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WO2024159213A2 - Composés fluorés et leurs utilisations - Google Patents

Composés fluorés et leurs utilisations Download PDF

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Publication number
WO2024159213A2
WO2024159213A2 PCT/US2024/013326 US2024013326W WO2024159213A2 WO 2024159213 A2 WO2024159213 A2 WO 2024159213A2 US 2024013326 W US2024013326 W US 2024013326W WO 2024159213 A2 WO2024159213 A2 WO 2024159213A2
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WIPO (PCT)
Prior art keywords
compound
disease
sigma
receptor
cancer
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Ceased
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PCT/US2024/013326
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WO2024159213A3 (fr
Inventor
Run-Duo GAO
Takashi Tsukamoto
Robert R. Luedtke
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Johns Hopkins University
University of North Texas Health Science Center
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Johns Hopkins University
University of North Texas Health Science Center
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Publication of WO2024159213A2 publication Critical patent/WO2024159213A2/fr
Publication of WO2024159213A3 publication Critical patent/WO2024159213A3/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine

Definitions

  • the sigma-1 receptor is a chaperone protein that is activated during stressful situations and has been postulated to play a modulatory role in the activity of ion channels and the function of G-Protein Coupled Receptors (GPCRs), including glutamatergic and dopaminergic receptors.
  • GPCRs G-Protein Coupled Receptors
  • Sigma-1 receptor ligands have been proposed as potential therapeutic agents for the treatment of several conditions and disorders. To date, however, no sigma-1 receptor targeted therapeutic agents are on the market.
  • SUMMARY The presently disclosed subject matter provides sigma-1 receptor ligands and their use for treating cognitive impairments. More particularly, in some aspects, the presently disclosed subject matter provides a compound selected from:
  • the compound is selected from: . .
  • a pharmaceutical composition comprising a presently disclosed sigma-1 receptor ligand and a pharmaceutically acceptable carrier.
  • the presently disclosed subject matter provides a method for treating a disease, condition, or disorder associated with a sigma-1 receptor, the method comprising
  • the disease, condition, or disorder associated with a sigma-1 receptor is selected from a cognitive impairment or a cognitive deficit, a neurodegenerative disease, depression, anxiety, a neuropsychiatric disorder, nociceptive pain, dementia, frontotemporal dementia, psychostimulant abuse, retinopathy, stroke, traumatic brain injury, a viral infection, and a cancer.
  • the cognitive deficit includes a memory deficit or a learning deficit.
  • the neurodegenerative disease is selected from multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.
  • the neuropsychiatric disorder is selected from schizophrenia and Tourette syndrome.
  • the psychostimulant abuse includes cocaine abuse and methamphetamine abuse.
  • the viral infection comprises a COVID-19 infection.
  • the cancer is selected from breast cancer, lung cancer, prostate cancer, ovarian cancer, and colorectal cancer.
  • administration of a compound of any one of claims 1 to 3 facilitates brain derived neurotrophic factor (BDNF) secretion or release.
  • BDNF brain derived neurotrophic factor
  • FIG. 1 shows plasma ( ⁇ g/mL) and brain ( ⁇ g/g) levels of 2 following intraperitoneal administration (10 mg/kg) in mice;
  • FIG. 2A, FIG. 2B, FIG. 2C, FIG. 2D, and FIG. 2E demonstrate the ability of ( ⁇ )-2 (10 mg/kg, i.p.) to attenuate the adverse cognitive effects of scopolamine (1 mg/kg, i.p.) on learning and memory in 7-10-week-old male BALB/c mice in AAT.
  • FIG. 2A Balb/c mice were not injected with test compound or vehicle;
  • FIG. 2B Balb/c mice were injected with both vehicle solvents in the absence of drug or scopolamine;
  • FIG. 2C Balb/c mice were injected with scopolamine (1 mg/kg, i.p.) and vehicle (10% DMSO and 90% sterile filtered water, i.p.);
  • FIG. 2D mice injected with ( ⁇ )-2 (10 mg/kg, i.p.) and scopolamine (1 mg/kg, i.p.);
  • the sigma-1 receptor is a chaperone protein that is activated during stressful situations and has been postulated to play a modulatory role in the activity of ion channels and the function of G-Protein Coupled Receptors (GPCRs), including glutamatergic and dopaminergic receptors.
  • GPCRs G-Protein Coupled Receptors
  • Sigma-1 receptor ligands have been proposed as potential therapeutic agents for the treatment of several conditions and disorders including, but not limited to, cognitive (memory and learning) deficits; depression; anxiety; neuropsychiatric disorders, such as schizophrenia and Tourette syndrome; nociceptive pain; and dementia, as well as for the treatment of psychostimulant (cocaine and methamphetamine) abuse, amyotrophic lateral sclerosis (ALS), retinopathy, and traumatic brain injury.
  • Sigma-1 receptor ligands also have been proposed as anti-viral agents, which could interfere with the initial steps of viral infections, slow the course of viral infection, and prevent the spread of viral infections while allowing a protective immune response to develop.
  • Sig-1R-based medications could be used as early intervention, prevention of viral infections, such as COVID-19, as well as other viral infections.
  • Sigma-1 receptor ligands also have been proposed as tumor detection, tumor staging, anti-tumor drug development, and for the evaluation of therapeutic strategies. While there has been extensive interest in targeting the sigma-1 receptor, there are currently no sigma-1 receptor targeted therapeutic agents on the market. Further, there is currently no strategy for the pharmacological treatments for age-associated cognitive disorders in patients with neurodegenerative disorders. The presently disclosed subject matter provides sigma-1 receptor pharmacologically selective ligands for treating cognitive
  • the presently disclosed subject matter provides compounds that bind with high affinity (1-10 nM range) at the sigma-1 receptor while binding with low affinity at sigma-2 receptors and dopamine D2-like receptors.
  • A. Sigma-1 Receptor Ligands In some embodiments, the presently disclosed subject matter provides a compound selected from: In certain embodiments, the compound is selected from: .
  • the compounds of the present disclosure do not include those which are known in art to be too unstable to synthesize and/or isolate.
  • the present disclosure is meant to include compounds in racemic, scalemic, and optically pure forms.
  • Optically active (R)- and (S)-, or D- and L-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • R Optically active
  • S D- and L-isomers
  • D- and L-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefenic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center.
  • the presently disclosed compounds are selective for the sigma-1 receptor.
  • the term “selectivity” or “selective” refers to a difference in the binding affinity (K i ) of a compound for a sigma receptor, for example, a sigma-1 receptor, compared to a non-sigma receptor, e.g., dopamine D2 receptor (D2R), or, for example, another sigma receptor subtype, e.g., a sigma-2 receptor.
  • the presently disclosed sigma-1 receptor ligand has at least 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 100-fold, or 500-fold higher affinity, or more, for binding to a sigma-1 receptor compared to a non-sigma receptor, or a sigma-2 receptor, as assessed by a comparison of binding dissociation constant
  • the presently disclosed subject matter provides a method for treating a disease, condition, or disorder associated with a sigma-1 receptor, the method comprising administering a therapeutically effective amount of presently disclosed sigma-1 receptor ligand, or a pharmaceutical composition thereof, to a subject in need of treatment thereof.
  • the disease, condition, or disorder associated with a sigma-1 receptor includes a cognitive impairment or a cognitive deficit Cognition generally is the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses and encompasses various aspects of high-level intellectual functions and processes including, but not limited to, attention, memory, knowledge, decision making, planning, reasoning, judgment, perception, comprehension, language, and visuospatial function, among others.
  • Cognitive deficit is an inclusive term used to describe the impairment of different domains of cognition. “Cognitive deficit” can be used interchangeably with "cognitive impairment.”
  • Cognitive deficit or impairment can be a short-term condition or a progressive and permanent condition. Alzheimer’s disease is the most well-known condition associated with cognitive impairment.
  • Cognitive deficit is not limited to any particular disease or condition, but can be a manifestation of an underlying condition.
  • Cognitive deficit or cognitive impairment can include, but is not limited to, trouble remembering things (frequently asking the same question or repeating the same story again and again); difficulty in learning new things and concentrating; vision problems and trouble speaking; difficulty recognizing people and places; finding new places or situations overwhelming; confusion or agitation; mood changes; changes in behavior or speech; and difficulty with usual daily tasks.
  • Some disease conditions associated with cognitive deficits or cognitive impairment include, but are not limited to, Alzheimer’s disease, Huntington’s disease, stroke, developmental disorders, such as Down syndrome, traumatic brain injury, multiple sclerosis, Parkinson’s disease, Lewy body dementia, meningitis, acquired immune deficiency
  • the disease, condition, or disorder associate with a sigma-1 receptor includes a neurodegenerative disease, depression, anxiety, a neuropsychiatric disorder, nociceptive pain, dementia, frontotemporal dementia, psychostimulant abuse, retinopathy, stroke, traumatic brain injury, a viral infection, and a cancer.
  • the neurodegenerative disease is selected from multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.
  • the neuropsychiatric disorder is selected from schizophrenia and Tourette syndrome.
  • the psychostimulant abuse includes cocaine abuse and methamphetamine abuse.
  • the viral infection comprises a COVID-19 infection.
  • the cancer is selected from breast cancer, lung cancer, prostate cancer, ovarian cancer, and colorectal cancer.
  • administration of a compound of any one of claims 1 to 3 facilitates brain derived neurotrophic factor (BDNF) secretion or release.
  • BDNF brain derived neurotrophic factor
  • the term “treating” can include reversing, alleviating, inhibiting the progression of, preventing, or reducing the likelihood of the disease, disorder, or condition to which such term applies, or one or more symptoms or manifestations of such disease, disorder, or condition.
  • Preventing refers to causing a disease, disorder, condition, or symptom or manifestation of such, or worsening of the severity of such, not to occur.
  • the presently disclosed compounds can be administered prophylactically to prevent or reduce the incidence or recurrence of the disease, disorder, or condition.
  • the “subject” treated by the presently disclosed methods in their many embodiments is desirably a human subject, although it is to be understood that the methods described herein are effective with respect to all vertebrate species, which are intended to be included in the term “subject.”
  • a “subject” can include a human subject for medical purposes, such as for the treatment of an existing condition or disease or the prophylactic treatment for preventing the onset of a condition or disease, or an animal subject for
  • Suitable animal subjects include mammals including, but not limited to, primates, e.g., humans, monkeys, apes, and the like; bovines, e.g., cattle, oxen, and the like; ovines, e.g., sheep and the like; caprines, e.g., goats and the like; porcines, e.g., pigs, hogs, and the like; equines, e.g., horses, donkeys, zebras, and the like; felines, including wild and domestic cats; canines, including dogs; lagomorphs, including rabbits, hares, and the like; and rodents, including mice, rats, and the like.
  • an animal may be a transgenic animal.
  • the subject is a human including, but not limited to, fetal, neonatal, infant, juvenile, and adult subjects.
  • a “subject” can include a patient afflicted with or suspected of being afflicted with a condition or disease.
  • the terms “subject” and “patient” are used interchangeably herein.
  • the term “subject” also refers to an organism, tissue, cell, or collection of cells from a subject.
  • the “effective amount” of an active agent or drug delivery device refers to the amount necessary to elicit the desired biological response.
  • the effective amount of an agent or device may vary depending on such factors as the desired biological endpoint, the agent to be delivered, the makeup of the pharmaceutical composition, the target tissue, and the like.
  • the term “combination” is used in its broadest sense and means that a subject is administered at least two agents, more particularly a presently disclosed sigma-1 receptor ligand and at least one other therapeutic agent. More particularly, the term “in combination” refers to the concomitant administration of two (or more) active agents for the treatment of a, e.g., single disease state.
  • the active agents may be combined and administered in a single dosage form, may be administered as separate dosage forms at the same time, or may be administered as separate dosage forms that are administered alternately or sequentially on the same or separate days.
  • the active agents are combined and administered in a single dosage form.
  • the active agents are administered in separate dosage forms (e.g., wherein it is desirable to vary the amount of one but not the other).
  • the single dosage form may include additional active agents for the treatment of the disease state.
  • the presently disclosed sigma-1 receptor ligands can be administered alone or in combination with adjuvants that enhance stability of the compounds, alone or in combination with one or more therapeutic agents, facilitate administration of pharmaceutical
  • compositions containing them in certain embodiments provide increased dissolution or dispersion, increase inhibitory activity, provide adjunct therapy, and the like, including other active ingredients.
  • combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents are used as monotherapies.
  • the timing of administration of a presently disclosed sigma-1 receptor ligand and at least one additional therapeutic agent can be varied so long as the beneficial effects of the combination of these agents are achieved. Accordingly, the phrase “in combination with” refers to the administration of a compound described herein and at least one additional therapeutic agent either simultaneously, sequentially, or a combination thereof.
  • a subject administered a combination of a compound described herein and at least one additional therapeutic agent can receive a compound and at least one additional therapeutic agent at the same time (i.e., simultaneously) or at different times (i.e., sequentially, in either order, on the same day or on different days), so long as the effect of the combination of both agents is achieved in the subject.
  • the agents can be administered within 1, 5, 10, 30, 60, 120, 180, 240 minutes or longer of one another. In other embodiments, agents administered sequentially, can be administered within 1, 5, 10, 15, 20 or more days of one another.
  • the compound described herein and at least one additional therapeutic agent are administered simultaneously, they can be administered to the subject as separate pharmaceutical compositions, each comprising either a compound or at least one additional therapeutic agent, or they can be administered to a subject as a single pharmaceutical composition comprising both agents.
  • the effective concentration of each of the agents to elicit a particular biological response may be less than the effective concentration of each agent when administered alone, thereby allowing a reduction in the dose of one or more of the agents relative to the dose that would be needed if the agent was administered as a single agent.
  • the effects of multiple agents may, but need not be, additive or synergistic.
  • the agents may be administered multiple times. In some embodiments, when administered in combination, the two or more agents can have a synergistic effect.
  • Qa/QA + B/QB Synergy Index (SI) wherein: Q A is the concentration of a component A, acting alone, which produced an end point in relation to component A; Qa is the concentration of component A, in a mixture, which produced an end point; Q B is the concentration of a component B, acting alone, which produced an end point in relation to component B; and Qb is the concentration of component B, in a mixture, which produced an end point.
  • SI Synergy Index
  • compositions and Administration In another aspect, the present disclosure provides a pharmaceutical composition including one presently disclosed sigma-1 receptor ligand alone or in combination with one or more additional therapeutic agents in admixture with a pharmaceutically acceptable excipient.
  • pharmaceutical compositions include the pharmaceutically acceptable salts of the compounds described above. Pharmaceutically acceptable salts are generally well known to those of ordinary skill in the
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent or by ion exchange, whereby one basic counterion (base) in an ionic complex is substituted for another.
  • bases include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent or by ion exchange, whereby one acidic counterion (acid) in an ionic complex is substituted for another.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p- toluenesulfonic, citric, tartaric, methanesulfonic, trifluoroacetic acid (TFA), and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galacturonic acids and the like (see, for example, Berge et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • salts suitable for use with the presently disclosed subject matter include, by way of example but not limitation, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate,
  • agents may be formulated into liquid or solid dosage forms and administered systemically or locally.
  • the agents may be delivered, for example, in a timed- or sustained-slow release form as is known to those skilled in the art. Techniques for formulation and administration may be found in Remington: The Science and Practice of Pharmacy (20 th ed.) Lippincott, Williams & Wilkins (2000).
  • Suitable routes may include oral, buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intra-articular, intra-sternal, intra-synovial, intra-hepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injections or other modes of delivery.
  • the agents of the disclosure may be formulated and diluted in aqueous solutions, such as in 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.
  • penetrants are generally known in the art.
  • Use of pharmaceutically acceptable inert carriers to formulate the compounds herein disclosed for the practice of the disclosure into dosages suitable for systemic administration is within the scope of the disclosure.
  • the compositions of the present disclosure in particular, those formulated as solutions, may be administered parenterally, such as by intravenous injection.
  • the compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration. Such carriers enable the
  • agents of the disclosure may be formulated by methods known to those of skill in the art, and may include, for example, but not limited to, examples of solubilizing, diluting, or dispersing substances, such as saline; preservatives, such as benzyl alcohol; absorption promoters; and fluorocarbons.
  • the presently disclosed sigma-1 receptor ligand is administered intranasally in a form selected from the group consisting of a nasal spray, a nasal drop, a powder, a granule, a cachet, a tablet, an aerosol, a paste, a cream, a gel, an ointment, a salve, a foam, a paste, a lotion, a cream, an oil suspension, an emulsion, a solution, a patch, and a stick.
  • the term administrating via an "intranasal route" refers to administering by way of the nasal structures.
  • compositions suitable for use in the present disclosure include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. Generally, the compounds according to the disclosure are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. A non-limiting dosage is 10 to 30 mg per day.
  • these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • the preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions. Pharmaceutical preparations for oral use can be obtained by combining the active
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl- cellulose, sodium carboxymethyl-cellulose (CMC), and/or polyvinylpyrrolidone (PVP: povidone).
  • fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol
  • cellulose preparations for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl- cellulose, sodium carboxymethyl-cellulose (CMC), and/or polyvinylpyrrolidone (PVP: povidone).
  • disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dye-stuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions that can be 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 can 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 may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs).
  • PEGs liquid polyethylene glycols
  • stabilizers may be added.
  • the terms “a,” “an,” and “the” refer to “one or more” when used in this application, including the claims.
  • reference to “a subject” includes a plurality of subjects, unless the context clearly is to the contrary (e.g., a plurality of subjects), and so forth.
  • the terms “comprise,” “comprises,” and “comprising” are used in a non-exclusive sense, except where the context requires otherwise.
  • the term “include” and its grammatical variants are intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that can be substituted or added to the listed items.
  • the term “about,” when referring to a value can be meant to encompass variations of, in some embodiments, ⁇ 100% in some embodiments ⁇ 50%, in some embodiments ⁇ 20%, in some embodiments ⁇ 10%, in some embodiments ⁇ 5%, in some embodiments ⁇ 1%, in some embodiments ⁇ 0.5%, and in some embodiments ⁇ 0.1% from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions.
  • the term “about” when used in connection with one or more numbers or numerical ranges should be understood to refer to all such numbers, including all numbers in a range and modifies that range by extending the boundaries above and below the numerical values set forth.
  • the HPLC solvent system consisted of deionized water and acetonitrile, both containing 0.1% formic acid.
  • Preparative HPLC purification was performed on an Agilent 1200 series HPLC system equipped with an Agilent G1315D DAD detector using a Phenomenex Luna 5 ⁇ m C18 column (21.2 mm ⁇ 250 mm, 5 ⁇ m).
  • Analytical HPLC was performed on an Agilent 1200 series HPLC system equipped with an Agilent G1315D DAD detector (detection at 220 nm) and an Agilent 6120 quadrupole MS detector.
  • the analytical HPLC conditions involve 5% acetonitrile/95% water for 0.25 min followed by a gradient to 40% acetonitrile/60% water over 1.5 min and continuation of 40% acetonitrile/60% water for 2.25 min with an Eclipse Plus C18 column (2.1 m ⁇ 50 mm, 3.5 micron) at a flow rate of 1.25 mL/min. Unless otherwise noted, all final compounds biologically tested were confirmed to be of ⁇ 95% purity by the HPLC methods described above. Compounds (+)-1 and (-)-1 were synthesized by using the previously reported methods. Sozio et al., 2015. EXAMPLE 2 Synthetic Schemes for Representative Compounds The presently disclosed active compounds may be prepared as described in the following reaction schemes.
  • S2R binding assay was carried out using homogenized rat liver tissue using 125 I-RHM-4. Xu et al., 2011. D2R binding assay was conducted using HEK cells stably transfected with the human D2long dopamine receptor isoform with 125 I-IABN. Luedtke et al., 2000. Binding affinity to D3R and D4R was measured using 125 I-IABN and HEK cells stably expressing human D3R and D4R, respectively. Luedtke et al., 2000.
  • a mild aversive electrical shock (0.69 mA) was delivered to the grid floor via a programmable animal shocker (San Diego Instruments, San Diego, CA, USA).
  • a mouse is initially placed in a start box at the base of the T-shaped apparatus (stem). After placing the mouse in the apparatus, a door was removed to initiate each trial. For the initial task, the mouse was allowed to transverse the test chamber and enter either the left or the right chamber (goal arms) to determine its innate spatial preference. This spatial preference was then designated to be the incorrect selection/choice for the remainder of the test, thus the mouse had to learn and remember the correct goal arm.
  • the mouse was required to move to the correct goal arm (opposite the originally selected chamber) within 5 seconds to achieve the criteria of learning/memory. If the mouse initially selected the incorrect goal arm or if the mouse did not select the correct goal arm with 5 seconds an aversive stimulus (0.69 mA shock) was initiated until the animal entered correct goal arm. Upon entering the correct goal arm the stimulus was terminated, the mouse was then allowed to rest in the apparatus for 10 seconds and then the mouse was placed in a neutral holding area for 1 min between trials.
  • the performance of the mouse was not considered in the data set if the mouse either achieved criteria by 5 trials or could not achieve criteria after 50 trials (i.e., the mouse was deemed to be confused and the session was terminated).
  • the ability to learn the avoidance task was considered inversely related to the number of trials a mouse takes to reach criterion.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des ligands du récepteur Sigma-1 et leur utilisation pour le traitement de maladies, d'états ou de troubles associés au récepteur sigma-1, y compris la déficience cognitive et les déficits cognitifs.
PCT/US2024/013326 2023-01-27 2024-01-29 Composés fluorés et leurs utilisations Ceased WO2024159213A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363481899P 2023-01-27 2023-01-27
US63/481,899 2023-01-27

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