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WO2020033322A1 - Composés protégeant contre la perte d'audition et procédés associés - Google Patents

Composés protégeant contre la perte d'audition et procédés associés Download PDF

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Publication number
WO2020033322A1
WO2020033322A1 PCT/US2019/045134 US2019045134W WO2020033322A1 WO 2020033322 A1 WO2020033322 A1 WO 2020033322A1 US 2019045134 W US2019045134 W US 2019045134W WO 2020033322 A1 WO2020033322 A1 WO 2020033322A1
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Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
alkyl
present disclosure
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English (en)
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Julian Simon
Sarwat Chowdhury
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Fred Hutchinson Cancer Center
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Fred Hutchinson Cancer Center
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/18—Bridged systems

Definitions

  • Aminoglycosides are clinically used drugs that cause dose-dependent sensorineural hearing loss (Smith et al ., New Engl J Med, (1977) 296:349-53) and are known to kill hair cells in the mammalian inner ear (Theopold, Acta Otolaryngol (1977) 84:57-64). In the U.S., over 2,000,000 people receive treatment with aminoglycosides per year. The clinical efficacy of these drugs in treating resistant bacterial infections and their low cost globally account for their continued use and need.
  • Cisplatin a chemotherapeutic agent is used for its benefit to life despite its toxic effects on the hair cells of the inner ear.
  • High frequency hearing loss >8 kHz
  • has been reported to be as high as 90% in children undergoing cisplatin therapy (Allen, et al, Otolaryngol Head Neck Surg (1998) 118:584-588).
  • the incidence of vestibulotoxic effects of such drugs on patient populations has been less well studied. Estimates range between 3% and 6% with continued reports in the literature of patients with aminoglycoside induced vestibulotoxicity (Dhanireddy et al. , Arch Otolarngol Head Neck Surg (2005) 131 :46-48).
  • the present disclosure features a compound of Formula (A)
  • Z is S or O
  • R 3 is H, Ci_ 6 alkyl, C 2-6 alkenyl, or C 2.g alkynyl;
  • R 3 , R 3 ', R 4 , and R 4 ' are each H, C 3.6 alkyl, C 3.6 haloalkyl, or aryl,
  • n 0 or 1
  • R 3 is H and R 4 is H, and provided that when n is 0 and m is 2, R 3 and R4 together with the C atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, C 3 _6 alkyl, C 3-6 haloalkyl, CN, and N0 2.
  • the present disclosure features a method of treating hearing loss, including administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the present disclosure describes compounds that can protect against drug (e.g., aminoglycoside antibiotic, platinum chemotherapeuticj-induced hearing loss. Contrary to therapeutic agents that act by a reversible mechanism of action, where mechanosensory hair cells are no longer protected against the toxic effects of ototoxins when the protective compound is removed from the medium, the compounds of the present disclosure incorporate chemically reactive functionality(ies) (e.g., halo-acetamide) that can react with nucleophilic functional groups near the compound's binding site on a molecular target to provide extended long-term protection. For example, pretreatment of a subject with the irreversible hearing protective compounds of the present disclosure can provide long-term protection.
  • drug e.g., aminoglycoside antibiotic, platinum chemotherapeuticj-induced hearing loss.
  • chemically reactive functionality(ies) e.g., halo-acetamide
  • substituents of compounds of the disclosure are disclosed in groups or in ranges. It is specifically intended that the disclosure include each and every individual subcombination of the members of such groups and ranges.
  • C ⁇ alkyl is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • substituted or “substitution” refers to the replacing of a hydrogen atom with a substituent other than H.
  • an "N-substituted piperidin-4- yl” refers to replacement of the H atom from the NH of the piperidinyl with a non hydrogen substituent such as, for example, alkyl.
  • alkyl refers to a saturated hydrocarbon group which is straight-chained (e.g., linear) or branched.
  • Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.
  • An alkyl group can contain from 1 to about 30, from 1 to about 24, from 2 to about 24, from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.
  • aryl refers to monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, and indenyl. In some embodiments, aryl groups have from 6 to about 20 carbon atoms. In some embodiments, aryl groups are monocyclic aromatic hydrocarbons, such as phenyl.
  • halo or halogen includes fluoro, chloro, bromo, and iodo.
  • alkylene refers to a linking alkyl group.
  • alkenyl refers to an alkyl group having one or more double carbon-carbon bonds.
  • the alkenyl group can be linear or branched.
  • Example alkenyl groups include ethenyl, propenyl, and the like.
  • An alkenyl group can contain from 2 to about 30, from 2 to about 24, from 2 to about 20, from 2 to about 10, from 2 to about 8, from 2 to about 6, or from 2 to about 4 carbon atoms.
  • alkenylene refers to a linking alkenyl group.
  • alkynylene refers to a linking alkynyl group.
  • alkoxy refers to an -O-alkyl group.
  • Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.
  • haloalkyl refers to an alkyl group having one or more halogen substituents.
  • Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CCl 3 , CHCl 2 , C 2 Cl 5 , and the like.
  • haloalkoxy refers to an -O-(haloalkyl) group.
  • cycloalkyl refers to non-aromatic carbocycles including cyclized alkyl, alkenyl, and alkynyl groups.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including spirocycles.
  • cycloalkyl groups can have from 3 to about 20 carbon atoms, 3 to about 14 carbon atoms, 3 to about 10 carbon atoms, or 3 to 7 carbon atoms. Cycloalkyl groups can further have 0, 1, 2, or 3 double bonds and/or 0, 1, or 2 triple bonds.
  • cycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of pentane, pentene, hexane, and the like.
  • a cycloalkyl group having one or more fused aromatic rings can be attached though either the aromatic or non-aromatic portion.
  • One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized, for example, having an oxo or sulfido substituent.
  • cycloalkylene refers to a linking cycloalkyl group.
  • heteroalkyl refers to an alkyl group having at least one heteroatom such as sulfur, oxygen, or nitrogen.
  • heteroalkylene refers to a linking heteroalkyl group.
  • heteroaryl refers to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen.
  • Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Any ring forming N atom in a heteroaryl group can also be oxidized to form an N-oxo moiety.
  • the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.
  • heteroaryl ene refers to a linking heteroaryl group.
  • heterocycloalkyl refers to non-aromatic heterocycles including cyclized alkyl, alkenyl, and alkynyl groups where one or more of the ring-forming carbon atoms are replaced by a heteroatom such as an O, N, or S atom.
  • Heterocycloalkyl groups can be mono- or polycyclic (e.g., having 2, 3,4 or more fused rings or having a 2-ring, 3- ring, 4-ring spiro system (e.g., having 8 to 20 ring-forming atoms).
  • Heterocycloalkyl groups include monocyclic and polycyclic groups.
  • heterocycloalkyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, l,3-benzodioxole, benzo-I,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like.
  • the heterocycloalkyl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.
  • heterocycloalkylene refers to a linking heterocycloalkyl group.
  • amino refers to NH 2.
  • alkylamino refers to an amino group substituted by an alkyl group.
  • dialkylamino refers to an amino group substituted by two alkyl groups.
  • leaving group is a group that can be displaced by nucleophiles.
  • leaving groups include halogen, mesyloxy, tosyloxy, and anhydride residues of carbonic acids such as t-butoxy-carbonyloxy.
  • the term "individual,” “subject,” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • terapéuticaally effective amount refers to the amount of a therapeutic agent (i.e., drug, or therapeutic agent composition) that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following:
  • preventing the disease for example, preventing a disease, condition or disorder in an individual who can be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;
  • inhibiting the disease for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder;
  • ameliorating the disease for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
  • the compounds of the present disclosure can form covalent bonds with their biological binding sites and can continue to provide protection even after the compound is removed from the medium.
  • the present disclosure features a compound of Formula (A)
  • Y is halo, C j.g alkyl, CN, N0 2 , C ⁇ g haloalkyl, aryl, or heteroaryl,
  • R- ! is H, Ci_ 6 alkyl, C 2-6 alkenyl, or C 2.g alkynyl;
  • R3, R3', R4, and R4' are each H, C
  • R 3 and R 4 together with the C atoms to which they are attached form a 5 or 6 membered bridged heterocycle
  • L is C 2- 5 alkylene or C 2-5 heteroalkylene each optionally substituted with 1, 2, 3, 4, 5, or 6 halo;
  • n 0 or 1
  • n 1 or 2;
  • R 3 , R 3 ', R 4 , and R 4 ' are each H.
  • R 3 and R4 together with the C atoms to which they are attached form a 7- or 8-membered bridged heterocycloalkyl ring, having a [3,2,l]heterocyclooctenyl structure
  • the [3,2,l]heterocyclooctenyl structure is bridged by N-L-N(R l )(R 2 ).
  • the bridged heterocycle can have the following structure:
  • the compounds of Formula (A) have Formula (A-l)
  • the compounds of Formula (A) have Formula (A-2)
  • R l is H or Ci_ 6 alkyl.
  • R ⁇ can be methyl.
  • R j can be ethyl.
  • L is a linear C 2-5 alkylene or C 2-5 haloalkylene.
  • L can be a linear C 3 alkylene.
  • L is a linear C 2 alkylene.
  • L is a linear C 4 alkylene.
  • L can be a linear C 3 haloalkylene.
  • L is a linear C 2 haloalkylene.
  • L is a linear C 4 haloalkylene.
  • L is C 2 alkylene connected to N, S or O.
  • the compounds of the present disclosure are:
  • X is a leaving group selected from Cl, Br, and I;
  • the present disclosure features a pharmaceutical composition that includes a compound of the present disclosure.
  • the pharmaceutical composition can be in the form of a liquid, a gel, a suspension, an aerosol, a tablet, a powder, a pill, a capsule, or an implant.
  • the present disclosure features a method of treating hearing loss, and/or a method of decreasing the likelihood of hearing loss, including administering to a subject in need thereof a therapeutically effective amount of a compound the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the treatment methods can further include administering a therapeutically effective amount of the compound the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, to the subject before, concurrently with, and/or after treatment of the subject with an aminoglycoside antibiotic agent, a platinum-based chemotherapeutic agent, or an ototoxic therapeutic agent.
  • administering the therapeutically effective amount of a compound the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure comprises topical administration to an inner ear of ( e.g ., intratympanic delivery to) the subject.
  • the present disclosure features topical administration of a therapeutically effective amount of a compound the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, to a hair cell in the inner ear of the subject.
  • the methods include oral administration, intravenous administration, intramuscular administration, and/or subcutaneous administration of a therapeutically effective amount of a compound the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • a pharmaceutical composition refers to a mixture of a compound of the present disclosure, having Formula (A), (A-l), (A-2) described herein, or
  • X and Y are as defined above,
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated.
  • the mammal is a human.
  • a therapeutically effective amount depends on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • the compounds of the present disclosure are optionally used singly or in combination with one or more therapeutic agents as components of mixtures (as in combination therapy).
  • compositions which include a compound of the present disclosure, are optionally formulated into any suitable dosage form, such as aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.
  • suitable dosage form such as aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled
  • Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • one can administer the drug in a targeted drug delivery system for example, in a liposome coated with organ-specific antibody. The liposomes will be targeted to and taken up selectively by the organ.
  • the drug can be provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • the pharmaceutical compositions includes at least one compound of the present disclosure, as an active ingredient in free-acid or free-base form, or in a pharmaceutically acceptable salt form.
  • the methods and pharmaceutical compositions described herein include the use of crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity.
  • compounds can exist as tautomers. All tautomers are included within the scope of the compounds presented herein.
  • many of the compounds described herein exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • compositions for oral use are optionally obtained by mixing one or more solid excipient with one or more of the compounds of the present disclosure, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets, pills, or capsules.
  • Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
  • disintegrating agents can be added, such as the cross- linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions that are used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules optionally contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers can be added.
  • the solid dosage forms disclosed herein can be in the form of a tablet, (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder), a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules"), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol.
  • a tablet including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet
  • a pill including a sterile
  • solid dosage forms e.g., tablets, effervescent tablets, and capsules
  • solid dosage forms are prepared by mixing particles of a compound of the present disclosure, with one or more pharmaceutical excipients to form a bulk blend composition.
  • these bulk blend compositions as homogeneous, it is meant that the particles of the compound of present disclosure, are dispersed evenly throughout the composition so that the composition can be subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.
  • the individual unit dosages can also include film coatings, which disintegrate upon oral ingestion or upon contact with diluent. These formulations are optionally manufactured by conventional pharmacological techniques.
  • the pharmaceutical solid dosage forms described herein include a compound of the present disclosure, and optionally one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof.
  • a film coating is provided around the formulation of the compound described herein.
  • some or all of the particles of the compound described herein are coated.
  • some or all of the particles of the compound described herein are microencapsulated.
  • the particles of the compound described herein are not microencapsulated and are uncoated.
  • Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol and the like.
  • Suitable filling agents for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropylmethycellulose (HPMC), hydroxypropylmethycellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
  • disintegrants are often used in the formulation, especially when the dosage forms are compressed with binder. Disintegrants help rupturing the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form.
  • Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross- linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross- linked polymer such as crospovidone, a cross-linked polyvinylpyrrol
  • Binders impart cohesiveness to solid oral dosage form formulations: for powder filled capsule formulation, they aid in plug formation that are optionally filled into soft or hard shell capsules and for tablet formulation, they ensure the tablet remaining intact after compression and help assure blend uniformity prior to a compression or fill step.
  • Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose (e.g.
  • Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as CarbowaxTM, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like.
  • stearic acid calcium hydroxide, talc, corn
  • Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins and the like.
  • Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic® (BASF), and the like.
  • Suitable antioxidants for use in the solid dosage forms described herein include, for example, e.g., butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.
  • BHT butylated hydroxytoluene
  • sodium ascorbate sodium ascorbate
  • tocopherol sodium ascorbate
  • additives used in the solid dosage forms described herein there is considerable overlap between additives used in the solid dosage forms described herein.
  • the above-listed additives should be taken as exemplary, and not limiting, of the types of additives that can be included in solid dosage forms of the pharmaceutical compositions described herein.
  • one or more layers of the pharmaceutical formulation are plasticized.
  • a plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w/w) of the coating composition.
  • Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.
  • a capsule can be prepared, for example, by placing the bulk blend of the formulation of the compound described above, inside of a capsule.
  • the formulations non-aqueous suspensions and solutions
  • the formulations are placed in a soft gelatin capsule.
  • the formulations are placed in standard gelatin capsules or non-gelatin capsules such as capsules comprising HPMC.
  • the formulation is placed in a sprinkle capsule, wherein the capsule can be swallowed whole or the capsule can be opened and the contents sprinkled on food prior to eating.
  • the therapeutic dose is split into multiple (e.g., two, three, or four) capsules.
  • the entire dose of the formulation is delivered in a capsule form.
  • the particles of the compound of the present disclosure described herein and one or more excipients are dry blended and compressed into a mass, such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates within less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes, after oral administration, thereby releasing the formulation into the gastrointestinal fluid.
  • dosage forms can include microencapsulated formulations.
  • one or more other compatible materials are present in the microencapsulation material.
  • Exemplary materials include, but are not limited to, pH modifiers, erosion facilitators, anti-foaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.
  • Microencapsulated compounds described herein can be formulated by methods that include, e.g., spray drying processes, spinning disk-solvent processes, hot melt processes, spray chilling methods, fluidized bed, electrostatic deposition, centrifugal extrusion, rotational suspension separation, polymerization at liquid-gas or solid-gas interface, pressure extrusion, or spraying solvent extraction bath.
  • spray drying processes spinning disk-solvent processes
  • hot melt processes hot melt processes
  • spray chilling methods fluidized bed
  • electrostatic deposition centrifugal extrusion
  • rotational suspension separation polymerization at liquid-gas or solid-gas interface
  • pressure extrusion or spraying solvent extraction bath.
  • several chemical techniques e.g., complex coacervation, solvent evaporation, polymer- polymer incompatibility, interfacial polymerization in liquid media, in situ polymerization, in-liquid drying, and desolvation in liquid media could also be used.
  • other methods such as roller compaction, extrusion/spheronization, coacerv
  • Controlled release refers to the release of the compounds described herein from a dosage form in which it is incorporated according to a desired profile over an extended period of time.
  • Controlled release profiles include, for example, sustained release, prolonged release, pulsatile release, and delayed release profiles.
  • immediate release compositions controlled release compositions allow delivery of an agent to a subject over an extended period of time according to a predetermined profile.
  • Such release rates can provide therapeutically effective levels of agent for an extended period of time and thereby provide a longer period of pharmacologic response while minimizing side effects as compared to conventional rapid release dosage forms.
  • Such longer periods of response provide for many inherent benefits that are not achieved with the corresponding short acting, immediate release preparations.
  • the formulations described herein, which include a compound of the present disclosure are delivered using a pulsatile dosage form.
  • a pulsatile dosage form is capable of providing one or more immediate release pulses at predetermined time points after a controlled lag time or at specific sites.
  • Pulsatile dosage forms can be administered using a variety of pulsatile formulations including, but are not limited to, those described in U.S. Pat. Nos. 5,011,692; 5,017,381; 5,229,135; 5,840,329; 4,871,549; 5,260,068; 5,260,069; 5,508,040; 5,567,441 and 5,837,284.
  • controlled release systems are suitable for use with the formulations described herein.
  • delivery systems include, e.g., polymer- based systems, such as polylactic and polyglycolic acid, polyanhydrides and polycaprolactone; porous matrices, nonpolymer-based systems that are lipids, including sterols, such as cholesterol, cholesterol esters and fatty acids, or neutral fats, such as mono-, di- and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings, bioerodible dosage forms, compressed tablets using conventional binders and the like. See, e.g., Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp.
  • pharmaceutical formulations include particles of the compounds described herein, e.g. compounds of present disclosure, and at least one dispersing agent or suspending agent for oral administration to a subject.
  • the formulations can be a powder and/or granules for suspension, and upon admixture with water, a substantially uniform suspension is obtained.
  • the aqueous suspensions and dispersions described herein can remain in a homogenous state, as defined in The LTSP Pharmacists' Pharmacopeia (2005 edition, chapter 905), for at least 4 hours.
  • the homogeneity should be determined by a sampling method consistent with regard to determining homogeneity of the entire composition.
  • an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 1 minute.
  • an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 45 seconds.
  • an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 30 seconds. In still another embodiment, no agitation is necessary to maintain a homogeneous aqueous dispersion.
  • compositions described herein can include sweetening agents such as, but not limited to, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohe
  • compounds described herein can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally recognized in the field.
  • appropriate formulations can include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally recognized in the field.
  • Parenteral injections can involve bolus injection or continuous infusion.
  • Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the pharmaceutical composition described herein can be in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water- soluble form. Additionally, suspensions of the active compounds can be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • compositions provided herein also include a mucoadhesive polymer, selected from among, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.
  • a mucoadhesive polymer selected from among, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.
  • an agent such as a compound of the present disclosure, is administered in an amount effective for amelioration of, or prevention of the development of symptoms of, the disease or disorder (i.e., a therapeutically effective amount).
  • a therapeutically effective amount can be an amount that is capable of at least partially preventing or reversing a disease or disorder.
  • the dose required to obtain an effective amount can vary depending on the agent, formulation, disease or disorder, and individual to whom the agent is administered.
  • Determination of effective amounts can also involve in vitro assays in which varying doses of agent are administered to cells in culture and the concentration of agent effective for ameliorating some or all symptoms is determined in order to calculate the concentration required in vivo. Effective amounts can also be based in in vivo animal studies.
  • An agent can be administered prior to, concurrently with and subsequent to the appearance of symptoms of a disease or disorder.
  • an agent is administered to a subject with a family history of the disease or disorder, or who has a phenotype that can indicate a predisposition to a disease or disorder, or who has a genotype which predisposes the subject to the disease or disorder.
  • compositions containing the compound(s) described herein can be administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.
  • the precise amounts also depend on the patient's state of health, weight, and the like.
  • effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • the administration of the compounds can be administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.
  • a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment will typically be in the range of about 0.02-about 5000 mg per day, in some embodiments, about 1 -about 1500 mg per day.
  • the desired dose can conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the pharmaceutical composition described herein can be in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compound.
  • the unit dosage can be in the form of a package containing discrete quantities of the formulation.
  • Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules.
  • Aqueous suspension compositions can be packaged in single-dose non-reclosable containers.
  • multiple-dose reclosable containers can be used and can, for example, include a preservative.
  • formulations for parenteral injection can be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.
  • the daily dosages appropriate for the compounds described herein are from about 0.01 mg/kg to about 20 mg/kg. In one embodiment, the daily dosages are from about 0.1 mg/kg to about 10 mg/kg.
  • An indicated daily dosage in the larger mammal, including, but not limited to, humans, is in the range from about 0.5 mg to about 1000 mg, conveniently administered in a single dose or in divided doses, including, but not limited to, up to four times a day or in extended release form.
  • Suitable unit dosage forms for oral administration include from about 1 to about 500 mg active ingredient. In one embodiment, the unit dosage is about 1 mg, about 5 mg, about, 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 400 mg, or about 500 mg.
  • Such dosages can be altered depending on a number of variables, not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD 50 and ED 50 .
  • Compounds exhibiting high therapeutic indices are preferred.
  • the data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with minimal toxicity.
  • the dosage can vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the compounds of the present disclosure, and compositions thereof can be used in combination with other therapeutic agents that are selected for their therapeutic value for the condition to be treated.
  • the compositions described herein and the other therapeutic agents do not have to be administered in the same pharmaceutical composition or at the same time, and because of different physical and chemical characteristics, can be administered by different routes at different times.
  • the determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is within the knowledge of the clinician.
  • the initial administration can be made according to established protocols recognized in the field, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the clinician.
  • a compound of the present disclosure is administered in combination with an aminoglycoside antibiotic agent, a platinum-based chemotherapeutic agent, or an ototoxic therapeutic agent.
  • a therapeutically effective amount of the compound the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure can be administered to the subject before, concurrently with, and/or after treatment of the subject with an aminoglycoside antibiotic agent, a platinum-based chemotherapeutic agent, or an ototoxic therapeutic agent.
  • the compounds of the present disclosure can be topically administered to an inner ear of ( e.g ., intratympanic delivery to) the subject, and/or to a hair cell in the inner ear of the subject.
  • a compound of the present disclosure is administered before, concurrently with, and/or after treatment with an aminoglycoside antibiotic agent selected from streptomycin, neomycin, framycetin, paromomycin, paromomycin sulfate, ribostamycin, kanamycin, amikacin, arbekacin, bekanamycin, dibekacin, tobramycin, spectinomycin, hygromycin B, gentamicin, netilmicin, sisomicin, isepamicin, verdamicin, and astromicin.
  • an aminoglycoside antibiotic agent selected from streptomycin, neomycin, framycetin, paromomycin, paromomycin sulfate, ribostamycin, kanamycin, amikacin, arbekacin, bekanamycin, dibekacin, tobramycin, spectinomycin, hygromycin B, gentamicin, netilmicin
  • a compound of the present disclosure is administered in combination with amikacin. In some embodiments, a compound of the present disclosure is administered in combination with neomycin. In some embodiments, a compound of the present disclosure is administered before, concurrently with, and/or after treatment with kanamycin. In some embodiments, a compound of the present disclosure is administered before, concurrently with, and/or after treatment with gentamicin. In some embodiments, a compound of the present disclosure is administered before, concurrently with, and/or after treatment with tobramycin.
  • a compound of the present disclosure is administered in a first treatment phase for 1-7 days, and then the compound of the present disclosure is administered in combination with an aminoglycoside antibiotic agent, a platinum-based chemotherapeutic agent, or an ototoxic therapeutic agent in a second treatment phase. In some embodiments, a compound of the present disclosure is administered for 7 days, and then the compound of the present disclosure is administered in combination with an aminoglycoside antibiotic agent, a platinum-based chemotherapeutic agent, or an ototoxic therapeutic agent.
  • a compound of the present disclosure is administered for 6 days, and then the compound of the present disclosure is administered in combination with an aminoglycoside antibiotic agent, a platinum-based chemotherapeutic agent, or an ototoxic therapeutic agent. In some embodiments, a compound of the present disclosure is administered for 5 days, and then the compound of the present disclosure is administered in combination with an aminoglycoside antibiotic agent, a platinum-based chemotherapeutic agent, or an ototoxic therapeutic agent. In some embodiments, a compound of the present disclosure is administered for 4 days, and then the compound of the present disclosure is administered in combination with an aminoglycoside antibiotic agent, a platinum-based chemotherapeutic agent, or an ototoxic therapeutic agent.
  • a compound of the present disclosure is administered for 3 days, and then the compound of the present disclosure is administered in combination with an aminoglycoside antibiotic agent, a platinum-based chemotherapeutic agent, or an ototoxic therapeutic agent. In some embodiments, a compound of the present disclosure is administered for 2 days, and then the compound of the present disclosure is administered in combination with an aminoglycoside antibiotic agent, a platinum-based chemotherapeutic agent, or an ototoxic therapeutic agent. In some embodiments, a compound of the present disclosure is administered for 1 day, and then the compound of the present disclosure is administered in combination with an aminoglycoside antibiotic agent, a platinum-based chemotherapeutic agent, or an ototoxic therapeutic agent.
  • the aminoglycoside antibiotic agent, platinum-based chemotherapeutic agent, or ototoxic therapeutic agent is administered without a compound of the present disclosure.
  • the compound of the present disclosure is administered an additional 7 days following the administration of the aminoglycoside antibiotic agent, platinum-based chemotherapeutic agent, or ototoxic therapeutic agent.
  • the compound of the present disclosure is administered an additional 6 days following the administration of the aminoglycoside antibiotic agent, platinum-based chemotherapeutic agent, or ototoxic therapeutic agent. In some embodiments, the compound of the present disclosure is administered an additional 5 days following the administration of the aminoglycoside antibiotic agent, platinum-based chemotherapeutic agent, or ototoxic therapeutic agent. In some embodiments, the compound of the present disclosure is administered an additional 4 days following the administration of the aminoglycoside antibiotic agent, platinum-based chemotherapeutic agent, or ototoxic therapeutic agent. In some embodiments, the compound of the present disclosure is administered an additional 3 days following the administration of the aminoglycoside antibiotic agent, platinum-based chemotherapeutic agent, or ototoxic therapeutic agent.
  • the compound of the present disclosure administered an additional 2 days following the administration of the aminoglycoside antibiotic agent, platinum-based chemotherapeutic agent, or ototoxic therapeutic agent. In some embodiments, the compound of the present disclosure is administered an additional 1 day following the administration of the aminoglycoside antibiotic agent, platinum-based chemotherapeutic agent, or ototoxic therapeutic agent.
  • the compound of the present disclosure and the aminoglycoside antibiotic agent, platinum-based chemotherapeutic agent, or ototoxic therapeutic agent are administered in combination in a single dosage form. In some embodiments the compound of the present disclosure and the aminoglycoside antibiotic agent, platinum-based chemotherapeutic agent, or ototoxic therapeutic agent are administered in combination in separate dosage forms.
  • a compound of the present disclosure is administered before, concurrently with, and/or after treatment with a chemotherapeutic agent. In some embodiments, a compound of the present disclosure is administered before, concurrently with, and/or after treatment with a chemotherapeutic agent selected from cisplatin and carboplatin. In some embodiments, a compound of the present disclosure is administered before, concurrently with, and/or after treatment with cisplatin. In some embodiments, a compound of the present disclosure is administered before, concurrently with, and/or after treatment with carboplatin.
  • Therapeutically-effective dosages can vary when the drugs are used in treatment combinations. Methods for experimentally determining therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens are described in the literature. For example, the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects, has been described extensively in the literature. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
  • dosages of the co-administered compounds will vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth.
  • the compound provided herein can be administered simultaneously with the biologically active agent(s), or sequentially (e.g., before or after administration with the biologically active agent(s)). If administered sequentially, the attending physician will decide on the appropriate sequence of administering protein in combination with the biologically active agent(s).
  • the multiple therapeutic agents can be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents can be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents can be given in multiple doses, or both can be given as multiple doses. If not simultaneous, the timing between the multiple doses can vary from more than zero weeks to less than four weeks.
  • the combination methods, compositions and formulations are not to be limited to the use of only two agents; the use of multiple therapeutic combinations is also envisioned.
  • the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought can be modified in accordance with a variety of factors. These factors include the disorder or condition from which the subject suffers, as well as the age, weight, sex, diet, and medical condition of the subject. Thus, the dosage regimen actually employed can vary widely and therefore can deviate from the dosage regimens set forth herein.
  • the pharmaceutical agents which make up the combination therapy disclosed herein can be a combined dosage form or in separate dosage forms intended for substantially simultaneous administration.
  • the pharmaceutical agents that make up the combination therapy can also be administered sequentially, with either therapeutic compound being administered by a regimen calling for two-step administration.
  • the two- step administration regimen can call for sequential administration of the active agents or spaced-apart administration of the separate active agents.
  • the time period between the multiple administration steps can range from, a few minutes to several hours, depending upon the properties of each pharmaceutical agent, such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the pharmaceutical agent. Circadian variation of the target molecule concentration can also determine the optimal dose interval.
  • the compounds described herein also can be used in combination with procedures that can provide additional or synergistic benefit to the patient.
  • patients are expected to find therapeutic and/or prophylactic benefit in the methods described herein, wherein pharmaceutical composition of a compound disclosed herein and/or combinations with other therapeutics are combined with genetic testing to determine whether that individual is a carrier of a mutant gene that is known to be correlated with certain diseases or conditions.
  • the compounds described herein and combination therapies can be administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound can vary.
  • the compounds can be used as a prophylactic and can be administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition.
  • the initial administration can be via any route practical, such as, for example, an intravenous injection, a bolus injection, infusion over about 5 minutes to about 5 hours, a pill, a capsule, transdermal patch, buccal delivery, and the like, or combination thereof.
  • a compound is preferably administered as soon as is practicable before the onset of a disease or condition, or after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease or condition.
  • the length of treatment can vary for each subject, and the length can be determined using the known criteria.
  • Examples 1 and 2 describe the synthesis and characterization of embodiments of compounds of the present disclosure.
  • Example 3 describes the testing of the protective properties of embodiments of compounds of the present disclosure.
  • Step _ One. _ ( ⁇ R.8S)- 1 1 -tert-butyl _ N-r3-(3-carbamoyl)1-4-(r(4- chlorophenvncarbamoyl1aminol-5-thia-l lazatricvclor6.2.l.0 2 . 6 1undeca-2 (64-3 -diene-3 - carboxamide (T)
  • the product was forwarded to the next step without further purification.
  • reaction mixture was then concentrated and purified by reversed-phase preparatory HPLC using Deltapack C18 column using water (with 0.1% TFA) and acetonitrile (with 0.1% TFA) isocratic elution at 15% B for 15 minutes followed by gradient elution from 15% B to 90%B in 10 minutes.
  • the eluted product was lyophilized to afford TFA salt of the desired product as white powder (7 mg, 28% yield).
  • FIGURE 1 illustrates the chemical structures of compounds PROTO- 1, ORC- 13661, PROTO-183, PROTO-185, and PROTO-200.
  • the bar graph demonstrates that protection persists even 24 hours after PROTO-200 is washed out.
  • test compound control, PROTO- 1 50 mM or PROTO-200 5 mM
  • test compound control, PROTO- 1 50 mM or PROTO-200 5 mM

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Abstract

L'invention concerne des composés, et des compositions pharmaceutiques qui comprennent de tels composés, pour prévenir, traiter et/ou protéger contre la mort des cellules sensorielles ciliées. L'invention concerne également des procédés d'utilisation de ces composés, seuls ou en combinaison avec d'autres agents thérapeutiques.
PCT/US2019/045134 2018-08-06 2019-08-05 Composés protégeant contre la perte d'audition et procédés associés Ceased WO2020033322A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014052914A1 (fr) * 2012-09-28 2014-04-03 University Of Washington Through Its Center For Commercialization Composés et procédés de prévention, de traitement et/ou de protection contre la mort de cellules ciliées sensorielles
US9493482B2 (en) * 2015-02-06 2016-11-15 University Of Washington Compounds and methods for preventing or treating sensory hair cell death

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014052914A1 (fr) * 2012-09-28 2014-04-03 University Of Washington Through Its Center For Commercialization Composés et procédés de prévention, de traitement et/ou de protection contre la mort de cellules ciliées sensorielles
US9902738B2 (en) * 2012-09-28 2018-02-27 University Of Washington Through Its Center For Commercialization Compounds and methods for preventing, treating and/or protecting against sensory hair cell death
US9493482B2 (en) * 2015-02-06 2016-11-15 University Of Washington Compounds and methods for preventing or treating sensory hair cell death

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHOWDHURY ET AL.: "Phenotypic Optimization of Urea-Thiophene Carboxamides to Yield Potent, Well Tolerated and Orally Active Protective Agents Against Aminoglycoside-Induced Hearing Loss", J MED CHEM., vol. 61, no. 1, 11 January 2018 (2018-01-11), pages 84 - 97, XP055501337, DOI: 10.1021/acs.jmedchem.7b00932 *

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