CH 2 CH(CH 3 )CH2CH2-, -CH(CH 2 CH 3 )-, -CH(CH 2 CH 3 )CH2-, and -CH2CH(CH 2 CH 3 )CH2-.
  • alicyclic saturated C1-20alkylene groups include, but are not limited to, cyclopentylene (e.g., cyclopent-1 ,3-ylene), and cyclohexylene (e.g., cyclohex-1 ,4-ylene).
  • alicyclic partially unsaturated C1-20alkylene groups include, but are not limited to, cyclopentenylene (e.g., 4-cyclopenten-1 ,3-ylene), cyclohexenylene (e.g., 2-cyclohexen-1 ,4-ylene, 3-cyclohexen-1 ,2-ylene, 2,5-cyclohexadien-1 ,4-ylene).
  • cyclopentenylene e.g., 4-cyclopenten-1 ,3-ylene
  • cyclohexenylene e.g., 2-cyclohexen-1 ,4-ylene, 3-cyclohexen-1 ,2-ylene, 2,5-cyclohexadien-1 ,4-ylene.
  • C5-20arylene refers to a bidentate moiety obtained by removing two hydrogen atoms, one from each of two different ring atoms of a C5-20aromatic compound, said compound having one ring, or two or more rings (e.g., fused), and having from 5 to 20 ring atoms, and wherein at least one of said ring(s) is an aromatic ring.
  • each ring has from 5 to 7 ring atoms.
  • the ring atoms may be all carbon atoms, as in “carboarylene groups,” in which case the group may conveniently be referred to as a "C5-20carboarylene” group.
  • the ring atoms may include one or more heteroatoms, including but not limited to oxygen, nitrogen, and sulfur, as in “heteroarylene groups.”
  • the group may conveniently be referred to as a “C5-20heteroarylene” group, wherein “C5-20” denotes ring atoms, whether carbon atoms or heteroatoms.
  • C5-20aryiene groups which do not have ring heteroatoms include, but are not limited to, those derived from benzene (i.e., phenyl) (C6), naphthalene (C 10), anthracene (C-u), phenanthrene (CI4), and pyrene (C16).
  • C5-20heteroarylene groups include, but are not limited to, C5heteroarylene groups derived from furan (oxole), thiophene (thiole), pyrrole (azole), imidazole (1 ,3-diazole), pyrazole (1 ,2-diazole), triazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, and oxatriazole; and C6heteroarylene groups derived from isoxazine, pyridine (azine), pyridazine (1 ,2-diazine), pyrimidine (1 ,3-diazine; e.g., cytosine, thymine, uracil), pyrazine (1 ,4-diazine), triazine, tetrazole, and oxadiazole (furazan).
  • C5-20Arylene-C1-20alkylene The term "C5-20arylene-C1-20alkyiene,” as used herein, pertains to a bidentate moiety comprising a C5-20aryiene moiety, -Arylene-, linked to a C1-20alkylene moiety, - Alkylene-, that is, -Arylene-Alkylene-.
  • C5-20aryiene-C1-20aikylene groups include, but are not limited to, phenylene-methylene, phenylene-ethylene, phenylene-propylene, and phenyiene-ethenylene (also known as phenylene- vinylene).
  • C5-20Alkylene-C1-20arylene The term "C5-20alkylene- C1-20arylene," as used herein, pertains to a bidentate moiety comprising a C5-20alkylene moiety, -Alkylene-, linked to a C1-20arylene moiety, - Arylene-, that is, -Alkyiene-Arylene-.
  • C5-20aikyiene-C1-20arylene groups include, but are not limited to, methylene-phenylene, ethylene-phenylene, propylene-phenylene, and ethenylene-phenylene (also known as vinylene- phenylene).
  • a reference to carboxylic acid also includes carboxylate (-COO-).
  • a reference to an amino group includes a salt, for example, a hydrochloride salt, of the amino group.
  • a reference to a hydroxyl group also includes conventional protected forms of a hydroxyl group.
  • a certain compound may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; el- and p-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers” (or "isomeric forms").
  • isomers are structural (or constitutional) isomers (i.e,, isomers which differ in the connections between atoms rather than merely by the position of atoms in space).
  • a reference to a methoxy group, -OCHs is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH.
  • a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl.
  • keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.
  • a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof.
  • Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein in a known manner.
  • a reference to a particular compound also includes ionic, salt, solvate (e.g., hydrate), protected forms, and prodrugs thereof, for example, as discussed below.
  • a corresponding salt of the active compound for example, a pharmaceutically-acceptable salt.
  • a pharmaceutically-acceptable salt examples are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. ScL Vol. 66, pp. 1 ⁇ 19.
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K+, alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al +3 .
  • suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4 + ) and substituted ammonium ions (e.g., NHsFT, NH2R2L NHF?3 + , NRr).
  • Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine.
  • An example of a common quaternary ammonium ion is N(CHs)4 ⁇
  • a salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, anions from the following organic acids: acetic, propionic, succinic, gycolic, stearic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetyoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanesulfonic, ethane disulfonic, oxalic, isethionic, and valeric.
  • organic acids include, but are not limited to, anions from the following organic acids: acetic, propionic, succinic, gycolic, stearic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-ace
  • solvate Is used herein In the conventional sense to refer to a complex of solute (e.g., active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a dl-hydrate, a tri-hydrate, etc. It may be convenient or desirable to prepare, purify, and/or handle the active compound in a chemically protected form.
  • chemically protected form pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions, that is, are in the form of a protected or protecting group (also known as a masked or masking group).
  • a protected or protecting group also known as a masked or masking group.
  • the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
  • an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH3); a benzyloxy amide (-NHCO- OCH2C6H5, -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CH3)3, -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OC(CH3)2C6HaC6H5, -NH-Bpoc), as a 9-fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2- trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NHCO
  • a carboxylic acid group may be protected as an ester or an amide, for example, as: a benzyl ester; a t-butyl ester; a methyl ester; or a methyl amide.
  • -SR thioether
  • benzyl thioether an acetamidomethyl ether
  • prodrug refers to a compound which, when metabolised, yields the desired active compound.
  • the prodrug is inactive, or less active than the active compound, but may provide advantageous handling, administration, or metabolic properties.
  • some prodrugs are esters of the active compound; during metabolysis, the ester group is cleaved to yield the active drug.
  • some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound.
  • the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
  • H may be in any isotopic form, including 1 H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 12 C, 13 C, and 14 G; O may be in any isotopic form, including 16 O and 18 O; and the like.
  • a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof.
  • Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein in a known manner.
  • Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine.
  • An example of a common quaternary ammonium ion is N/GHsR.
  • a salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, anions from the following organic acids: acetic, propionic, succinic, gycolic, stearic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaieic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetyoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanesulfonic, ethane disulfonic, oxalic, isethionic, and valeric.
  • organic acids include, but are not limited to, anions from the following organic acids: acetic, propionic, succinic, gycolic, stearic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaieic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic,
  • the term "chemically protected form,” as used herein, pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions, that is, are in the form of a protected or protecting group (also known as a masked or masking group).
  • a protected or protecting group also known as a masked or masking group.
  • ADT-OH 5-p-hydroxyphenyl-l,2-dithiole-3-thione
  • ADT-OH can be prepared using the method described in US 2008/0004245
  • N,N'-dicyclohexylcarbodiimide (431 mg, 2.09 mmol)
  • 4-dimethylaminopyridine (12 mg, 0.0995 mmol).
  • the resulting suspension was filtered through cotton wool and the filtrate was concentrated in vacuo. Purification by flash column chromatography, loading as a dichloromethane solution and eluting with ethyl acetate then methanol, gave a mixture of the phosphonium salt and silica.
  • Example 2 was synthesised starting from idebenone.
  • the idebenone was oxidised by a modified literature procedure [Bowden K., Heilbron I.M., Jones E.R.H., Weedon B.C.L. Acetylenic compounds, I, Preparation of acetylenic ketones by oxidation of acetylenic carbinols and glycols. J. Chem. Soc., 1946, 39-45], Jones reagent (0.3 M) was prepared by dissolving sodium dichromate dihydrate (8.940 g; 0.03 mol) in 80 ml of deionised water in an ice bath and the mixture was stirred at room temperature until the salt was completely dissolved.
  • the 10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1 ,4-dien-1-yl)decanoic acid (352 mg; 1.00 mmol) was dissolved in dichloromethane (8 ml). The solution was stirred at room temperature and ADTOH (226 mg; 1.00 mmol) was added to it. DMAP (12 mg, 0.10 mmol) and a solution of DCCI (309 mg; 1 .50 mmol) in the same solvent (5 ml) were added to the initial solution, which was stirred at room temperature for 18 h. The reaction mixture was washed with deionised water (4 x 15 ml).
  • Example 3 was prepared as follows by first preparing 10-(3-methyl-1 ,4-dioxo-1 ,4-dihydronaphthalen- 2-yl)decanoic acid by a modified version of a reported literature protocol [Salmon-Chemin L., Buisine E., Yardley V., Kohler S., Debreu M.A., Landry V., Sergheraert C., Croft S.L., Krauth-Siegel R.L., Davioud-Charvet E.
  • Example compounds 1 , 2 and 3 were screened for potential efficacy in the treatment of Charcot- Marie-Tooth disease type 2A using the animal model described below, which utilises the Fzo1 mutated C elegans strain discussed above.
  • C elegans strains were age synchronised by gravity flotation and ⁇ 80 L1 larvae were placed on 33 mm petri dishes (20 LTs per 33mm plate) containing 2 mL NGM agar (50 mM NaCI, 0.25% (w/v) bacteriological peptone, 1.7% (w/v) agar, 1 mM CaCh, 1 mM MgSCM, 25 mM KH2PO4 (pH 6), 12.9 pM cholesterol) and seeded with 200 pL of OP50 Escherichia coli bacteria.
  • NGM agar 50 mM NaCI, 0.25% (w/v) bacteriological peptone, 1.7% (w/v) agar, 1 mM CaCh, 1 mM MgSCM, 25 mM KH2PO4 (pH 6), 12.9 pM cholesterol
  • test compound treatments 100 pL of dilute test compound (100 pL of 2.3 pM intermediate of test compound dilution in 0.23% DMSO for 100 nM and 0.01 %, respectively) were diluted into a 2.3 mL plate volume to achieve the desired final concentration.
  • Control animals were grown on plates seeded with 100 pL of 0.23% DMSO (0.01 % final) as vehicle controls. Animals were grown on petri dishes for ⁇ 48 h at 20 °C to reach young adulthood, then washed off using 3 ml M9 buffer (3 g KH2PO4, 6 g Na2HPO4, 5 g NaCI, 1 ml 1 M MgSO4 per litre) and pooled into 60 cm petri dishes.
  • Average values were taken from movement scores between all three frames. In addition to software automation, each video was manually corrected for any false positives/ box deformations that could skew movement scores. Daily mean movement values were converted to area under the curve to denote total population movement scores across the entire lifecourse.
  • Figures 1 , 2 and 3 show lifespan curves for healthspan-deficient mutant containing a mutant Fzo1 screened with the example compounds 1 , 2 and 3. Data are from ⁇ 80 animals per strain, where lifespan and movement were assessed every day starting from day 1 of adult life until death. Survival effects were assessed using Kaplan Meier analysis
  • the effect of drug treatment is assessed by measuring the number of subjects survived or saved after that intervention over a period of time. The time starting from a defined point to the occurrence of death is called survival time.
  • the Kaplan Meier analysis shows that all three compounds, which come from three different chemical classes of mitochondrially targeted H2S donors all improve survival of the Fzo1 (mitofusin) mutated worms.
  • This worm is an animal model for Charcot -Marie- Tooth disease type 2a where in humans a mitofusin protein is also mutated .

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Abstract

The invention relates to compounds comprising a mitochondrial targeting group linked to a group capable of releasing hydrogen sulphide for use in the prevention, management and/or treatment of Charcot-Marie- Tooth disease type 2A in a subject in need thereof.

Description

Compounds for use in Treatment
Field
The present invention relates to compounds comprising a mitochondrial targeting group linked to a group capable of releasing hydrogen sulphide for use in the treatment of Charcot-Marie-Tooth disease type 2A (CMT2A).
Background
Mitochondria-targeted H2S donor compounds
In 2014, the first mitochondria-targeted H2S donor AP39 was reported [Szczesny et al, 2014], The compound is taken up inside the mitochondria because of its lipophilicity and the positive charge of decyl-TPP+. AP39 also showed an increase of intracellular levels of H2S mainly inside the mitochondria in a concentration-dependent manner, an increase in ATP production in endothelial cells, as well as an increase of protein persulfidation inside the mitochondria. However, AP39 is hygroscopic, has poor aqueous solubility, potential toxicity issues and has not been developed as a drug.
Idebenone
Coenzyme Q10 (CoQ10) or ubiquinone, exerts redox and antioxidant effects due to the presence of 1 ,4-benzoquinone ring. CoQ10 also has the ability to interact with other redox carriers in the mitochondrial electron transport chain [Escribano-Lopez et al, 2019], To obtain analogues, with the same antioxidant properties but with a better bioavailability, idebenone was developed by Takeda Chemical Industries (Osaka Japan) and launched in the market as a medicine against age-related brain dysfunction, in 1986 [Sugiyama and Fujita, 1985], No research has been performed to use the mitochondrial targeting properties of idebenone and derivatives to target H2S donors to the mitochondria.
A number of idebenone derivatives have been made as antioxidants:
Figure imgf000003_0001
A number of idebenone derivatives have also been made as donors of the gasotransmitter nitric oxide:
Figure imgf000004_0001
Figure imgf000005_0001
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000009_0001
There remains a pressing unmet clinical need for H2S donating molecules with improved properties which are targeted towards the mitochondria. “In Vitro Antioxidant Activity of Idebenone Derivative-Loaded Solid Lipid Nanoparticles” Lucia Montenegro et al., Molecules 2017, 22, 887 discloses idebenone derivatives for the treatment of neurodegenerative diseases involving mitochondria dysfunctions.
“Coenzyme Q Functionalized CdTe/ZnS Quantum Dots for Reactive Oxygen Species (ROS) Imaging”, Li-Xia Qin et al., Chem. Eur. J. 2011 , 17, 5262-5271 discloses CoQ derivatived QDs as probes to image redox coenzyme function in vitro and in vivo.
Charcot-Marie-Tooth disease type 2A
Charcot-Marie-Tooth disease type 2A (CMT2A) is a hereditary neurological disorder characterized by progressive peripheral neuropathy, primarily affecting the peripheral nerves responsible for motor and sensory functions.
CMT2A is primarily caused by mutations in the MFN2 gene, which encodes a protein called Mitofusin 2. This protein plays a critical role in mitochondrial fusion and maintaining the health of nerve cells. Mutations in MFN2 disrupt mitochondrial dynamics, leading to nerve cell dysfunction and degeneration. [Zuchner, S., et al (2004), Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nature Genetics, 36(5), 449-451] Individuals with CMT2A typically experience progressive muscle weakness and atrophy, often starting in the lower limbs and later affecting the upper limbs. Sensory loss may also be present. Symptoms may appear in childhood or adulthood, and the severity of the condition can vary among affected individuals. [Chung, K. W., et al (2006), Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations, Brain, 129(8), 2103-2118]
MFN2 mutations lead to mitochondrial fragmentation and impaired mitochondrial transport along axons, resulting in energy deficits within nerve cells. The progressive nerve damage in CMT2A is due to the loss of axonal integrity and subsequent axonal degeneration. [Baloh, R. Het al (2007), Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations, The Journal of Neuroscience, 27(2), 422-430]
Diagnosis of CMT2A involves clinical evaluation, nerve conduction studies, electromyography, and genetic testing to identify MFN2 mutations. [Reilly, M. M., & Shy, M. E. (2009), Diagnosis and new treatments in genetic neuropathies, Journal of Neurology, Neurosurgery & Psychiatry, 80(12), 1304- 1314]
Ongoing research is exploring potential therapeutic interventions, including gene therapy and mitochondrial-targeted treatments, aimed at slowing the progression of CMT2A. [Rocha, A. G., & Grice, G. L. (2020), The role of mitochondria in the pathogenesis of Charcot-Marie-Tooth disease, Cellular and Molecular Life Sciences, 77(9), 1697-1715] To aid the discovery of therapeutic agents, a number of animal models have been developed, notably the Fzo1 mutated C elegans. [Soh M.S. et al (2020), Disruption of genes associated with Charcot-Marie-Tooth type 2 lead to common behavioural, cellular and molecular defects in Caenorhabditis elegans PLoS 15(4): e0231600] Several mammalian models are also currently under development. There is currently no cure for CMT2A. Management primarily focuses on symptom relief and supportive care, which may include physical therapy, orthopaedic interventions, and assistive devices. [Pareyson, D., et (2015), Charcot-Marie-Tooth disease and related hereditary neuropathies: from gene function to associated phenotypes, Current Molecular Medicine, 15(10), 1076-1089] There is therefore a great need for therapeutics which can act upon the disease itself.
Summary of the Invention
It is one aim ofthe present invention, amongst others, to provide a compound for use in the treatment of CMT2A and a method of treating CMT2A that addresses at least one disadvantage of the prior art, whether identified here or elsewhere, or to provide an alternative to existing compounds and/or treatments.
According to aspects of the present invention, there is provided a compound for use and a method as set forth in the appended claims. Other features of the invention will be apparent from the dependent claims, and from the description which follows.
The present invention provides active compounds, specifically, mitochondrially targeted hhS donors, as described herein.
The term "active," as used herein, specifically includes both compounds with intrinsic activity (drugs) as well as prodrugs of such compounds, which prodrugs may themselves exhibit little or no intrinsic activity.
According to a first aspect of the present invention, there is provided a compound comprising a mitochondrial targeting group linked to a group capable of releasing hydrogen sulfide, or a pharmaceutically acceptable salt thereof, for use in the prevention, management and/or treatment of Charcot-Marie-Tooth disease type 2A (CMT2A).
According to a second aspect of the present invention, there is provided a pharmaceutical composition comprising a compound comprising a mitochondrial targeting group linked to a group capable of releasing hydrogen sulfide, or a pharmaceutically acceptable salt thereof, for use in the prevention, management and/or treatment of Charcot-Marie-Tooth disease type 2A (CMT2A), wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier, excipient, or diluent.
According to a third aspect of the present invention, there is provided a use of a compound comprising a mitochondrial targeting group linked to a group capable of releasing hydrogen sulfide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the prevention, management and/or treatment of Charcot-Marie-Tooth disease type 2A (CMT2A).
According to a fourth aspect of the present invention, there is provided a method of prevention, management and/or treatment of Charcot-Marie-Tooth disease type 2A (CMT2A) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound comprising a mitochondrial targeting group linked to a group capable of releasing hydrogen sulfide.
According to a further aspect of the present invention, there is provided a method of prevention, management and/or treatment of Charcot-Marie-Tooth disease type 2A (CMT2A) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound comprising a mitochondrial targeting group linked to a group capable of releasing hydrogen sulfide, ora pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier, excipient, or diluent.
The inventors have found that said compounds and the compounds as further defined herein may provide effective treatments for CMT2A by targeting mitochondria through the mitochondrial targeting groups described herein and releasing hydrogen sulphide, from the group capable of releasing hydrogen sulfide as described herein, in the mitochondria to produce the desired physiological effects.
Another aspect of the present invention pertains to methods of donating H2S, comprising contacting a cell with an effective amount of an active compound, as described herein, whether in vitro or in vivo.
Another aspect of the present invention pertains to a kit comprising (a) the active compound, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the active compound, for use in the prevention, management and/or treatment of Charcot-Marie-Tooth disease type 2A (CMT2A).
Another aspect of the present invention pertains to compounds obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
Another aspect of the present invention pertains to compounds obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein. Another aspect of the present invention pertains to novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.
Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein.
One of ordinary skill in the art is readily able to determine whether or not a candidate compound counteracts mitochondrial dysfunction and CMT2A in particular. For example, one assay which may conveniently be used in order to assess the level of mitochondrial dysfunction offered by a particular compound is described in the examples below.
For example, a sample of cells may be grown in vitro and an active compound brought into contact with said cells, and the effect of the compound on those cells observed. As an example of "effect," the morphological status of the cells (e.g., alive or dead, etc.) may be determined. Where the active compound is found to exert an influence on the cells, this may be used as a prognostic or diagnostic marker of the efficacy of the compound in methods of treating a patient carrying cells of the same cellular type.
Methods of Treatment
The invention provides compounds for use in methods of prevention, management and/or treatment of Charcot-Marie-Tooth disease type 2A (CMT2A), comprising administering to a subject in need thereof a therapeutically-effective amount of an active compound, preferably in the form of a pharmaceutical composition.
The invention suitably provides compounds for use in the treatment of Charcot-Marie-Tooth disease type 2A (CMT2A), comprising administering to a subject in need thereof a therapeutically-effective amount of an active compound, preferably in the form of a pharmaceutical composition.
Treatment
The term "treatment," as used herein in the context of treating a condition, pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, and cure of the condition. Treatment as a prophylactic measure (i.e., prophylaxis) is also included.
The term "therapeutically-effective amount," as used herein, pertains to that amount of an active compound, or a material, composition or dosage form comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio.
The term "treatment" includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously. Examples of treatments and therapies include, but are not limited to small molecules, gene therapy, cell therapy, antibody therapy.
Active compounds may also be used, as described above, in combination therapies, that is, in conjunction with other agents, for example, steroids.
One of ordinary skill in the art is readily able to determine whether or not a candidate compound treats a condition involving mitochondrial dysfunction for any particular cell type. For example, assays which may conveniently be used to assess the activity offered by a particular compound are described in the examples below.
Routes of Administration
The active compound or pharmaceutical composition comprising the active compound may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or topically (i.e., at the site of desired action).
Routes of administration include, but are not limited to, oral (e.g, by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc,); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g,, by nasal spray); ocular (e.g,, by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g,, via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrastemal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.
The Subject
The subject may be an animal, a mammal, a placental mammal, a marsupial, a monotreme a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey an ape or a human. Furthermore, the subject may be any of its forms of development, for example, a spore, a seed, an egg, a larva, a pupa, or a foetus.
Suitably, the subject is a human.
Formulations
While it is possible forthe active compound to be used (e.g., administered) alone, it is often preferable to present it as a formulation.
Thus, one aspect of the present invention pertains to a composition comprising a compound, as described herein, and a carrier. in one embodiment, the composition is a pharmaceutical composition (e.g., formulation, preparation, medicament) comprising a compound, as described herein, and a pharmaceutically acceptable carrier.
In one embodiment, the composition is a pharmaceutical composition comprising at least one compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.
In one embodiment, the composition further comprises other active agents, for example, other therapeutic or prophylactic agents.
Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts. See, for example, Handbook of Pharmaceutical Additives, 2nd Edition (eds. M. Ash and I. Ash), 2001 (Synapse Information Resources, Inc., Endicott, New York, USA), Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 2nd edition, 1994.
Another aspect of the present invention pertains to methods of making a pharmaceutical composition comprising admixing at least one active compound, as defined above, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the active compound.
The term "pharmaceutically acceptable" as used herein pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.
The formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing Into association the active compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.
The formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof.
Formulations may suitably be in the form of liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, lozenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols.
Formulations may suitably be provided as a patch, adhesive plaster, bandage, dressing, or the like which is impregnated with one or more active compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation, and absorption enhancers. Formulations may also suitably be provided in the form of a depot or reservoir.
The active compound may be dissolved in, suspended in, or admixed with one or more other pharmaceutically acceptable ingredients. The active compound may be presented in a liposome or other microparticulate which is designed to target the active compound, for example, to blood components or one or more organs.
Formulations suitable for oral administration (e.g, by ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.
Formulations suitable for buccal administration include mouthwashes, lozenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. Lozenges typically comprise the active compound in a flavored basis, usually sucrose and acacia or tragacanth. Pastilles typically comprise the active compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia. Mouthwashes typically comprise the active compound in a suitable liquid carrier.
Formulations suitable for sublingual administration include tablets, lozenges, pastilles, capsules, and pills.
Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in- oil), mouthwashes, lozenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
Formulations suitable for non-oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.
Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.
Tablets may be made by conventional means, e.g., compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross- linked povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl p-hydroxybenzoate, propyl p- hydroxybenzoate, sorbic acid); flavours, flavour enhancing agents, and sweeteners. Molded tablets may be made by molding 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 compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the stomach.
Ointments are typically prepared from the active compound and a paraffinic or a water-miscible ointment base.
Creams are typically prepared from the active compound and an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane- 1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
Emulsions are typically prepared from the active compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax, and the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low. Thus the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
Formulations suitable for intranasal administration, where the carrier is a liquid, include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the active compound.
Formulations suitable for intranasal administration, where the carrier is a solid, include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
Formulations suitable for pulmonary administration (e.g., by inhalation or insufflation therapy) include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases. Formulations suitable for ocular administration include eye drops wherein the active compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active compound.
Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-iiquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active compound, such carriers as are known in the art to be appropriate.
Formulations suitable for parenteral administration (e.g., by injection), include aqueous or non- aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the active compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate). Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
Typically, the concentration of the active compound in the liquid is from about 1 ng/ml to about 10 pg/ml, for example from about 10 ng/ml to about 1 pg/ml. The formulations may be presented in unit- dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
It will be appreciated by one of skill in the art that appropriate dosages of the active compounds, and compositions comprising the active compounds, can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient. The amount of compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.
Kits
One aspect of the invention pertains to a kit comprising (a) the active ingredient, preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the active compound, etc.
The written instructions may also include a list of indications for which the active ingredient is a suitable treatment.
As will be appreciated by one of skill in the art, features and suitable embodiments of one aspect of the invention will also pertain to other aspects of the invention.
The active compounds
The compound for use as described herein comprises a mitochondrial targeting group linked to a group capable of releasing hydrogen sulfide. Said mitochondrial targeting group and group capable of releasing hydrogen sulfide are suitably as further defined herein. The mitochondrial targeting group and group capable of releasing hydrogen sulfide are linked in the compound. Suitably the mitochondrial targeting group and the group capable of releasing hydrogen sulfide are linked by a linker group.
Suitably the compound for use of the first aspect is of the formula (I):
MTG-L-S; wherein MTG represents the mitochondrial targeting group; wherein L is a linker group; and wherein S is the group capable of releasing hydrogen sulfide. The linker group L suitably joins the mitochondrial targeting group and the group capable of releasing hydrogen sulfide. Suitably L covalently joins said groups.
L suitably comprises a group B which is an optionally substituted alkyl chain, optionally substituted alkenyl chain, or optionally substituted alkynyl chain.
Suitably B is an unsubstituted C1-20 alkyl chain, suitably a C6-14 alkyl chain, suitably a C8-12 alkyl chain.
L suitably comprises a group Z selected from a direct bond, -C(=O)NH-, -NHC(=O)-, -O-, -S-, - S(=O)2NH-, -NHS(=O)2-, -OC(=O)-, -C(=O)O-, -OC(=O)CH2O- and -OCH2C(=O)O-. Suitably Z is -OC(=O)-, -C(=O)O-, -OC(=O)CH2O- or -OCH2C(=O)O-. Suitably Z is -OC(=O)-, -OC(=O)CH2O- or -C(=O)O-. Suitably Z is -C(=O)O- or -OC(=O)CH2O-. Suitably Z is -C(=O)O-.
Suitably the linker group L comprises a group Y which is an optionally substituted 5 or 6 membered cycloalkyl or aryl ring. Suitably Y is an optionally substituted phenyl group and wherein groups Z and A are attached para to each other on the phenyl group (i.e. in a 1 ,4 arrangement).
The Y group may be optionally substituted with one or more of C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkylthio, hydroxy, amino, nitro, thiol, chloro, fluoro, bromo, CF3, CHF2 or CH2F groups.
Suitably Y is an unsubstituted phenyl group and groups Z and A are attached para to each other on the phenyl group.
Suitably L has the formula (II):
-B-Z-Y- wherein B is an optionally substituted alkyl chain, optionally substituted alkenyl chain, or optionally substituted alkynyl chain; wherein Z is selected from: a direct bond, -C(=O)NH-, -NHC(=O)-, -O-, -S-, -S(=O)2NH-, -NHS(=O)2-, -OC(=O)- , -C(=O)O-, -OC(=O)CH2O- and -OCH2C(=O)O-; and wherein Y is an optionally substituted 5 or 6 membered cycloalkyl or aryl ring. In some embodiments, the group capable of releasing hydrogen sulfide is selected from a thiocarbamoyl group, a 5-thioxo-5H-1 ,2-dithiol-3-yl group, a 5-thioxo-5H-1 ,2-dithiol-4-yl group, a 5- oxo-5H-1 ,2-dithiol-3-yl group, a 5-oxo-5H-1 ,2-dithiol-4-yl group, a 5-hydroxyimino-5H-1 ,2-dithiol-3-yl group, a 5-hydroxyimino-5H-1 ,2-dithiol-4-yl group, a phosphinodithioate group or a phosphinodithioic acid group.
The group capable of releasing hydrogen sulfide may be selected from:
Figure imgf000022_0001
wherein X is S, O or N-OH and R4, R5 and R6 are independently selected from H or C1-7 alkyl groups.
Suitably the S group is selected from:
Figure imgf000022_0002
wherein X is S or O.
Suitably the S group is selected from:
Figure imgf000022_0003
Suitably the mitochondrial targeting group (MTG) is a lipophilic cation, a mitochondrial targeting peptide or a 1 ,4-benzoquinone.
In some embodiments, the MTG is a lipophilic cation selected from a phosphonium cation, an arsonium cation, an ammonium cation, flupritine, MKT-077, a pyridinium ceramide, a quinolium, a liposomal cation, a sorbitol guanidine, a cyclic guanidine or a rhodamine. Flupritine and MKT-077 are described in Zimmer et al. (Br J Pharmacol, 1998, 123(6), 1 154-8) and Modica-Napolitano et al (Cancer Res., 1996, 56, 544-550). In such embodiments wherein the MTG is a lipophilic cation, the skilled person will appreciate that the compound will contain a counterion to the cation, in order for the compound to be charge- balanced. Any suitable counterion known in the art may be used, for example a chloride or bromide anion.
Suitably the MTG is a phosphonium cation. Suitably the phosphonium cation MTG has the formula (HI):
Figure imgf000023_0001
wherein X1, X2 and X3 are each independently C1-12 alkyl, C6-10 aryl, or C1-12 alkylene-Ce-io aryl, wherein the alkyl and alkylene groups and moieties are optionally substituted by one or more, for example one, two or three, of the following groups: halogen atoms, hydroxyl, C1-12 alkoxy or halo- C1- 12 alkoxy groups, and wherein each aryl group or moiety is unsubstituted or substituted by one, two or three halogen atoms, hydroxyl, C1-12 alkoxy or halo- C1-12 alkoxy groups.
In such embodiments, suitably each alkyl or alkylene group or moiety is unsubstituted or substituted by one or more, such as 1 or 2, halogen atoms. Suitably the alkyl and/or alkylene group or moiety is unsubstituted.
Suitably X1, X2 and X3 are each a C6-10 aryl group, for example a phenyl group. Suitably X1, X2 and X3 are the same.
In such embodiments, the mitochondrial targeting group is suitably a triphenylphosphonium cation: Ph3P+-.
In such embodiments, the compound suitably comprises a counterion, for example chloride or bromide anion.
In some embodiments, the MTG is a mitochondrial targeting peptide. Suitable mitochondrial targeting peptides are as described in Horton et al (Chemistry and Biology 15, 375-382) and Hoye et al (Accounts of Chemical Research, 41 , 1 , 87-97).
In some embodiments, the MTG is a 1 ,4-benzoquinone or a 1 ,4-naphthoquinone. In such embodiments, the MTG suitably has the formula (IV):
Figure imgf000024_0001
wherein R1 and R2 are independently selected from H, halogen, a C1-6 alkyl group, a C1-6 alkoxy group or together form a cycloalkyl or aryl ring; and wherein R3 is H, halogen, a C1-6 alkyl group or a C1-6 alkoxy group.
Suitably R1 and R2 are independently selected from H, a C1-6 alkyl group, a C1-6 alkoxy group or together form a cycloalkyl or aryl ring.
Suitably R3 is H, a C1-6 alkyl group or a C1-6 alkoxy group.
Suitably R1 and R2 are independently selected from a C1-6 alkyl group, a C1-6 alkoxy group or together form a cycloalkyl or aryl ring.
Suitably R3 is a C1-6 alkyl group or a C1-6 alkoxy group.
In some embodiments R1 and R2 are both Ci-s alkoxy groups, suitably C1.3 alkoxy groups, suitably - OMe.
In such embodiments, suitably R3 is an C1-6 alkyl group, suitably a C1.3 alkoxy group. Suitably R1 and R2 are both -OMe and R3 is an C1-3 alkyl group. Suitably R1 and R2 are both -OMe and R3 is a methyl group.
In embodiments wherein R1 and R2 together form a cycloalkyl or aryl ring, the cycloalkyl or aryl ring is suitably a 5-, 6- and 7-membered cycloalkyl or aryl ring, suitably a 5-, 6- and 7-membered aryl ring. The cycloalkyl or aryl ring may be optionally substituted, suitably with one or more of C1-C4 alkyl, C1- 04 alkoxy, C1-C4 alkylamino, C1-C4 alkylthio, hydroxy, amino, nitro, thiol, chloro, fluoro, bromo, CF3, CHF2 or CH2F groups.
In such embodiments R1 and R2 suitably form a 5- or 6- membered aryl ring, suitably a 6-membered aryl ring. Therefore in such embodiments, the MTG is suitably a 1 ,4-naphthoquinone group.
In some embodiments, the compound has the formula (I): MTG-L-S; wherein the MTG group is selected from: a phosphonium cation, suitably of formula (III) as defined above; or a 1 ,4-benzoquinone or 1 ,4-naphthoquinone, suitably of formula (IV) as defined above: wherein the L group has the formula (II): -B-Z-Y-; wherein
B is an unsubstituted C1-20 alkyl group;
Z is selected from -OC(=O)-, -OC(=O)CH2O- and -C(=O)O-; and
Y is an optionally substituted phenyl group and wherein groups Z and A are attached para to each other on the phenyl group; and wherein the S group is selected from:
Figure imgf000025_0001
wherein X is S, O or N-OH and R4, R5 and R6 are independently selected from H or C1-7 alkyl groups.
In such embodiments, suitably the MTG group is selected from:
Ph3P+-;
Figure imgf000025_0002
the S group is selected from:
Figure imgf000025_0003
wherein X is S or O.
In some embodiments, the compound is selected from:
Figure imgf000026_0001
Figure imgf000027_0001
In some embodiments, the compound is selected from:
Figure imgf000027_0002
Figure imgf000028_0001
In some embodiments, the compound is selected from:
10
Figure imgf000029_0001
In some embodiments, the compound is selected from:
Figure imgf000030_0001
Other suitable example compounds may be as described in WO 2023041906 A1 and EP 2760455 B1 , which are incorporated herein by reference.
Chemical Terms
The term "carbo," "carbyl," "hydrocarbo," and "hydrocarbyl," as used herein, pertain to compounds and/or groups which have only carbon and hydrogen atoms.
The term "hetero," as used herein, pertains to compounds and/or groups which have at least one heteroatom, for example, multivalent heteroatoms (which are also suitable as ring heteroatoms) such as boron, silicon, nitrogen, phosphorus, oxygen, and sulfur, and monovalent heteroatoms, such as fluorine, chlorine, bromine, and iodine.
The term "saturated," as used herein, pertains to compounds and/or groups which do not have any carbon-carbon double bonds or carbon-carbon triple bonds. The term "unsaturated," as used herein, pertains to compounds and/or groups which have at ieast one carbon-carbon double bond or carbon-carbon triple bond.
The term "aliphatic," as used herein, pertains to compounds and/or groups which are linear or branched, but not cyclic (also known as "acyclic" or "open-chain" groups).
The term "cyclic," as used herein, pertains to compounds and/or groups which have one ring, or two or more rings (e.g., spiro, fused, bridged).
The term "ring," as used herein, pertains to a closed ring of from 3 to 10 covalently linked atoms, more preferably 3 to 8 covalently linked atoms.
The term "aromatic ring," as used herein, pertains to a closed ring of from 3 to 10 covalently linked atoms, more preferably 5 to 8 covalently linked atoms, which ring is aromatic.
The term "heterocyclic ring,” as used herein, pertains to a closed ring of from 3 to 10 covalently linked atoms, more preferably 3 to 8 covalently linked atoms, wherein at least one of the ring atoms is a multivalent ring heteroatom, for example, nitrogen, phosphorus, silicon, oxygen, and sulfur, though more commonly nitrogen, oxygen, and sulfur.
The term "alicyclic," as used herein, pertains to compounds and/or groups which have one ring, or two or more rings (e.g., spiro, fused, bridged), wherein said ring(s) are not aromatic.
The term "aromatic," as used herein, pertains to compounds and/or groups which have one ring, or two or more rings (e.g., fused), wherein at least one of said ring(s) is aromatic.
The term "heterocyclic," as used herein, pertains to cyclic compounds and/or groups which have one heterocyclic ring, or two or more heterocyclic rings (e.g., spiro, fused, bridged), wherein said ring(s) may be alicyclic or aromatic.
The term "heteroaromatic," as used herein, pertains to cyclic compounds and/or groups which have one heterocyclic ring, or two or more heterocyclic rings (e.g., fused), wherein said ring(s) is aromatic. Substituents
The phrase "optionally substituted," as used herein, pertains to a parent group which may be unsubstituted or which may be substituted.
Unless otherwise specified, the term "substituted,” as used herein, pertains to a parent group which bears one or more substituents. The term "substituent" is used herein in the conventional sense and refers to a chemical moiety which is covalently attached to, appended to, or if appropriate, fused to, a parent group. A wide variety of substituents are well known, and methods for their formation and introduction into a variety of parent groups are also well known.
In one suitable embodiment, the substituent(s), often referred to herein as R, are independently selected from: halo; hydroxy; ether (e.g., Cualkoxy); formyl; acyl (e.g., C1-7alkylacyl , C5-20arylacyl); acylhalide; carboxy; ester; acyloxy; amido; acylamido; thioamido; tetrazolyl; amino; nitro; nitroso; azido; cyano; isocyano; cyanato; isocyanato; thiocyano; isothiocyano; sulfhydryl; thioether (e.g., C1- Talkylthio); sulfonic acid; sulfonate; sulfone; sulfonyloxy; sulfinyloxy; sulfamino; sulfonamino; sulfinamino; sulfamyl; sulfonamido; C1-7aikyl (including, e.g., C1-7haloalkyl, Ci-rhydroxyalkyl, C1- 7carboxyalkyl, C1-7amlnoalkyl, C5-20aryl- C1-7alkyl); Cs zoheterocyclyl; or Gs-soaryl (including, e.g., C5- 2ocarboaryl, C5-20heteroaryl, C1-7alkyl- C5-20aryl and C5-20haloaryl)).
In one suitable embodiment, the substituent(s), often referred to herein as R, are independently selected from:
-F, -Cl, -Br, and -I;
-OH;
-OMe, -OEt, -O(tBu), and -OCH2Ph;
-SH;
-SMe, -SEt, ~S(tBu), and -SCH2Ph;
-C(=O)H;
-C(=O)Me, -C(=O)Et, -C(=O)(tBu), and -C(=O)Ph;
-C(=O)OH;
-C(=O)OMe, -C(=O)OEt, and -C(=O)O(tBu);
-C(=O)NH2, -C(=O)NHMe, -C(=O)NMe2, and -C(=O)NHEt;
-NHC(=O)Me, -NHC(=O)Et, -NHC(=O)Ph, succinimidyl, and maleimidyl;
-NH2, -NHMe, -NHEt, -NH(iPr), -NH(nPr), -NMe2, -NEt2, -N(IPr)2, -N(nPr)2,
-N(nBu)2, and -N(tBu)2;
-CN;
-NO2;
-Me, -Et, -nPr, -IPr, -nBu, -tBu;
-CF3, -CHF2, -CH2F, -CCI3, -CBr3, -CH2CH2F, -CH2CHF2, and -CH2CF3;
-OCF3, -OCHF2, -OCH2F, -OCCI3, -OCB1-3, -OCH2CH2F, -OCH2CHF2, and -OCH2CF3;
-CH2OH, -CH2CH2OH, and -CH(OH)CH2OH;
-CH2NH2,-CH2CH2NH2, and -CH2CH2NMe2; and, optionally substituted phenyl. In one suitable embodiment, the substituent(s), often referred to herein as R, are independently selected from: -F, -Cl, -Br, -I, -OH, -OMe, -OEt, -SH, -SMe, -SEt, -C(=O)Me, -C(=O)OH, -C(=O)OMe, -CONH2, -CONHMe, -NH2, -NMe2, -NEt2, -N(nPr)2, -N(iPr)2, -CN, -NO2, -Me, -Et, -CF?„ -OCF3, - CH2OH, -CH2CH2OH, -CH2NH2, -CH2CH2NH2, and -Ph.
In one suitable embodiment, the substituent(s), often referred to herein as R, are independently selected from: hydroxy; ether (e.g., C1-7alkoxy); ester; amido; amino; and, C1-7alkyl (including, e.g., C1-7haloalkyl, C1-7hydroxyalkyl, C1-7carboxyalkyl, C1-7aminoalkyl, C5-20aryl-C1-7alkyl).
In one suitable embodiment, the substituent(s), often referred to herein as R, are independently selected from:
-OH;
-OMe, -OEt, -O(tBu), and -OCH2Ph;
-C(=O)OMe, -C(=O)OEt, and -C(=O)O(tBu);
-C(=O)NH2, -C(::O)NHMe, -C(=O)NMe2, and -C(=O)NHEt;
-NH2, -NHMe, -NHEt, -NH(iPr), -NH(nPr), -NMe2, -NEt2, -N(iPr)2, -N(nPr)2,
-N(nBu)2, and -N(tBu)2;
-Me, -Et, -nPr, -iPr, -nBu, -tBu;
-CFs, -CHF2, -CH2F, -CCIs, -CBr3, -CH2CH2F, -CH2CHF2, and -CH2CF3;
-CH2OH, -CH2CH2OH, and -CH(OH)CH2OH; and, -CH2NH2,-CH2CH2NH2, and -CH2CH2NMe2.
The substituents are described in more detail below.
C1-20alkyl: The term " C1-20alkyl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a C1-7hydrocarbon compound having from 1 to 20 carbon atoms, which may be aliphatic or alicyclic, or a combination thereof, and which may be saturated, partially unsaturated, or fully unsaturated.
Examples of (unsubstituted) saturated linear C 1.20aIky I groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl (amyl), n-octyl, n-nonyl and n-decyl.
Examples of (unsubstituted) saturated branched C1-7alkyl groups include, but are not limited to, iso - propyl, iso-butyl, sec-butyl, tert-butyl, and neo-pentyl.
Examples of saturated alicyclic (also carbocyclic) C1-7alkyl groups (also referred to as "C3-7cycloalkyl" groups) include, but are not limited to, unsubstituted groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornane, as well as substituted groups (e.g., groups which comprise such groups), such as methylcyclopropyl, dimethylcyclopropyl, methylcyclobutyl, dimethylcyclobutyl, methylcyclopentyl, dimethylcyclopentyl, methylcyclohexyl, dimethylcyclohexyl, cyclopropylmethyl and cyclohexylmethyl.
Examples of (unsubstituted) unsaturated C1-20alkyl groups which have one or more carbon-carbon double bonds (also referred to as "C2-7alkenyl" groups) include, but are not limited to, ethenyl (vinyl, -CH=CH2), 2-propenyl (allyl, -CH-CH=CH2), isopropenyl (-C(CH3)=CH2), butenyl, pentenyl, and hexenyl.
Examples of (unsubstituted) unsaturated C1-20alkyl groups which have one or more carbon-carbon triple bonds (also referred to as "C2-2oalkynyl" groups) include, but are not limited to, ethynyl (ethinyl) and 2-propynyl (propargyl).
Examples of unsaturated alicyclic (also carbocyclic) C1-7alkyl groups which have one or more carbon- carbon double bonds (also referred to as "C3-20cycloalkenyl" groups) include, but are not limited to, unsubstituted groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl, as well as substituted groups (e.g., groups which comprise such groups) such as cyclopropenylmethyl and cyclohexenylmethyl.
Additional examples of substituted C3-20-cycloalkyl groups include, but are not limited to, those with one or more other rings fused thereto, for example, those derived from: indene (C9), indan (2, 3- dihydro-1 H-indene) (C9), tetraline (1 ,2,3,4-tetrahydronaphthalene (C10), adamantane (C10), decalin (decahydronaphthalene) (C12), fluorene (C13), phenalene (C13). For example, 2H-inden-2-yl is a C5cycloalkyl group with a substituent (phenyl) fused thereto.
C3-20heterocyclyl: The term "C3-20heterocyclyl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a C3-20heterocyclic compound, said compound having one ring, or two or more rings (e.g., spiro, fused, bridged), and having from 3 to 20 ring atoms, of which from 1 to 10 are ring heteroatoms, and wherein at least one of said ring(s) is a heterocyclic ring. Preferably, each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms.
In this context, the prefixes (e.g., C3-20, C3-7, C5-6, etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term "C5- eheterocyclyl," as used herein, pertains to a heterocyclyl group having 5 or 6 ring atoms. Examples of groups of heterocyclyl groups include C3-20heterocyclyl, Ca-yheterocyclyl, C5-7heterocyclyL
Examples of (non-aromatic) monocyclic heterocyclyl groups include, but are not limited to, those derived from:
N-i: aziridine (C3), azetidine (C4), pyrrolidine (tetrahydropyrrole) (C5), pyrroline (e.g., 3-pyrroline, 2,5- dihydropyrrole) (C5), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C5), piperidine (C6), dihydropyridine (C6), tetrahydropyridine (C6), azepine (C7); O1: oxirane (C3), oxetane (C4), oxolane (tetrahydrofuran) (C5), oxole (dihydrofuran) (C5), oxane (tetrahydropyran) (C6), dihydropyran (C6), pyran (C6), oxepin (C7); S-i: thiirane (C3), thietane (C4), thioiane (tetrahydrothiophene) (C5), thiane (tetrahydrothiopyran) (C6), thiepane (C7); O2: dioxolane (C5), dioxane (C6), and dioxepane (C7); O3: trioxane (C6); N2: imidazolidine (C5), pyrazolidine (diazoiidine) (C5), imidazoline (C5), pyrazoline (dihydropyrazole) (C5), piperazine (C6); N1O1: tetrahydrooxazole (C5), dihydrooxazoie (C5), tetrahydroisoxazole (C5), dihydroisoxazole (C5), morpholine (C6), tetrahydrooxazine (C6), dihydrooxazine (C6), oxazine (Ce); N1S1: thiazoline (C5), thiazolidine (C5), thiomorpholine (Ce); N2O1 : oxadiazine (C6); O1S1: oxathiole (C5) and oxathiane (thioxane) (C6); and, N1O1S1: oxathiazine (C6).
Examples of substituted (non-aromatic) monocyclic heterocyclyl groups include saccharides, in cyclic form, for example, furanoses (C5), such as arabinofuranose, lyxofuranose, ribofuranose, and xylofuranse, and pyranoses (C6), such as allopyranose, altropyranose, glucopyranose, mannopyranose, guiopyranose, idopyranose, galactopyranose, and talopyranose.
Examples of heterocyclyl groups which are also heteroaryl groups are described below with aryl groups. C5-20aryl: The term "C5-20aryl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of a C5-20aromatic compound, said compound having one ring, or two or more rings (e.g., fused), and having from 5 to 20 ring atoms, and wherein at least one of said ring(s) is an aromatic ring. Preferably, each ring has from 5 to 7 ring atoms. In this context, the prefixes (e.g., C3-20, C5-7, C5-6, etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term "C5-6aryl," as used herein, pertains to an aryl group having 5 or 6 ring atoms. Examples of groups of aryl groups include C3-20aryl, C5-7aryl, C5-6aryl.
The ring atoms may be all carbon atoms, as in "carboaryl groups" (e.g.,C5-20carboaryl). Examples of carboaryl groups include, but are not limited to, those derived from benzene (i.e., phenyl) (C6), naphthalene (C10), azulene (C10), anthracene (C14), phenanthrene (C14), naphthacene (C18), and pyrene (C16).
Examples of aryl groups which comprise fused rings, at least one of which is an aromatic ring, include, but are not limited to, groups derived from indene (Cs), isoindene (Cs), and fluorene (C13).
Alternatively, the ring atoms may include one or more heteroatoms, including but not limited to oxygen, nitrogen, and sulfur, as in "heteroaryl groups." In this case, the group may conveniently be referred to as a "C5-20heteroaryl" group, wherein "C5-20" denotes ring atoms, whether carbon atoms or heteroatoms. Preferably, each ring has from 5 to 7 ring atoms, of which from 0 to 4 are ring heteroatoms. Examples of monocyclic heteroaryl groups include, but are not limited to, those derived from: N 1: pyrrole (azole) (C5), pyridine (azine) (C6); Oi: furan (oxole) (C5); Si: thiophene (thiole) (C5); N1O1: oxazole (C5), isoxazole (C5), isoxazine (C6); N2O1: oxadiazole (furazan) (C5); N3O1: oxatriazole (C5);
N1S1: thiazole (C5), isothiazole (C5); N2: imidazole (1 ,3-diazole) (C5), pyrazole (1 ,2-diazole) (C5), pyridazine(1 ,2-diazine) (C6), pyrimidine (1 ,3-diazine) (C6) (e.g., cytosine, thymine, uracil), pyrazine (1 ,4-diazine) (C6); N3: triazole (C5), triazine (C6); and, Na: tetrazole (C5).
Examples of heterocyclic groups (some of which are also heteroaryl groups) which comprise fused rings, include, but are not limited to: Cgheterocyclic groups (with 2 fused rings) derived from benzofuran (O1), isobenzofuran (O 1), indole (N1), isoindole (N1), purine (Na) (e.g., adenine, guanine), benzimidazole (N2), benzoxazole (N1O1), benzisoxazole (N1O1), benzodioxoie (O2), benzofurazan (N2O1), benzotriazole (N3), benzothiofuran (Si), benzothiazole (N1S1), benzothiadiazole (N2S); Cioheterocyclic groups (with 2 fused rings) derived from benzodioxan (O2), quinoline (N1), isoquinoline (N1), benzoxazine (N1O1), benzodiazine (N2), pyridopyridine (N2), quinoxaline (N2), quinazoline (N2); Cisheterocyclic groups (with 3 fused rings) derived from carbazole (Ni), dibenzofuran (Oi), dibenzothiophene (Si); and, C laheterocyclic groups (with 3 fused rings) derived from acridine (Ni), xanthene (Oi), phenoxathiin (O1S1), phenazine (N2), phenoxazine (NiOi), phenothiazine (NiSi), thianthrene (S2), phenanthridine (N1), phenanthroline (N2), phenazine (N2).
Heterocyclic groups (including heteroaryl groups) which have a nitrogen ring atom in the form of an -NH- group may be N-substituted, that is, as -NR-. For example, pyrrole may be N-methyl substituted, to give N-methypyrrole. Examples of N-substitutents include, but are not limited to C1-7alkyl, C3- 2oheterocyclyl, C5-20aryl, and acyl groups.
Heterocyclic groups (including heteroaryl groups) which have a nitrogen ring atom in the form of an -N= group may be substituted in the form of an N-oxide, that is, as -N(— >O)= (also denoted -N+(->O- )=). For example, quinoline may be substituted to give quinoline N-oxide; pyridine to give pyridine N- oxide; benzofurazan to give benzofurazan N-oxide (also known as benzofuroxan). Cyclic groups may additionally bear one or more oxo (=O) groups on ring carbon atoms. Monocyclic examples of such groups include, but are not limited to, those derived from: C5: cyclopentanone, cyclopentenone, cyclopentadienone; C6: cyclohexanone, cyclohexenone, cyclohexadienone; Oi: furanone (C5), pyrone (C6); N1: pyrrolidone (pyrrolidinone) (C5), piperidinone (piperidone) (C6), piperidinedionefC6); N2: imidazolidone (imidazolidinone) (C5), pyrazolone (pyrazolinone) (C5), piperazinone (C6), piperazinedione (C6), pyridazinone (C6), pyrimidinone (C6) (e.g., cytosine), pyrimidinedione (C6) (e.g., thymine, uracil), barbituric acid (C6); N1S1: thiazolone (C5), isothiazolone (C5); N1O1: oxazolinone (C5).
Polycyclic examples of such groups include, but are not limited to, those derived from: C9: indenedione; Ni: oxindole (C9); O1: benzopyrone (e.g., coumarin, isocoumarin, chromone) (C10); N1O1: benzoxazolinone (C9), benzoxazolinone (C10); N2: quinazolinedione (C10); Na: purinone (C9) (e.g., guanine).
Still more examples of cyclic groups which bear one or more oxo (=O) groups on ring carbon atoms include, but are not limited to, those derived from: cyclic anhydrides (-C(=O)-O-C(=O)- in a ring), including but not limited to maleic anhydride (C5), succinic anhydride (C5), and glutaric anhydride (C6); cyclic carbonates (-O-C(=O)-O- in a ring), such as ethylene carbonate (C5) and 1 ,2-propylene carbonate (C5); imides ■ ■C(":O)-NF^-C(:::O)- in a ring), including but not limited to, succinimide (C5), maleimide (C5), phthalimide, and glutarimide (Ce); lactones (cyclic esters, -O-C(=O)- in a ring), including, but not limited to, p-propiolactone, y- butyrolactone, 6-valerolactone (2-piperidone), and £-caprolactone; lactams (cyclic amides, -NR- C(=O)- in a ring), including, but not limited to, p-propiolactam (C4), y-butyrolactam (2-pyrrolidone) (C5), 6-valerolactam (Ge), and s-caprolactam (C7); cyclic carbamates (-O-C(=O)-NR- in a ring), such as 2-oxazolidone (C5); cyclic ureas (-NR-C(=:O)-NR- in a ring), such as 2-imidazoiidone (C5) and pyrimidine-2, 4-dione (e.g., thymine, uracil) (Ce).
The above C1-20alkyl, C3-20heterocyclyl, and C5-20aryl groups, whether alone or part of another substituent, may themselves optionally be substituted with one or more groups selected from themselves and the additional substituents listed below.
Hydrogen: -H. Note that if the substituent at a particular position is hydrogen, it may be convenient to refer to the compound as being "unsubstituted" at that position.
Halo: -F, -Cl, -Br, and -I.
Hydroxy: -OH.
Ether: -OR, wherein R is an ether substituent, for example, a C1-7alkyl group (also referred to as a C1-7alkoxy group, discussed below), a C3-20heterocyclyl group (also referred to as a C3. 2ohetercyclyloxy group), or a C5-20aryl group (also referred to as a C5-20aryloxy group), preferably a C1-7alkyl group.
Civalkoxy: -OR, wherein R is a C1-7alkyl group. Examples of C1-7alkoxy groups include, but are not limited to, -OCHs (methoxy), -OCH2CH3 (ethoxy) and -OC(CHs)3 (tert-butoxy).
Oxo (keto, -one): =O. Examples of cyclic compounds and/or groups having, as a substituent, an oxo group (~O) include, but are not limited to, carbocyclics such as cyclopentanone and cyclohexanone; heterocyclics, such as pyrone, pyrrolidone, pyrazolone, pyrazolinone, piperidone, piperidinedione, piperazinedione, and imidazolidone; cyclic anhydrides, including but not limited to maleic anhydride and succinic anhydride; cyclic carbonates, such as propylene carbonate; imides, including but not limited to, succinimide and maleimide; lactones (cyclic esters, -O-C(=O)- in a ring), including, but not limited to, p-propiolactone, y-butyrolactone, 6-valerolactone, and s-caprolactone; and lactams (cyclic amides, -NH-C(=O)- in a ring), including, but not limited to, p-propiolactam, y-butyrolactam, 6- valeroiactam, and s-caprolactam. imino (imine): =NR, wherein R is an imino substituent, for example, hydrogen, Ci-ralkyl group, a C3- 2oheterocyclyl group, or a C5-20aryl group, preferably hydrogen or a Ci-yalkyl group. Examples of imino groups include, but are not limited to, =NH, =NMe, =NEt, and :::NPh.
Formyl (carbaidehyde, carboxaldehyde): ■C(:::O)H.
Acyl (keto): -C(":O)F< wherein R is an acyl substituent, for example, a C1-20alkyl group (also referred to as C1-20alkylacyl or C1-20alkanoyl), a C3-20heterocyclyl group (also referred to as C3- 2oheterocyclylacyl), or a C5-20aryl group (also referred to as Gs-soaryiacyl), preferably a C1-20aikyl group. Examples of acyl groups include, but are not limited to, -C(=O)CH3 (acetyl), - C(=O)CH2CH3 (propionyl), -C(=O)C(CH3)3 (butyryl), and -C(=O)Ph (benzoyl, phenone).
Acylhalide (haloformyl, halocarbonyl): -C(=O)X, wherein X is -F, -Cl, -Br, or -I, preferably -Cl, -Br, or
Carboxy (carboxylic acid): -COOH.
Ester (carboxylate, carboxylic acid ester, oxycarbonyl): -C(=O)OR, wherein R is an ester substituent, for example, a C i-zalky! group, a C3-20heterocyclyl group, or a C5-20aryl group, preferably a Ci .?alkyl group. Examples of ester groups include, but are not limited to, -C(=O)OCH3, -C(=O)OCH2CH3, - C(=O)OC(CH3)3, and -C(=O)OPh.
Acyloxy (reverse ester): -OC(=:O)R, wherein R is an acyloxy substituent, for example, a C1.7alk.yl group, a C3-20heterocyclyl group, or a C5-20aryl group, preferably a Ci-yalkyl group. Examples of acyloxy groups include, but are not limited to, -OC(=O)CH3 (acetoxy), -OC(=O)CH2CH3, - OC(=O)C(CH3)3,
-OC(=O)Ph, and -OC(=O)CH2Ph.
Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide): -C(=;O)NR1R2, wherein R1 and R2 are independently amino substituents, as defined for amino groups. Examples of amido groups include, but are not limited to, -C(=O)NH2> -C(=O)NHCH3, -C(=O)NH(CH3)2, -C(=O)NHCH2CH3, and - G(=:O)N(CH2CH3)2, as well as amido groups in which R1 and R2, together with the nitrogen atom to which they are attached, form a heterocyclic structure as in, for example, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinocarbonyl. Acylamido (acylamino): -NR1C(=O)R2, wherein R1 is an amide substituent, for example, a C1-7alkyl group, a C3-20heterocyclyl group, or a C5-20aryl group, preferably a C1 7alk.yl group, and R2 is an acyl substituent, for example, a C1-7alkyl group, a C3-20heterocyclyl group, or a C5-20 aryl group, preferably a C1-7alkyl group.
Amino: -NR1R2, wherein R1 and R2 are independently amino substituents, for example, hydrogen, a Cualkyi group (also referred to as C1-7alkyiamino or di-C1-7alkylamino), a C3-20heterocyclyl group, or a C5-20aryl group, preferably H or a C1-7alkyl group, or, in the case of a "cyclic" amino group, R1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms. Examples of amino groups include, but are not limited to, -NH2, -NHCH3, - NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, and -NHPh. Examples of cyclic amino groups include, but are not limited to, aziridine, azetidino, piperidino, piperazine, morpholino, and thiomorpholino.
Nitro: -NO2. Nitroso: -NO. Azido: -N3. Cyano (nitrile, carbonitrile): -CN. Isocyano: -NC. Cyanato: - OCN. Isocyanate: -NCO. Thiocyano (thiocyanato): -SON. Isothiocyano (isothiocyanato): -NCS. Sulfhydryl (thiol, mercapto): -SH.
Thioether (sulfide): -SR, wherein R is a thioether substituent, for example, a C1-7alkyl group (also referred to as a C1-7alkylth io group), a C3-20heterocyclyl group, or a C5-20aryl group, preferably a C1- 7alkyl group. Examples of C1-7alkylthio groups include, but are not limited to, -SCH3 and -SCH2CH3. Sulfonic acid (sulfo): -S(=O)2OH.
Sulfonate (sulfonic acid ester): -S(=O)2OR, wherein R is a sulfonate substituent, for example, a C1- 7alkyl group, a C3-20heterocyclyl group, or a C5-20aryl group, preferably a Ci-yalkyl group. Examples of sulfonate groups include, but are not limited to, -S(=O)2OCH3 and -S^OfrOCHiCHs
Sulfone (sulfonyl): -S(=O)2R, wherein R is a sulfone substituent, for example, a C1-7alkyl group, a C3-20heterocyclyl group, or a C5-20aryl group, preferably a C1-7alkyl group. Examples of sulfone groups include, but are not limited to, -S(=O)2CH3 (methanesulfonyl, mesyl), -S(=O)2CF3, -S(=O)2CH2CH3, and 4-methylphenylsulfonyl (tosyl).
Sulfonyloxy: -OS(=O)2R, wherein R is a sulfonyloxy substituent, for example, a C1-7alkyl group, a C3- 2oheterocyclyl group, or a C5-20aryi group, preferably a C1-7alkyi group. Examples of sulfonyloxy groups include, but are not limited to, -OS(=O)2CH3 and -OS(=O)2CH2CH3.
Sulfinyloxy: -OS(=O)R, wherein R is a sulfinyloxy substituent, for example, a C1-7alkyl group, a C3- 2oheterocyciyl group, or a C5-20aryl group, preferably a C1-7aikyl group. Examples of sulfinyloxy groups include, but are not limited to, -OS(=O)CH3 and -OS(=O)CH2CH3. Sulfamino: -NR1S(=O)2OH, wherein R1 is an amino substituent, as defined for amino groups.
Examples of sulfamino groups include, but are not limited to, -NHS(=O)2OH and -N(CH3)S(=O)2OH.
Sulfonamino: -NR1S(=O)2R, wherein R1 is an amino substituent, as defined for amino groups, and R is a sulfonamino substituent, for example, a Cualkyl group, a C3-2oheterocyclyl group, or a C5-20aryl group, preferably a C1-7alkyl group.
Examples of sulfonamino groups include, but are not limited to, -NHS(=O)2CH3 and - N(CH3)S(=O)2C6H5.
Sulfinamino: -NR1S(=:O)R, wherein R1 is an amino substituent, as defined for amino groups, and R is a sulfinamino substituent, for example, a C1-7alkyl group, a C3-2oheterocyclyl group, or a C5-20aryl group, preferably a C1-7alkyl group.
Examples of sulfinamino groups include, but are not limited to, "NHS(=O)CH3 and - N(CH3)S(=O)C6H5.
Sulfamyl: -S(=O)NR1R2, wherein R1 and R2 are independently amino substituents, as defined for amino groups. Examples of sulfamyl groups include, but are not limited to, -S(=O)NH2, - S(=O)NH(CH3), ~S(=O)N(CH3)2, -S(=O)NH(CH2CH3), -S(=O)N(CH2CH3)2, and -S(=O)NHPh.
Sulfonamide: -S(=O)2NR1R2, wherein R1 and R2 are independently amino substituents, as defined for amino groups. Examples of sulfonamide groups include, but are not limited to, -S(=O)2NH2, - S(=O)2NH(CH3), -S(=O)2N(CH3)2, -S(=O)2NH(CH2CH3), -S(=O)2N(CH2CH3)2, and -S(=O)2NHPh.
As mentioned above, a C1-20alkyl group may be substituted with, for example, hydroxy (also referred to as a C1-20hydroxyalkyl group), C1-20alkoxy (also referred to as a C1-7alkoxyalkyl group), amino (also referred to as a C1-20aminoalkyl group), halo (also referred to as a C1-20haloalkyl group), carboxy (also referred to as a C1-20carboxyalkyl group), and C5-20aryl (also referred to as a Co^oaryl-C1-7alkyl group).
Similarly, a C5-20aryl group may be substituted with, for example, hydroxy (also referred to as a C5- 2ohydroxyaryl group), halo (also referred to as a Cs-2ohaloaryl group), amino (also referred to as a C5- 2oaminoaryl group, e.g., as in aniline), C1-7alkyl (also referred to as a C1-7alkyl”C5-20aryl group, e.g., as in toluene), and C1-7alkoxy (also referred to as a C1-7alkoxy-C5-20aryl group, e.g., as in anisole).
These and other specific examples of such substituted groups are also discussed below. C1-20haloalkyl group: The term "C1-20haloalkyl group," as used herein, pertains to a C1-20alkyi group in which at least one hydrogen atom (e.g., 1 , 2, 3) has been replaced with a halogen atom (e.g., F, Cl, Br, I). If more than one hydrogen atom has been replaced with a halogen atom, the halogen atoms may independently be the same or different. Every hydrogen atom may be replaced with a halogen atom, in which case the group may conveniently be referred to as a C1-20perhaloalkyl group." Examples of C1-7haioaikyl groups include, but are not limited to, -CF3, -CHF2, -CH2F, -CCI3, -CBrs, - CH2CH2F, -CH2CHF2, and -CH2CF3. C1-20hydroxyalkyl: The term "C1-7hydroxyalkyl group," as used herein, pertains to a C1-20alkyl group in which at least one hydrogen atom has been replaced with a hydroxy group. Examples of C1- ?hydroxyalkyl groups include, but are not limited to, -GH2OH,-CH2CH2OH, and -CH(OH)CH2OH. C1-20carboxyaikyi: The term "C1-20carboxyaikyl group," as used herein, pertains to a C1-20alkyl group in which at least one hydrogen atom has been replaced with a carboxy group. Examples of C1- 2ocarboxyalkyl groups include, but are not limited to, -GH2COOH and -CH2CH2COOH. C1-20aminoalkyl: The term "C1-20aminoalkyl group," as used herein, pertains to a C1-20alkyl group in which at least one hydrogen atom has been replaced with an amino group. Examples of C1- 2oaminoalkyl groups include, but are not limited to, -CH2NH2,-CH2CH2NH2, and -CH2CH2N(CH3)2. C1-20alkyl-C5-20aryl: The term "C1-20alkyl-C5-20aryl," as used herein, describes certain C5-20aryl groups which have been substituted with a C1-20alkyl group. Examples of such groups include, but are not limited to, tolyl (as in toluene), xylyl (as in xylene), mesityl (as in mesitylene), styryl (as in styrene), and cumenyl (as in cumene). C5-20aryl-C1-20alkyl: The term "C5-20aryl-C1-20alkyl," as used herein, describers certain C1-20alkyl groups which have been substituted with a Cs-2oaryl group.
Examples of such groups include, but are not limited to, benzyl (phenylmethyl), tolylmethyl, phenylethyl, and triphenylmethyl (trityl). C5-20haloaryl: The term "C5-20haloaryl," as used herein, describes certain C5-20aryl groups which have been substituted with one or more halo groups. Examples of such groups include, but are not limited to, halophenyl (e.g., fluorophenyl, chlorophenyl, bromophenyl, or iodophenyl, whether ortho-, meta-, or para-substituted), dihalophenyl, trihalophenyl, tetrahalophenyl, and pentahalophenyl.
Bidentate Substituents. Some substituents are bidentate, that is, have two points for covalent attachment. For example, a bidentate group may be covalently bound to two different atoms on two different groups, thereby acting as a linker therebetween. Alternatively, a bidentate group may be covalently bound to two different atoms on the same group, thereby forming, together with the two atoms to which it is attached (and any intervening atoms, if present) a cyclic or ring structure. In this way, the bidentate substituent may give rise to a heterocyclic group/compound and/or an aromatic group/compound. Typically, the ring has from 3 to 8 ring atoms, which ring atoms are carbon or divalent heteroatoms (e.g., boron, silicon, nitrogen, phosphorus, oxygen, and sulfur, typically nitrogen, oxygen, and sulfur), and wherein the bonds between said ring atoms are single or double bonds, as permitted by the valencies of the ring atoms. Typically, the bidentate group is covalently bound to vicinal atoms, that is, adjacent atoms, in the parent group. C1-20alkylene: The term "C1-20alkylene," as used herein, pertains to a bidentate moiety obtained by removing two hydrogen atoms, either both from the same carbon atom, or one from each of two different carbon atoms, of a C1-20hydrocarbon compound having from 1 to 20 carbon atoms, which may be aliphatic or alicyclic, or a combination thereof, and which may be saturated, partially unsaturated, or fully unsaturated.
Examples of linear saturated C1-20alkylene groups include, but are not limited to, -(Chhjn- where n is an integer from 1 to 20, for example, -CH2- (methylene), -CH2CH2- (ethylene), -CH2CH2CH2- (propylene), and -CH2CH2CH2CH2-(butylene).
Examples of branched saturated C1-20alkylene groups include, but are not limited to, -CH(CH3)-, - CH(CH3)CH2-, -CH(CH3)CH2CH2-, -CH(CH3)CH2CH2CH2-, -CH2CH(CH3)CH2-, CH2CH(CH3)CH2CH2-, -CH(CH2CH3)-, -CH(CH2CH3)CH2-, and -CH2CH(CH2CH3)CH2-.
Examples of linear partially unsaturated C1-20alkylene groups include, but are not limited to, -CH=CH- (vinylene), -CH-CH-CH2-, -CH=CH-CH2-CH2-, -CH-CH-CH2-CH-CH2-, -CH-CH-CH-C-H-, - CH=CH-CH=CH-CH2-, -CH=CH-CH=CH-CH2-CH2-, -CH=CH-CH2-CH=CH-, and -CH=CH-CH2-CH2- CH=CH-.
Examples of branched partially unsaturated C1-20alkylene groups include, but are not limited to, - C(CH3)=CH-, -C(CH3)=CH-CH2-, and -CH=CH-CH(CH3)-.
Examples of alicyclic saturated C1-20alkylene groups include, but are not limited to, cyclopentylene (e.g., cyclopent-1 ,3-ylene), and cyclohexylene (e.g., cyclohex-1 ,4-ylene).
Examples of alicyclic partially unsaturated C1-20alkylene groups include, but are not limited to, cyclopentenylene (e.g., 4-cyclopenten-1 ,3-ylene), cyclohexenylene (e.g., 2-cyclohexen-1 ,4-ylene, 3-cyclohexen-1 ,2-ylene, 2,5-cyclohexadien-1 ,4-ylene). C5-20arylene: The term "C5-20arylene," as used herein, pertains to a bidentate moiety obtained by removing two hydrogen atoms, one from each of two different ring atoms of a C5-20aromatic compound, said compound having one ring, or two or more rings (e.g., fused), and having from 5 to 20 ring atoms, and wherein at least one of said ring(s) is an aromatic ring. Preferably, each ring has from 5 to 7 ring atoms. The ring atoms may be all carbon atoms, as in "carboarylene groups," in which case the group may conveniently be referred to as a "C5-20carboarylene" group.
Alternatively, the ring atoms may include one or more heteroatoms, including but not limited to oxygen, nitrogen, and sulfur, as in "heteroarylene groups." In this case, the group may conveniently be referred to as a "C5-20heteroarylene" group, wherein "C5-20" denotes ring atoms, whether carbon atoms or heteroatoms.
Preferably, each ring has from 5 to 7 ring atoms, of which from 0 to 4 are ring heteroatoms.
Examples of C5-20aryiene groups which do not have ring heteroatoms (i.e., C5-20carboarylene groups) include, but are not limited to, those derived from benzene (i.e., phenyl) (C6), naphthalene (C 10), anthracene (C-u), phenanthrene (CI4), and pyrene (C16).
Examples of C5-20heteroarylene groups include, but are not limited to, C5heteroarylene groups derived from furan (oxole), thiophene (thiole), pyrrole (azole), imidazole (1 ,3-diazole), pyrazole (1 ,2-diazole), triazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, and oxatriazole; and C6heteroarylene groups derived from isoxazine, pyridine (azine), pyridazine (1 ,2-diazine), pyrimidine (1 ,3-diazine; e.g., cytosine, thymine, uracil), pyrazine (1 ,4-diazine), triazine, tetrazole, and oxadiazole (furazan). C5-20Arylene-C1-20alkylene: The term "C5-20arylene-C1-20alkyiene,” as used herein, pertains to a bidentate moiety comprising a C5-20aryiene moiety, -Arylene-, linked to a C1-20alkylene moiety, - Alkylene-, that is, -Arylene-Alkylene-.
Examples of C5-20aryiene-C1-20aikylene groups include, but are not limited to, phenylene-methylene, phenylene-ethylene, phenylene-propylene, and phenyiene-ethenylene (also known as phenylene- vinylene). C5-20Alkylene-C1-20arylene: The term "C5-20alkylene- C1-20arylene," as used herein, pertains to a bidentate moiety comprising a C5-20alkylene moiety, -Alkylene-, linked to a C1-20arylene moiety, - Arylene-, that is, -Alkyiene-Arylene-.
Examples of C5-20aikyiene-C1-20arylene groups include, but are not limited to, methylene-phenylene, ethylene-phenylene, propylene-phenylene, and ethenylene-phenylene (also known as vinylene- phenylene).
Included in the above are the well known ionic, salt, solvate (e.g., hydrate), and protected forms of these substituents. For example, a reference to carboxylic acid (-COOH) also includes carboxylate (-COO-). Similarly, a reference to an amino group includes a salt, for example, a hydrochloride salt, of the amino group. A reference to a hydroxyl group also includes conventional protected forms of a hydroxyl group.
Similarly, a reference to an amino group also includes conventional protected forms of an amino group.
For convenience, many chemical moieties are represented herein using well known abbreviations, including but not limited to, methyl (Me), ethyl (Et), n-propyl (nPr), iso-propyl (IPr), n-butyl (nBu), tert- butyl (tBu), n-hexyl (nHex), cyclohexyl (cHex), phenyl (Ph), biphenyl (biPh), benzyl (Bn), naphthyl (naph), methoxy (MeO), ethoxy (EtO), benzoyl (Bz), and acetyl (Ac).
For convenience, many chemical compounds are represented herein using well known abbreviations, including but not limited to, methanol (MeOH), ethanol (EtOH), iso-propanol (i-PrOH), methyl ethyl ketone (MEK), acetic acid (AcOH), dichloromethane (methylene chloride, DCM), trifluoroacetic acid (TFA), dimethylformamide (DMF), and tetra hydrofuran (THF).
Isomers, Salts. Solvates, Protected Forms, and Prodrugs. A certain compound may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; el- and p-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").
Note that, except as discussed below for tautomeric forms, specifically excluded from the term "isomers," as used herein, are structural (or constitutional) isomers (i.e,, isomers which differ in the connections between atoms rather than merely by the position of atoms in space). For example, a reference to a methoxy group, -OCHs, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl.
However, a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C1-20alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
The above exclusion does not pertain to tautomeric forms, for example, keto-, enol-, and enolate- forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.
Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein in a known manner.
Unless otherwise specified, a reference to a particular compound also includes ionic, salt, solvate (e.g., hydrate), protected forms, and prodrugs thereof, for example, as discussed below.
It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the active compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. ScL Vol. 66, pp. 1 ~19.
For example, if the compound is anionic, or has a functional group which may be anionic (e.g., - COOH may be -COO-), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K+, alkaline earth cations such as Ca2+ and Mg2+, and other cations such as Al+3. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4+) and substituted ammonium ions (e.g., NHsFT, NH2R2L NHF?3+, NRr). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine. An example of a common quaternary ammonium ion is N(CHs)4\ If the compound is cationic, or has a functional group which may be cationic (e.g., -NH2 may be -NH3+), then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous. Examples of suitable organic anions include, but are not limited to, anions from the following organic acids: acetic, propionic, succinic, gycolic, stearic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetyoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanesulfonic, ethane disulfonic, oxalic, isethionic, and valeric.
It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the active compound. The term "solvate" Is used herein In the conventional sense to refer to a complex of solute (e.g., active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a dl-hydrate, a tri-hydrate, etc. It may be convenient or desirable to prepare, purify, and/or handle the active compound in a chemically protected form. The term "chemically protected form," as used herein, pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions, that is, are in the form of a protected or protecting group (also known as a masked or masking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts, Wiley, 1991), and Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).
For example, a hydroxy group may be protected as an ether (-OR) or an ester (-OC(=;O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyidimethylsilyi ether; or an acetyl ester (-OC(=:O)CH3, -OAc).
For example, an aldehyde or ketone group may be protected as an acetal or ketal, respectively, in which the carbonyl group (>C=O) is converted to a diether (>C(OR)2), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
For example, an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH3); a benzyloxy amide (-NHCO- OCH2C6H5, -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CH3)3, -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OC(CH3)2C6HaC6H5, -NH-Bpoc), as a 9-fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2- trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NH-Alloc), as a 2(-phenylsulfonyl)ethyloxy amide (-NH-Psec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical (>N-O»).
For example, a carboxylic acid group may be protected as an ester or an amide, for example, as: a benzyl ester; a t-butyl ester; a methyl ester; or a methyl amide.
For example, a thiol group may be protected as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH2NHC(=O)CH3).
It may be convenient or desirable to prepare, purify, and/or handle the active compound in the form of a prodrug. The term "prodrug," as used herein, pertains to a compound which, when metabolised, yields the desired active compound. Typically, the prodrug is inactive, or less active than the active compound, but may provide advantageous handling, administration, or metabolic properties. For example, some prodrugs are esters of the active compound; during metabolysis, the ester group is cleaved to yield the active drug. Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound. For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H (D), and 3H (T); C may be in any isotopic form, including 12C, 13C, and 14G; O may be in any isotopic form, including 16O and 18O; and the like.
Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein in a known manner.
Unless otherwise specified, a reference to a particular compound also includes ionic, salt, solvate (e.g., hydrate), protected forms, and prodrugs thereof, for example, as discussed below.
It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the active compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. ScL Vol. 66, pp. 1 ~19.
For example, if the compound is anionic, or has a functional group which may be anionic (e.g,, - COOH may be -COO-), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K+, alkaline earth cations such as Ca2‘ and Mg2+, and other cations such as Al+3. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NHT) and substituted ammonium ions (e.g., NH:jR+, NH2R2L NHR3+, NR<+). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine. An example of a common quaternary ammonium ion is N/GHsR.
If the compound is cationic, or has a functional group which may be cationic (e.g., -NH2 may be - NHs+), then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous. Examples of suitable organic anions include, but are not limited to, anions from the following organic acids: acetic, propionic, succinic, gycolic, stearic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaieic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetyoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanesulfonic, ethane disulfonic, oxalic, isethionic, and valeric.
It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the active compound. The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g., active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
It may be convenient or desirable to prepare, purify, and/or handle the active compound in a chemically protected form. The term "chemically protected form," as used herein, pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions, that is, are in the form of a protected or protecting group (also known as a masked or masking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts, Wiley, 1991), and Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).
For example, a hydroxy group may be protected as an ether (-OR) or an ester (-OC(-O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(==O)CH3, -OAc).
For example, an aldehyde or ketone group may be protected as an acetal or ketal, respectively, in which the carbonyl group (>C=O) is converted to a diether (>C(OR)2), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
For example, an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRGO-OR), for example, as: a methyl amide (-NHCO-GH3); a benzyloxy amide (-NHCO- 0CH2C0H5, -NH-Cbz): as a t-butoxy amide (-NHCO-OC(CH3)3, -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHGO-OC(CH3)2C6H4C6H5, -NH-Bpoc), as a 9-fluorenyl methoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2- trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NH-Alloc), as a 2(-phenylsulfonyl)ethyloxy amide (-NH-Psec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical (>N-O®).
For example, a carboxylic acid group may be protected as an ester or an amide, for example, as: a benzyl ester; a t-butyl ester; a methyl ester; or a methyl amide. For example, a thiol group may be protected as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH2NHC(=O)CH3).
It may be convenient or desirable to prepare, purify, and/or handle the active compound in the form of a prodrug. The term "prodrug," as used herein, pertains to a compound which, when metabolised, yields the desired active compound. Typically, the prodrug is inactive, or less active than the active compound, but may provide advantageous handling, administration, or metabolic properties. For example, some prodrugs are esters of the active compound; during metaboiysis, the ester group is cleaved to yield the active drug. Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound. For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
Synthesis of Example 1
10-oxo-10(4-(3-thioxo-3H-1 ,2-dithio-5-yl)phenoxy)decyl)triphenylphosphonium bromide (AP39)
Figure imgf000049_0001
A solution of 10-bromodecanoic acid (500 mg, 1.99 mmol) in acetonitrile (5 mL) was added to a stirred solution of triphenylphosphine (522 mg, 1 .99 mmol) in acetonitrile (5 mL). The solution was heated at reflux for 70 h, cooled to room temperature then concentrated in vacuo. The resulting material was washed with toluene (2 x 10 mL), concentrated in vacuo then dissolved in dichloromethane (30 mL). To this stirred solution was added 5-p-hydroxyphenyl-l,2-dithiole-3-thione (ADT-OH) (456 mg, 1.99 mmol), [ADT-OH can be prepared using the method described in US 2008/0004245] N,N'-dicyclohexylcarbodiimide (431 mg, 2.09 mmol) and 4-dimethylaminopyridine (12 mg, 0.0995 mmol). After 22 h, the resulting suspension was filtered through cotton wool and the filtrate was concentrated in vacuo. Purification by flash column chromatography, loading as a dichloromethane solution and eluting with ethyl acetate then methanol, gave a mixture of the phosphonium salt and silica. Redissolution in dichloromethane, filtration through paper and concentration in vacuo gave the pure phosphonium salt (1 .05 g, 73%) as an orange foam. Rf = 0.7 (methanol); 1 H NMR (300 MHz, CDC13): δ = 7.95-7.65 (m, 17H; 3 Ph and Ar 2- and 6-H), 7.42 (s, 1 H; =CH), 7.23 (d, J= 8.0 Hz, 2H; Ar 3- and 5-H), 3.90-3.79 (m, 2H; CH2C=0), 2.58 (t, J = 8.5 Hz, 2H; CH2P), 1.80-1.55 (m, 4H; 2 x CH2), 1.42-1 .19 ppm (m, 10H; 5 x CH2); 31P NMR (121 MHz, CDCI3): δ = 25.7 ppm; HRMS (ESI) calculated for C37H38O2PS3 [M-Br]+ requires 641 .1766, found 641.1751.
Synthesis of Example 2
(4-(3-thioxo-3/7-1 ,2-dithiol-5-yl)phenoxy)-10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1 ,4-dien- 1-yl)decanoate
Figure imgf000050_0001
Example 2 was synthesised starting from idebenone. The idebenone was oxidised by a modified literature procedure [Bowden K., Heilbron I.M., Jones E.R.H., Weedon B.C.L. Acetylenic compounds, I, Preparation of acetylenic ketones by oxidation of acetylenic carbinols and glycols. J. Chem. Soc., 1946, 39-45], Jones reagent (0.3 M) was prepared by dissolving sodium dichromate dihydrate (8.940 g; 0.03 mol) in 80 ml of deionised water in an ice bath and the mixture was stirred at room temperature until the salt was completely dissolved. 7.5 ml of concentrated sulfuric acid was added dropwise, with cooling in an ice bath and some of the sodium dichromate re-precipitated. The final mixture was then stirred at room temperature, until the dichromate was completely dissolved and then the volume of the solution was adjusted to 100 ml with deionised water. Idebenone (400 mg; 1.18 mmol) was dissolved in acetone (100 ml) in a 2-necked, round-bottomed flask and the solution was stirred in an ice bath. The Jones reagent (63 ml; 18.91 mmol) was then added dropwise using a dropping funnel. After the Jones reagent was added to the initial solution, the resulting mixture was stirred at 50°C for a further 2 h. The solution volume was then reduced in vacuo to one third and the product was extracted with ethyl acetate (3 x 40 ml). The organic phases were combined and washed with a saturated solution of sodium bicarbonate (4 x 30 ml) and then with deionised water (2 x 30 ml). The organic solution was dried over MgSCM and the solvent removed under reduced pressure, which gave the acid intermediate 10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1 ,4-dien-1- yl)decanoic acid as a red oil (376 mg; 94%; 1.11 mmol).
The 10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1 ,4-dien-1-yl)decanoic acid (352 mg; 1.00 mmol) was dissolved in dichloromethane (8 ml). The solution was stirred at room temperature and ADTOH (226 mg; 1.00 mmol) was added to it. DMAP (12 mg, 0.10 mmol) and a solution of DCCI (309 mg; 1 .50 mmol) in the same solvent (5 ml) were added to the initial solution, which was stirred at room temperature for 18 h. The reaction mixture was washed with deionised water (4 x 15 ml). The organic phase was dried over MgSCM, the solvent was evaporated in vacuo and the crude product obtained was loaded onto a silica gel flash chromatography column, and silica gel flash chromatography was carried out using a solvent mixture of petroleum ether/ethyl acetate 2/1 , which gave the product Example 2 as a red oil (252 mg; 45%; 0.45 mmol) (cLogP = 6.10). HRMS (ES)+ found m/z (rel. intensity) 561.1445 (MH+; 30%), C28H33O6S3 requires 561 .1439, 226.9663 ([MH- idebenone]+; 100%). IR spectrum Vmax/crn 1 = 1762 (C=O) (w), 1705 (C=O) (m), 1642 (s), 1605 (s), 1546 (w), 1436 (m), 1379 (w), 1263 (m), 1204 (m), 1172 (m), 1094 (w), 1025 (w), 836 (w). 1H-NMR 6H (400 MHz, CDCh) = 7.70 (2H, d, part of AA’BB’, J = 8.0 Hz, aryl C/7), 7.42 (1 H, s, alkene C/7), 7.25 (2H, d, part of AA’BB’, J = 8.0 Hz, aryl C/7), 4.01 (6H, s, 2 x CW3O), 2.60 (2H, t, J = 8.0 Hz, CH2), 2.47 (2H, t, J = 8.0 Hz, CH2), 2.03 (3H, s, CCH3), 1.77 (2H, m, CH2), 1.42-1.34 (12H, m, 6 x C/72). 13C-NMR 6c (100 MHz, CDCh) = 215.51 (C=S), 184.72 (C=O), 184.18 (C=O), 171.78 (COO), 171.72 (S-C=CH), 153.71 (aryl CO), 144.30, 143.02, 138.71 , 136.01 (alkene CH), 129.10 (aryl CC), 128.21 (aryl CH), 122.96 (aryl CH), 61 .19 (CH3O), 34.36 (CH2), 29.79 (CH2), 29.28 (CH2), 29.19 (CH2), 28.72 (CH2), 26.40 (CH2), 24.79 (CH2), 11.95 (CCH3).
Synthesis of Example 3
4-(3-oxo-3H-1 ,2-d ith iol-5-yl)ph eny 1 10-(3-methyl-1 ,4-dioxo-1 ,4-dihydronaphthalen-2-yl)decanoate
Figure imgf000051_0001
Example 3 was prepared as follows by first preparing 10-(3-methyl-1 ,4-dioxo-1 ,4-dihydronaphthalen- 2-yl)decanoic acid by a modified version of a reported literature protocol [Salmon-Chemin L., Buisine E., Yardley V., Kohler S., Debreu M.A., Landry V., Sergheraert C., Croft S.L., Krauth-Siegel R.L., Davioud-Charvet E. 2- and 3-substituted 1 ,4-naphthoquinone derivatives as subversive substrates of trypanothione reductase and lipoamide dehydrogenase from Trypanosoma cruzi: synthesis and correlation between redox cycling activities and in vitro cytotoxicity. J. Med. Chem, 2001 , 44(4):548- 565. doi: 10.1021 Zjm0010791], To a stirred solution containing 2-methyl-1 ,4-naphthoquinone (300 mg; 1.74 mmol) and undecanedioic acid (1.129 g; 5.22 mmol) in 50 ml of degassed 30% aqueous acetonitrile, silver nitrate (88 mg; 0.522 mmol) was added. A solution of ammonium peroxodisulfate (516 mg; 2.26 mmol) in 12 ml of degassed 30% aqueous acetonitrile was added dropwise to the stirred solution over a 15 minutes period. The resulting solution was stirred under nitrogen atmosphere at 70°C for 3 h. After cooling the solution to room temperature, the residue was extracted with dichloromethane (3 x 50 ml) and the organic phases were combined and washed with deionised water (3 x 50 ml). The organic solution was dried over MgSCM and the solvent removed under reduced pressure. The crude product was loaded onto a silica gel flash chromatography column, which was eluted with an initial solvent mixture of 3/1 petroleum ether (bp 40-60°C)/ethyl acetate, followed by 2/1 petroleum ether (bp 40-60°C)/ethyl acetate solvent mixture to give the title product as yellow solid (292 mg; 49%; 0.853 mmol). The following procedure is a modified version of another reported literature protocol [Gero D., Torregrossa R., Perry A., Waters A., Le Trionnaire S., Whatmore J.J, Wood M.E., Whiteman M. The novel mitochondria-targeted hydrogen sulfide (H2S) donors AP123 and AP39 protect against hyperglycemic injury in microvascular endothelial cells in vitro. Pharm. Res., 2016, 113(Pt A):186- 198. doi: 10.1016/j.phrs.2O16.08.019, 186-198], 10-(3-methyl-1 ,4-dioxo-1 ,4-dihydronaphthalen-2- yl)decanoic acid (292 mg; 0.853 mmol) was dissolved in dichloromethane (8 ml). The mixture was stirred at room temperature and 5-(4-hydroxyphenyl)-3/7-1 ,2-dithiol-3-one (179 mg; 0.853 mmol) was added to it. 4-dimethylaminopyridine (10 mg; 0.085 mmol) and A/-(3-dimethylaminopropyl)-A/'- ethylcarbodiimide hydrochloride (245 mg; 1 .28 mmol) were added to the initial solution, which was stirred at room temperature for 18 h. The reaction mixture was washed with deionised water (6 x 15 ml), the organic phase was dried over MgSCM and the solvent was removed under reduced pressure. The crude product obtained was loaded onto a silica gel flash chromatography column using a solvent mixture of petroleum ether (bp 40-60 °C)/ethyl acetate 4/1 to provide Example 3 as a yellow solid (420 mg; 92%; 0.785 mmol) (cLogP = 6.75). 1H-NMR δH (400 MHz, CDCI3) = 8.00-7.99 (2H, m, aryl CH ), 7.63-7.56 (4H, m, aryl C/7), 7.15 (2H, d, part of AA’BB’, J = 8.0 Hz, aryl C/7), 6.74 (1 H, s, alkene C/7), 2.56-2.50 (4H, m, C/72C(O) and CH2C=C), 2.12 (3H, s, CH3), 1.69-1.57 (2H, m, CH2), 1.34-1.27 (12H, m, 6 x C/72).13C-NMR 6c (100 MHz, CDCb) = 193.99 (S-C=O), 185.39 (C=O), 184.76 (C=O), 171.79 (COO), 169.23 (aryl CC), 153.41 (aryl CC), 147.51 (aryl CC), 143.13 (aryl CC), 133.36 (aryl CH), 133.33 (aryl CH), 132.20 (aryl CC), 132.16 (aryl CC), 130.02 (aryl CC), 127.81 (aryl CH), 126.27 (aryl CH), 126.20 (aryl CH), 122.76 (aryl CH), 118.02 (alkene CH), 34.36 (CH2), 29.95 (CH2), 29.33 (CH2), 29.30 (CH2), 29.18 (CH2), 29.02 (CH2), 28.74 (CH2), 27.10 (CH2), 24.80 (CH2), 12.68 (CH3).
Other suitable example compounds may be as described in WO 2023041906 A1 and EP 2760455 B1 , which are incorporated herein by reference. Such example compounds may synthesised according to the procedures disclosed in said documents.
The structures of further example compounds are given below.
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0002
Figure imgf000055_0001
Figure imgf000056_0001
Biological screening methods and results
Microfluidic Lifespan and healthspan measurement of C elegans
Example compounds 1 , 2 and 3 were screened for potential efficacy in the treatment of Charcot- Marie-Tooth disease type 2A using the animal model described below, which utilises the Fzo1 mutated C elegans strain discussed above.
C elegans strains were age synchronised by gravity flotation and ~80 L1 larvae were placed on 33 mm petri dishes (20 LTs per 33mm plate) containing 2 mL NGM agar (50 mM NaCI, 0.25% (w/v) bacteriological peptone, 1.7% (w/v) agar, 1 mM CaCh, 1 mM MgSCM, 25 mM KH2PO4 (pH 6), 12.9 pM cholesterol) and seeded with 200 pL of OP50 Escherichia coli bacteria. For test compound treatments, 100 pL of dilute test compound (100 pL of 2.3 pM intermediate of test compound dilution in 0.23% DMSO for 100 nM and 0.01 %, respectively) were diluted into a 2.3 mL plate volume to achieve the desired final concentration. Control animals were grown on plates seeded with 100 pL of 0.23% DMSO (0.01 % final) as vehicle controls. Animals were grown on petri dishes for ~48 h at 20 °C to reach young adulthood, then washed off using 3 ml M9 buffer (3 g KH2PO4, 6 g Na2HPO4, 5 g NaCI, 1 ml 1 M MgSO4 per litre) and pooled into 60 cm petri dishes. From these pooled samples, ~70 young adults were collected and loaded into microfluidic chips (Infinity chips; Nemalife Inc., TX) using a 2.5 mL syringe, where the animals remained throughout the rest of the life-course. Using the Infinity screening system (Nemalite Inc., TX), on every day of the life-course chips were washed for 90 seconds with liquid NGM to remove progeny followed by a further 90 second recording for subsequent computational analysis of animal survival and locomotion. Chips were then injected with ~200 pL of either 20mg/ mL OP50 + 0.01 % DMSO control or 100 nM of test compound. Specifically, 980 pL of 20 mg/mL OP50 was supplemented with 20 pL of the required intermediate dilution (i.e, 20 pL of 5 pM AP39 or 0.5% DMSO). Chips were then stored in petri dishes at 20°C for the next 24 h with a damp, sterile tissue and parafilmed to avoid the microfluidic arena drying out. Lifespan analysis was performed using the Infinity System screening platform (Nemalife Inc., TX). Specifically, 90 second videos were split into three still image frames 183 (frames 1 , 300 and 900) and the Infinity screening system automates a bounding box around every (~70-80) whole animal in the microfluidic chip. Using the Infinity System software (Nemalife Inc., TX), computational coefficients determine animal displacements from outside this bounding box and were used for both lifespan and healthspan analysis. Animals were deemed dead if coefficients were 0.01. For healthspan analysis, movement rate was employed as one of the most robust measures of animal healthspan. For quantification, animals that obtained coefficients of 0.01-0.40 (i.e - unable to move more than half its body length between subsequent frames) were deemed inactive. Animals with scores of 0.41-1 were classed as ‘active’ animals (i.e - moving half of, or more than its full body-length in displacement between subsequent frames). Both lifespan and healthspan were determined every day using videos of microfluidic-housed populations. Average values were taken from movement scores between all three frames. In addition to software automation, each video was manually corrected for any false positives/ box deformations that could skew movement scores. Daily mean movement values were converted to area under the curve to denote total population movement scores across the entire lifecourse.
The testing of example compounds 1 , 2 and 3 provided the results shown in Figures 1 , 2 and 3, respectively. Figures 1 , 2 and 3 show lifespan curves for healthspan-deficient mutant containing a mutant Fzo1 screened with the example compounds 1 , 2 and 3. Data are from ~80 animals per strain, where lifespan and movement were assessed every day starting from day 1 of adult life until death. Survival effects were assessed using Kaplan Meier analysis
The effect of drug treatment is assessed by measuring the number of subjects survived or saved after that intervention over a period of time. The time starting from a defined point to the occurrence of death is called survival time. The Kaplan Meier analysis shows that all three compounds, which come from three different chemical classes of mitochondrially targeted H2S donors all improve survival of the Fzo1 (mitofusin) mutated worms. This worm is an animal model for Charcot -Marie- Tooth disease type 2a where in humans a mitofusin protein is also mutated .

Claims

Claims
1. A compound comprising a mitochondrial targeting group linked to a group capable of releasing hydrogen sulfide, or a pharmaceutically acceptable salt thereof, for use in the prevention, management and/or treatment of Charcot-Marie-Tooth disease type 2A (CMT2A).
2. The compound for use according to claim 1 , wherein the compound is of the formula (I):
MTG-L-S; wherein MTG represents the mitochondrial targeting group; wherein L is a linker group; and wherein S is the group capable of releasing hydrogen sulfide.
3. The compound for use according to claim 2, wherein L comprises a group B which is an optionally substituted alkyl chain, optionally substituted alkenyl chain, or optionally substituted alkynyl chain.
4. The compound for use according to claim 2 or claim 3, wherein L comprises a group Z selected from a direct bond, -C(=O)NH-, -NHC(=O)-, -O-, -S-, -S(=O)2NH-, -NHS(=O)2-, -OC(=O)-, -C(=O)O-, - OC(=O)CH2O- and -OCH2C(=O)O-.
5. The compound for use according to any one of claims 2 to 4, wherein L comprises a group Y which is an optionally substituted 5 or 6 membered cycloalkyl or aryl ring.
6. The compound for use according to any one of claims 2 to 5, wherein L has the formula (II):
-B-Z-Y- wherein B is an optionally substituted alkyl chain, optionally substituted alkenyl chain, or optionally substituted alkynyl chain; wherein Z is selected from: a direct bond, -C(=O)NH-, -NHC(=O)-, -O-, -S-, -S(=O)2NH-, -NHS(=O)2-, -OC(=O)-, -C(=O)O- , -OC(=O)CH2O- and -OCH2C(=O)O-; and wherein Y is an optionally substituted 5 or 6 membered cycloalkyl or aryl ring.
7. The compound for use according to any one of the preceding claims, wherein the group capable of releasing hydrogen sulfide is selected from a thiocarbamoyl group, a 5-thioxo-5H-1 ,2-dithiol-3-yl group, a 5-thioxo-5H-1 ,2-dithiol-4-yl group, a 5-oxo-5H-1 ,2-dithiol-3-yl group, a 5-oxo-5H-1 ,2-dithiol- 4-yl group, a 5-hydroxyimino-5H-1 ,2-dithiol-3-yl group, a 5-hydroxyimino-5H-1 ,2-dithiol-4-yl group, a phosphinodithioate group or a phosphinodithioic acid group.
8. The compound for use according to any one of the preceding claims, wherein the group capable of releasing hydrogen sulfide is selected from:
Figure imgf000059_0001
wherein X is S, O or N-OH and R4, R5 and R6 are independently selected from H or C1-7 alkyl groups.
9. The compound for use according to any one of the preceding claims, wherein the mitochondrial targeting group is a lipophilic cation, a mitochondrial targeting peptide or a 1 ,4-benzoquinone.
10. The compound for use according to any one of the preceding claims, wherein the mitochondrial targeting group is a lipophilic cation selected from a phosphonium cation, an arsonium cation, an ammonium cation, flupritine, MKT-077, a pyridinium ceramide, a quinolium, a liposomal cation, a sorbitol guanidine, a cyclic guanidine and a rhodamine.
11. The compound for use according to claim 10, wherein the mitochondrial targeting group is a phosphonium cation.
12. The compound for use according to any one of claims 1 to 9, wherein the mitochondrial targeting group has the formula (IV):
Figure imgf000059_0002
wherein R1 and R2 are independently selected from H, halogen, a C1-6 alkyl group, a C1-6 alkoxy group or together form a cycloalkyl or aryl ring; and wherein R3 is H, halogen, a C1-6 alkyl group or a C1-6 alkoxy group.
13. The compound for use according to claim 2 having the formula (I): MTG-L-S; wherein the MTG group is selected from: a phosphonium cation, a 1 ,4-benzoquinone or a 1 ,4-naphthoquinone; wherein the L group has the formula (II): -B-Z-Y-; wherein
B is an unsubstituted C1-20 alkyl group;
Z is selected from -OC(=O)-, -OC(=O)CH2O- and -C(=O)O-; and
Y is an optionally substituted phenyl group and wherein groups Z and A are attached para to each other on the phenyl group; and wherein the S group is selected from:
Figure imgf000060_0001
wherein X is S, O or N-OH and R4, R5 and R6 are independently selected from H or C1-7 alkyl groups.
14. The compound for use according to claim 13, wherein: wherein the MTG group is selected from:
Figure imgf000060_0002
wherein the S group is selected from:
Figure imgf000060_0003
wherein X is S or O.
15. The compound for use according to claim 1 , wherein the compound is selected from:
Figure imgf000061_0001
Figure imgf000062_0001
16. The compound for use according to claim 1 , wherein the compound is selected from:
Figure imgf000062_0002
Figure imgf000063_0001
17. The compound for use according to claim 1 , wherein the compound is selected from:
Figure imgf000064_0001
18. The compound for use according to claim 1 , wherein the compound is selected from:
Figure imgf000065_0001
19. A pharmaceutical composition comprising a compound comprising a mitochondrial targeting group linked to a group capable of releasing hydrogen sulfide, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 18, for use in the prevention, management and/or treatment of Charcot-Marie-Tooth disease type 2A, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier, excipient, or diluent.
20. A method of prevention, management and/or treatment of Charcot-Marie-Tooth disease type 2A in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound comprising a mitochondrial targeting group linked to a group capable of releasing hydrogen sulfide, or a pharmaceutically acceptable salt thereof.
PCT/GB2024/052912 2023-11-17 2024-11-15 Compounds for use in treatment Pending WO2025104452A1 (en)

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