Treatment of amyotrophic lateral sclerosis using dangencan

Abstract

Applicants disclose methods and compositions for treating a patient suffering from amyotrophic lateral sclerosis (ALS), comprising administering a heteroaryl ketone fused aza-naphthane compound. In embodiments, the heteroaryl ketone fused aza-naphthane compound is Dargencolan: (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl) phenyl) sulfonyl)-4, 4a, 5, 6, 7, 8-hexahydro-1-H-pyrazolo [3, 4-g] isoquinolin-4a-yl) (pyridin-2-yl) methanone, the chemical structure of which is shown as follows: # imgabs 0 # suitable doses include the administration of 150 and 300 milligrams of Dargencolan per day. Suitable doses include daily administration of Datangencan with food, or with water, or with food and water. Daily administration of dazulan can effectively increase exposure of dazulan and can increase exposure of dazulan up to about 2 times when sustained for seven or more days. Administration of such heteroaryl ketone fused aza-naphthane compounds includes oral administration, enteral administration, or other modes of administration. A pharmaceutical composition comprising daricor is useful for the treatment of a patient suffering from ALS. Suitable pharmaceutical compositions comprising daricor include, for example, pharmaceutical compositions for oral administration and pharmaceutical compositions for enteral administration.

Description

Background Art

[0001] Amyotrophic lateral sclerosis (ALS) is a devastating and ultimately fatal neurodegenerative disease with few treatment options. Survival after onset is only about 3 to 5 years, and most patients die of respiratory failure. Characteristics of ALS include, for example, loss of motor neurons in the spinal cord, brainstem, and cerebral cortex, leading to muscle weakness and ultimately paralysis. Initial symptoms vary, with some patients first experiencing weakness in the upper limbs and others first experiencing weakness in the lower limbs. Approximately one-third of ALS patients have bulbar onset, presenting with speech disorders (dysarthria) or swallowing disorders (dysphagia) early in the disease.

[0002] Numerous ideas have been proposed to try to identify the underlying cause of ALS, including neuronal damage due to excessive glutamate ("excitotoxicity"); neuronal damage due to high levels of oxygen free radicals (e.g., conditions related to superoxide dismutase (SOD)); protein misfolding; inflammation; abnormal axonal transport; mitochondrial dysfunction; and endoplasmic reticulum dysfunction (see, e.g., Xu et al., Translational Neurodegeneration 2021;10:29). Hormonal abnormalities may be a factor: high levels of estrogen and progesterone may have a protective effect or may slow disease progression (Pape et al., Rev Neurol (Paris). May 2020;176(5):301–315). Cortisol levels have been reported to be dysregulated in ALS patients (Patacchioli et al., J Endocrinol Invest. 2003;26:RC23–RC25; Spataro et al., J Neurol Sci. 2015;358(1–2):282–286).

[0003] Treatment of ALS may include administration of riluzole (which inhibits glutamatergic neurotransmission) or edaravone (an antioxidant) in an attempt to slow the progression of ALS. Other drugs used to treat ALS patients include (thickened riluzole); Exservan TM (riluzole oral film); RELYVRIO TM (AMX-0035), which is a combination of two drugs, sodium phenylbutyrate and tauroursodeoxycholic acid; and (dextromethorphan HBr and quinidine sulfate), used to treat pseudobulbar affect (PBA). Qalsody TM(Tofersen) has been approved by the FDA for the treatment of patients with ALS associated with superoxide dismutase 1 (SOD1) gene mutations. However, the treatment of all patients includes palliative care because the disease still progresses despite the administration of the approved drug therapy.

[0004] Accordingly, to provide better patient care and slow the progression of the disease, improved methods and compositions for treating patients with ALS are needed. SUMMARY OF THE INVENTION

[0005] Disclosed herein are novel methods for treating amyotrophic lateral sclerosis (ALS). The methods include administering to a subject an effective amount of a heteroaryl ketone-fused azadecalin compound. Preferably, the heteroaryl ketone-fused azadecalin compound is a compound that modulates the glucocorticoid receptor (GR). A compound that modulates the GR is referred to as a GR modulator (GRM); a GRM compound that has little or no modulating effect on other steroid hormone receptors (such as the progesterone receptor, the aldosterone receptor, or the androgen receptor) is referred to as a selective GRM (SGRM). In an embodiment, the method for treating ALS disclosed herein includes administering to the subject the SGRM heteroaryl ketone-fused azadecalin compound (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, also referred to as "dazucorilant" or "CORT133176", which has the following structure:

[0006] Dazucorilant is disclosed in Example 1 of U.S. Patent 8,859,774, the entire content of which is incorporated herein by reference.

[0007] In an embodiment, the GRM (e.g., SGRM) is administered orally. In an embodiment, the GRM or SGRM can be administered by injection, infusion, transdermal administration, or other means or routes. In an embodiment, the GRM (e.g., dazucorilant) can be administered with food, or with water, or with both food and water. In other embodiments, the GRM (e.g., dazucorilant) can be administered in the absence of food.

[0008] In an embodiment, an effective amount of GRM (e.g., SGRM, such as dacuzolam) is a daily dose of 50 to 500 milligrams per day (mg / day); for example, in an embodiment, the daily dose of GRM (e.g., SGRM, such as dacuzolam) is 50, 75, 100, 125, 150, 200, 225, 250, 300, 350, 375, 400, 450, 500, 525, or 600 mg / day. Generally, the administration of GRM (e.g., SGRM, such as dacuzolam) is given once daily; however, in an embodiment, the administration can be twice daily, or three times daily, or can be every other day, or every three days, or every four days, or at other intervals as needed or convenient. GRM (e.g., SGRM, such as dacuzolam) can be continuously administered to a patient as needed; for example, the administration of GRM (e.g., SGRM, such as dacuzolam) can be continued for weeks, months, or years as needed.

[0009] The methods herein provide an improved method for treating ALS. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1A Shows the plasma concentration of dacuzolam 300 mg (with food and without food) in a PK study of dacuzolam administration to healthy human volunteers. Higher dacuzolam exposure was observed when dacuzolam was administered to fed subjects compared to the dacuzolam exposure observed in fasting subjects.

[0011] Figure 1B Shows the pharmacokinetic parameters of dacuzolam administration to healthy human volunteers. Higher dacuzolam exposure was observed when dacuzolam was administered to fed subjects compared to the dacuzolam exposure observed in fasting subjects.

[0012] Figure 2A Shows the steady-state PK curve of dacuzolam after 14 days of QD dosing in a brain penetration study.

[0013] Figure 2B Shows the pharmacokinetic parameters of dacuzolam administration to healthy human volunteers who were administered dacuzolam at the indicated doses daily for 14 consecutive days. An increase in dacuzolam exposure greater than dose-proportional was observed.

[0014] Figure 3 Shows the timeline of a Phase 2 study of dacuzolam for the treatment of ALS disclosed herein. DETAILED DESCRIPTION

[0015] INTRODUCTION

[0016] The method disclosed herein can be used to treat a patient suffering from ALS by administering an effective amount of a heteroaryl ketone-fused azadecane glucocorticoid receptor modulator (GRM), preferably a heteroaryl ketone-fused azadecane selective glucocorticoid receptor modulator (SGRM) effective for treating ALS. In a preferred embodiment, the SGRM is dazucorilant (also known as CORT113176): (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, which has the following structure:

[0017]

[0018] In an embodiment, the method disclosed herein can be used to treat a patient suffering from ALS by administering an effective amount of a heteroaryl ketone-fused azanaphthalene GRM or SGRM and another ALS treatment, which is effective for treating ALS. In an embodiment, the other ALS treatment can include, for example, administering riluzole or edaravone, or other drugs. In a preferred embodiment, dazucorilant and riluzole or edaravone or other drugs (e.g., Exservan TM ; RELYVRIO TM ; or or other drugs for treating ALS) are administered to a patient suffering from ALS.

[0019] In an embodiment of the method disclosed herein, an effective amount of a heteroaryl ketone-fused quinazoline GRM or SGRM (e.g., dacuzaklan) is administered to a patient suffering from ALS, effective to treat the patient. In an embodiment, an effective amount for treating ALS by administering GRM or SGRM (such as dacuzaklan) can be, for example, 10 milligrams per day (mg / day), or 20 mg / day, or 25 mg / day, or 30 mg / day, or 50 mg / day, or 75 mg / day, or 100 mg / day, or 125 mg / day, or 150 mg / day, or 175 mg / day, or 200 mg / day, or 225 mg / day, or 250 mg / day, or 300 mg / day, or 350 mg / day, or 375 mg / day, or 400 mg / day, or 450 mg / day, or 500 mg / day, or 525 mg / day, or 600 mg / day, or 700 mg / day, or 800 mg / day, or 900 mg / day, or 1000 mg / day, or other effective amount, effective to treat ALS. In an embodiment, the heteroaryl ketone-fused quinazoline GRM or SGRM (e.g., dacuzaklan) can be administered orally and can be administered without food, or can be administered with food, or with water, or with food and water. In an embodiment, the heteroaryl ketone-fused quinazoline GRM or SGRM (e.g., dacuzaklan) can be administered once daily (QD), or can be administered two, three or other multiple times per day. Administration of the heteroaryl ketone-fused quinazoline GRM or SGRM (e.g., dacuzaklan) can be continued for weeks, months or years as needed; for example, administration of dacuzaklan can continue for at least 2, 5, 10, 36, 52, 104, 156 or 208 weeks, or longer.

[0020] An effective amount of dacuzaklan or other GRM or SGRM can be administered to the patient by an oral route, e.g., via the mouth, in the form of a capsule, pill, tablet, liquid, emulsion or other composition suitable for oral administration. Experiments have shown that in healthy volunteers to whom dacuzaklan was administered orally, distribution of dacuzaklan in the cerebrospinal fluid was observed, indicating that dacuzaklan crosses the blood-brain barrier in humans. Compared with single-day administration of the same dose of dacuzaklan only, multi-day administration of dacuzaklan results in increased levels of dacuzaklan in plasma; the plasma level of dacuzaklan reaches steady state in about 7 days.

[0021] In an embodiment, administration of a GRM or SGRM (such as dacarbazine) may be assisted or effected via a straw, feeding tube, oral syringe, or other appliance or device that aids a patient in ingesting an oral treatment. Thus, in an embodiment, administration of a GRM or SGRM (such as dacarbazine) may be effected via a feeding tube or other enteral administration means (e.g., nasogastric tube, orogastric tube, duodenal tube, or gastrostomy tube) to replace or supplement administration of a capsule, pill, or solution to a patient.

[0022] Definitions

[0023] Unless otherwise specified, as used herein, "about" means plus or minus 5% of a specified value.

[0024] As used herein, the term "patient" refers to a person who is, will be, or has been receiving medical care for a disease or condition (such as, for example, ALS).

[0025] As used herein, the terms "amyotrophic lateral sclerosis" and "ALS" refer to the neurodegenerative disease of the same name, which is characterized by the progressive degeneration of motor neurons in the brain and spinal cord, leading to progressive muscle weakness, persistent disability, and death; death typically occurs within 3 - 5 years after the onset of symptoms. Only a small percentage of ALS patients survive beyond 10 years, 50% of patients die within 30 months after the onset of symptoms, and only 20% of patients survive 5 to 10 years (Riva et al., 2016 J. Neurol. 263:1241–1254). Respiratory failure is the most common cause of death in ALS patients (Riva et al. 2016 J. Neurol. 263:1241–1254; Turner et al. 2013 Lancet Neurol. 12:310–322).

[0026] As used herein, the ENCALS risk profile refers to a score of a patient with ALS that takes into account seven patient characteristics (which is a weighted average of patient characteristics) in a single score and serves as an estimate of the patient's overall prognosis (see, e.g., Westeneng et al., Lancet Neurol. 2018;17(5):423–433; van Eijk et al., Neurology. 2019;92(5):e451–e460; van Eijk et al., Neurology. 2021;97(11):528–536). (“ENCALS” is an acronym for the European Network for the Cure of ALS.) The ENCALS risk profile is a calculator for inclusion and exclusion criteria based on a multivariable risk profile, developed by combining the prognostic characteristics of patients. The ENCALS risk profile aims to provide the ability to assess patient eligibility for a larger proportion of the patient population and to maximize the generalizability of trial results. It is useful for characterizing and identifying patients who may be suitable for inclusion in a study.

[0027] The El Escorial Definite classification is defined as the presence of upper and lower motor neuron signs clinically in three or more regions on the day of screening. The El Escorial Definite classification uses the El Escorial criteria to provide a diagnosis of ALS based on signs of motor neuron degeneration through clinical examination or specialized tests. The ENCALS risk profile considers a patient to be classified as “definite ALS” only if the patient has at least three affected regions, regardless of the presence of a known pathogenic mutation.

[0028] The ALSFRS-R is a questionnaire for certified healthcare providers that is used to assess the degree of functional impairment of a patient.

[0029] As used herein, the term “effective amount” or “therapeutically effective amount” refers to the amount of an agent that is effective in treating, eliminating, or alleviating at least one symptom of the disease being treated. In some cases, the “therapeutically effective amount” or “effective amount” may refer to the amount of a functional reagent or pharmaceutical composition that can be used to exhibit a detectable therapeutic or inhibitory effect. This effect can be detected by any test method known in the art.

[0030] As used herein, the terms "administer", "administering", "administered", or "being administered" refer to providing a compound or composition (e.g., those described herein) to an object or patient. For example, a compound or composition can be administered orally to a patient (i.e., the object receives the compound or composition through the mouth in the form of a pill, capsule, liquid, or other form suitable for oral administration. Oral administration can be buccal (where the compound or composition is held in the mouth, e.g., sublingually, and absorbed therein). Administration can be enteral (including, for example, through a tube, such as a nasogastric tube, orogastric tube, duodenal tube, or gastrostomy tube). Based on the compound or composition can be delivered by injection, i.e., by a needle, microneedle, pressure syringe, or other means of piercing the skin or forcing the compound or composition through the skin of the object. Injection can be intravenous (i.e., into a vein); intraarterial (i.e., into an artery); intraperitoneal (i.e., into the peritoneum); intramuscular (i.e., into a muscle); or by other injection routes. The route of administration can also include rectal, vaginal, transdermal, transpulmonary (e.g., by inhalation), subcutaneous (e.g., by absorption from an implant containing the compound or composition into the skin), or by other routes.

[0031] As used herein, the term "AUC" refers to the area under the curve (the change in plasma concentration of a drug over time after administration). AUC provides a method of measuring the plasma concentration of a drug administered, which is not limited by a single time measurement.

[0032] As used herein, the term "AUC 0-24 " refers to the AUC from 0 to 24 hours after administration (where time 0 is the time of administration of the drug of interest).

[0033] As used herein, the term "AUC inf " refers to the AUC extrapolated from time 0 to infinity (where time 0 is the time of administration of the drug of interest).

[0034] As used herein, the term "AUC 最终 (AUC last )" refers to the AUC corresponding to the time from time 0 until the last measurable concentration of the drug administered (e.g., dacuzolam).

[0035] As used herein, the term "C 最大值 " refers to the maximum plasma concentration of the drug administered (e.g., dacuzolam) after administration.

[0036] As used herein, the term "combination / co - therapy" refers to administering at least two agents to a subject for treating a disease. The at least two agents can be administered simultaneously, or can be administered sequentially in any order during the entire treatment period or a portion of the treatment period. The at least two agents can be administered according to the same or different dosing regimens. In some cases, one agent is administered according to a predetermined regimen and another agent is administered intermittently. In some cases, both agents are administered intermittently. In some embodiments, one agent (e.g., an SGRM such as dacuromine) can be administered daily, and another agent (e.g., riluzole, edaravone, or other drug) can be administered daily, every two days, every three days, or every four days, or according to another schedule. In some embodiments, one agent (e.g., an SGRM such as dacuromine) is administered daily, every two days, every three days, or every four days, or according to another schedule; in such embodiments, other agents (e.g., riluzole, edaravone, or other drug) can be administered daily, or every two days, every three days, or every four days, or according to another schedule.

[0037] As used herein, the term "glucocorticoid receptor" ("GR") refers to the type II GR, which is an intracellular receptor that specifically binds to glucocorticoids such as cortisol and / or cortisol analogs (such as dexamethasone) (see, e.g., Turner and Muller, J. Mol. Endocrinol. October 1, 2005 35 283 - 292). (The term "glucocorticoid" can be abbreviated as "GC".) The type II glucocorticoid receptor is also referred to as the cortisol receptor. The term includes isoforms of GR, recombinant GR, and mutant GR.

[0038] The term "glucocorticoid receptor modulator (GRM)" refers to any compound that modulates the glucocorticoid that binds to GR or modulates any biological response associated with the binding of GR to an agonist. For example, a GRM that is an agonist (such as dexamethasone) is capable of increasing the activity of tyrosine aminotransferase (TAT) in HepG2 cells (human hepatocellular carcinoma cell line; ECACC, UK). A GRM that is an antagonist (such as mifepristone) is capable of decreasing the activity of tyrosine aminotransferase (TAT) in HepG2 cells. The activity of TAT can be detected as described in the literature: A. Ali et al., J. Med. Chem., 2004, 47, 2441 - 2452.

[0039] As used herein, the term "selective glucocorticoid receptor modulator" (SGRM) refers to a selective GRM, i.e., any composition or compound that selectively modulates the glucocorticoid that binds to the GR or selectively modulates any biological response associated with the binding of an agonist to the GR. By "selective," the drug preferentially binds to the GR rather than other nuclear receptors, such as the progesterone receptor (PR), the mineralocorticoid receptor (MR), or the androgen receptor (AR). Preferably, the affinity of the selective glucocorticoid receptor modulator for the GR is 10 times the affinity of its binding to the MR, AR, or PR, both the MR and PR, both the MR and AR, both the AR and PR, or the MR, AR, and PR (K d value of 1 / 10). Dazucorilant is an SGRM.

[0040] Exemplary heteroaryl ketone-fused phenanthridine GRM and SGRM compounds include those described in U.S. Patent No. 8,859,774; U.S. Patent No. 9,273,047; U.S. Patent No. 9,707,223; and U.S. Patent No. 9,956,216, the entire contents of all of which are incorporated herein by reference. In an embodiment, the heteroaryl ketone-fused phenanthridine GRM is the SGRM dazucorilant (Example 1 of U.S. Patent 8,859,774).

[0041] As used herein, the term "compound" is used to denote a molecular moiety having a unique, recognizable chemical structure. The molecular moiety ("compound") can exist in free form, in which it is not associated with other molecules. A compound can also exist as part of a larger aggregate, in which it is associated with one or more other molecules but still retains its chemical identity. A solvate is an example of such an associated form, in which the molecular moiety having a defined chemical structure ("compound") is associated with one or more solvent molecules. A hydrate is a solvate in which the associated solvent is water. Reference to a "compound" refers to the molecular moiety itself (having the stated structure), whether it exists in free form or in an associated form.

[0042] As used herein, the term "composition" is intended to cover a product containing specific ingredients, such as the compound, its tautomeric forms, its derivatives, its analogs, its stereoisomers, its polymorphs, its deuterated species, its pharmaceutically acceptable salts, esters, ethers, metabolites, isomer mixtures, its pharmaceutically acceptable solvates and a specific amount of a pharmaceutically acceptable composition, as well as any product directly or indirectly produced by the combination of a specific amount of specific ingredients. For a pharmaceutical composition, the term is intended to cover a product comprising an active ingredient and inert ingredients constituting a vehicle, as well as any product directly or indirectly formed by the combination, compounding or aggregation of any two or more ingredients, or the decomposition of one or more ingredients, or other types of reactions or interactions of one or more ingredients. Accordingly, the pharmaceutical compositions of the present invention are intended to cover any composition prepared by mixing the compounds of the present invention with their pharmaceutically acceptable vehicles.

[0043] As used herein, the term "pharmaceutically acceptable vehicle" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delaying agents, etc. that are compatible with the administration of a drug. The use of such media and agents for pharmaceutically active substances is well known in the art. These media or agents should be considered for use in the composition unless any conventional media or agent is incompatible with the active compound. Supplementary active compounds can also be incorporated into the composition.

[0044] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable vehicles" refer to substances that assist in the administration of an active agent to a subject and are absorbed by the subject, and can be included in the compositions of the present invention without causing significant adverse toxicological effects to the patient. These terms as used herein are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delaying agents, etc. that are compatible with the administration of a drug. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline solution, lactated Ringer's solution, common sucrose, common glucose, binders, fillers, disintegrants, encapsulating agents, plasticizers, lubricants, coatings, sweeteners, flavoring agents and coloring agents, etc. Those of ordinary skill in the art should understand that other pharmaceutical excipients can be used in the present invention. The use of such media and agents for pharmaceutically active substances is well known in the art. These media or agents should be considered for use in the composition unless any conventional media or agent is incompatible with the active compound. Supplementary active compounds can also be incorporated into the composition. Those of ordinary skill in the art should understand that other pharmaceutical excipients can be used in the present invention.

[0045] "Salt" refers to the acid or base salt of a compound used in the methods disclosed herein. Illustrative examples of pharmaceutically acceptable salts are: salts of inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), salts of organic acids (acetic acid, propionic acid, glutamic acid, citric acid, etc.), and quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts. It is understood that pharmaceutically acceptable salts are non-toxic. Other information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pennsylvania, 1985, which is incorporated herein by reference.

[0046] Pharmaceutical Compositions and Administration

[0047] In an embodiment, the present invention provides a pharmaceutical composition for treating ALS, the pharmaceutical composition comprising a pharmaceutically acceptable excipient and a GRM (such as, for example, dacuzolam). In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient and an SGRM. In a preferred embodiment, the pharmaceutical composition comprises dacuzolam and one or more pharmaceutically acceptable excipients.

[0048] Suitable formulations can be prepared and administered in various oral, parenteral, and topical dosage forms. GRMs can be administered orally. For example, GRMs can be administered as tablets, capsules, or liquid formulations as described herein. Oral formulations include tablets, pills, powders, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, etc. suitable for patient ingestion.

[0049] For example, dacuzolam has been formulated in different ways: for example, Lipid Formulation Classification System (LFCS) type III formulations; and LFCS type IV formulations. These formulations are encapsulated in hard shell capsules (type III and type IV); and encapsulated in soft gelatin (soft gel) capsules (LFCS type IV), and have been evaluated.

[0050] For preparing pharmaceutical compositions from GRMs and SGRMs, pharmaceutically acceptable carriers can be solid or liquid. Solid form formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Solid carriers can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. Details on formulation and administration techniques are widely described in the scientific and patent literature, see, for example, the latest version of Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania ("Remington").

[0051] In the powder, the carrier is a fine powder solid, which is mixed with the fine powder active ingredient GRM or SGRM (for example, dacuzolan). In tablets, the active ingredient is mixed with a carrier having the required binding properties in a suitable ratio and pressed into the required shape and size.

[0052] The powders and tablets preferably contain 5% or 10% to 70% of the active compound (for example, dacuzolan). Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting point wax, cocoa butter, etc. The term "formulation" is intended to include formulations in which the active compound is accompanied by an encapsulating material as a carrier, which provides a capsule in which the active ingredient, with or without other carriers, is surrounded by the carrier and thus associated therewith. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid dosage forms suitable for oral administration.

[0053] Suitable solid excipients are carbohydrate or protein fillers, which include but are not limited to: sugars, including lactose, sucrose, mannitol or sorbitol; starches from corn, wheat, rice, potatoes or other plants; celluloses, such as methylcellulose, hydroxypropylmethylcellulose or sodium carboxymethylcellulose; gums, including gum arabic and tragacanth; and proteins, such as gelatin and collagen. If necessary, disintegrants or solubilizers can be added, such as cross-linked polyvinylpyrrolidone, agar, alginic acid, or its salts, such as sodium alginate.

[0054] The sugar-coated core has a suitable coating agent, such as a concentrated sugar solution, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, lacquer solution and a suitable organic solvent or solvent mixture. Dyes or pigments can be added to the tablet or sugar coating for product labeling or to characterize the amount (i.e., dose) of the active compound. The pharmaceutical formulations of the present invention can also be in the form of oral administration: for example, push-fit capsules made of gelatin, and sealed soft capsules made of gelatin and coating agents (such as glycerol or sorbitol). The push-fit capsules can contain GR regulators mixed with fillers or binders (such as lactose or starch), lubricants (such as talc or magnesium stearate), and optionally stabilizers. In the soft capsules, the GR regulator compound can be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin or liquid polyethylene glycol, with or without stabilizers.

[0055] Formulations in liquid form include solutions, suspensions and emulsions, such as water or water / propylene glycol solutions. Liquid formulations can include salts, such as sodium chloride, or sugars (for example, such as sucrose). For parenteral injection, the liquid formulation can be formulated as a solution in an aqueous polyethylene glycol solution.

[0056] The pharmaceutical compositions disclosed herein may be provided in salt form and can be formed with many acids, including but not limited to hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, etc. The salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base forms. In other cases, the formulation may be a lyophilized powder in 1 mM - 50 mM histidine, 0.1% - 2% sucrose, 2% - 7% mannitol in the pH range of 4.5 to 5.5, which is combined with a buffer before use.

[0057] GRM and SGRM can be administered by oral and enteral administration. Alternatively, GRM and SGRM can also be administered by injection, i.e., intravenous, intramuscular, intradermal, subcutaneous, intraduodenal, or intraperitoneal administration. In an embodiment, the composition according to the present invention can be used for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or an organ cavity. The formulation for administration will generally comprise a solution of the composition according to the present invention dissolved in a pharmaceutically acceptable carrier. Acceptable carriers and solvents that can be used include water and Ringer's solution (isotonic sodium chloride). In addition, a sterile non-volatile oil is generally used as a solvent or suspension medium. For intravenous injection administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. The suspension can be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension dissolved in a non-toxic parenterally acceptable diluent or solvent such as a 1,3-butanediol solution.

[0058] Also included are solid form formulations for conversion to a liquid form formulation for oral administration immediately before use. Such liquid forms include solutions, suspensions, and emulsions. In addition to the active ingredient, the formulation may also contain coloring agents, flavoring agents, stabilizers, buffering agents, artificial and natural sweeteners, dispersing agents, thickening agents, solubilizing agents, etc.

[0059] The oily suspension can be formulated by suspending SGRM in vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil) or mineral oil (such as liquid paraffin) or a mixture thereof. The oily suspension may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. A sweetening agent can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These preparations can be preserved by adding an antioxidant (such as ascorbic acid). For examples of injectable oily carriers, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical preparation of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil or a mineral oil as described above or a mixture thereof. Suitable emulsifiers include: natural gums, such as gum arabic and tragacanth, natural phospholipids, such as soy lecithin, esters or partial esters of fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion can also contain sweetening agents and flavoring agents, as in the case of syrups and elixirs. Such preparations can also contain a demulcent, a preservative or a coloring agent.

[0060] The pharmaceutical preparation is preferably in the form of a unit dosage form. In this form, the preparation is subdivided into unit doses containing an appropriate amount of the active component GRM or SGRM (such as, for example, dacuzolan). The unit dosage form can be a packaged preparation, the package containing discrete, quantitated preparations, such as packaged tablets, capsules and powders in vials or ampoules. Additionally, the unit dosage form itself can be a capsule, tablet, cachet or lozenge, or a packaged form of an appropriate amount of these dosage forms.

[0061] The amount of the active component in the unit dose preparation can vary or be adjusted within the range of: 1 mg to 1000 mg, more typically, 10 mg to 600 mg, most typically, 50 mg to 500 mg. Depending on the specific application and the potency of the active component, suitable doses also include about 10 mg, 20, 30, 40, 50, 60, 70, 75, 80, 90, 100, 150, 200, 250, 300, 400, 500 or 600 mg. If necessary, the composition can also contain other compatible therapeutic agents.

[0062] In some embodiments, GRM is administered in one dose. In other embodiments, GRM is administered in more than one dose, such as 2 doses, 3 doses, 4 doses, 5 doses, 6 doses, 7 doses or more doses. In some cases, the doses are equal. In other cases, the doses are unequal. The dose can be increased or gradually decreased during administration. The amount administered will vary depending on, for example, the patient characteristics.

[0063] Single or multiple administrations of the formulation can be carried out according to the dose and frequency that the patient requires and can tolerate. In an embodiment, an effective amount of GRM (such as dacuzolam) is administered as a single dose. In other embodiments, the GRM is administered in more than one dose within 2 - 12 hours, such as 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours or other time periods, for example, 2 doses, 3 doses or more doses. The formulation should provide a sufficient amount of the active agent to effectively treat ALS. Thus, in one embodiment, the daily dosage of the pharmaceutical formulation for oral administration of GRM (such as dacuzolam) is about 1 to about 20 milligrams per kilogram of body weight per day (mg / kg / day), or the daily dosage is about 1.5 to 15 mg / kg / day, or about 2 to 10 mg / kg / day.

[0064] Any suitable dose of GRM can be used in the methods disclosed herein. The dose of GRM (e.g., dacuzolam) administered can be at least about 10 milligrams per day (mg / day), or about 20 mg / day, or about 25 mg / day, or about 30 mg / day, or about 50 mg / day, or about 75 mg / day, or about 100 mg / day, or about 125 mg / day, or about 150 mg / day, or about 175 mg / day, or about 200 mg / day, or about 225 mg / day, about 250 mg / day, about 300 mg / day, about 350 mg / day, about 375 mg / day, about 400 mg / day, about 450 mg / day, about 500 mg / day, about 525 mg / day, about 600 mg / day or more. In an embodiment, the GRM is administered orally. In some embodiments, the GRM is administered in at least one dose. In other words, the GRM can be administered in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses. In an embodiment, the GRM is administered orally in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses.

[0065] The duration of treatment with GRM or SGRM for treating ALS can vary according to the severity of the subject's disease and the subject's response to GRM or SGRM. In an embodiment, the treatment can continue until needed. In an embodiment, the treatment can continue until the patient can receive oral medications. In some embodiments, dacuzolam can be administered for up to about 2 years or more. In an embodiment, the administration of a heteroaryl ketone fused naphthyridine GRM or SGRM (such as dacuzolam) can continue for 1, 2, 3, 4, 5, 10, 15, 20, 24, 30, 36, 48, 50, 52, 100, 104, 156 or 208 weeks or longer, as needed to treat the patient. In an embodiment, the GRM (such as dacuzolam) can be continuously administered as long as the patient needs such administration, or as long as the patient can still receive such GRM administration.

[0066] In some embodiments, the administration of GRM or SGRM is not continuous and can suspend one or more regimens and then resume the administration of one or more regimens. Suitable periods for stopping the administration include 1 to 10 weeks, 2 to 8 weeks, 3 to 6 weeks, and 4 to 5 weeks.

[0067] SGRM can be used in combination with other active agents known to modulate the glucocorticoid receptor or with adjuvants that may be ineffective alone but can contribute to the efficacy of the active agent. For example, dexucanabinol can be administered to patients with ALS together with riluzole or edaravone or with both riluzole and edaravone. Dexucanabinol can be administered to patients with ALS together with other drugs, including Exservan TM ; RELYVRIO TM ; sodium phenylbutyrate; tauroursodeoxycholic acid; dextromethorphan; quinidine sulfate; or other drugs for the treatment of ALS or related conditions. Such administration can be by oral administration; by enteral administration; or by other means or a combination of means.

[0068] In some embodiments, co - administration includes administering a second active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of one active agent, GRM or SGRM. This second active agent can be, for example, riluzole or edaravone. Co - administration includes administering the two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other) or sequentially in any order. In some embodiments, co - administration can be accomplished by co - formulating, i.e., preparing a single pharmaceutical composition containing both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active agents and / or adjuvants can be linked or conjugated to each other.

[0069] After preparing a pharmaceutical composition containing a GR modulator of the present invention in an acceptable carrier, it can be placed in a suitable container and labeled for the treatment of the indicated condition. For the administration of GRM or SGRM, such a label should include, for example, relevant instructions on the amount, frequency, and method of administration.

[0070] Examples

[0071] The following examples are provided for illustration only and not for limitation. Those skilled in the art will readily find that there are multiple non - critical parameters that can be varied or modified and yield substantially the same or similar results.

[0072] Example 1. In vitro testing of Dazukelan

[0073] Dazucolan binds competitively and reversibly to the GR with high affinity (0.28 nM). Dazucolan was able to inhibit the effect of dexamethasone (a potent and selective GR agonist) on tyrosine aminotransferase (TAT) activity in human hepatoma cell line (K i , 14 nM) and rat hepatoma cell line (K i , 4.2 nM), which has demonstrated its functional GR antagonism in vitro. Dazucolan can prevent the increase in TAT activity induced by dexamethasone in primary monkey and human hepatocytes. Dazucolan has a higher selectivity for the GR than other nuclear hormone receptors and a series of other receptors, enzymes and ion channels. For example, dazucolan has high selectivity for the GR relative to the progesterone receptor (PR), androgen receptor and estrogen receptor, with no significant binding to these receptors at a concentration of 10 μM (0%, 1.5% and 37.5% respectively). The GR selectivity for the mineralocorticoid receptor (MR) was demonstrated using an MR reporter gene assay, in which dazucolan showed an inhibition rate of 23% at a concentration of 5 μM.

[0074] The in vivo distribution of dazucolan was determined in a quantitative whole body autoradiography (QWBA) study in rats. After single oral administration of 14 14C-dazucolan to male and female rats, the radioactivity was steadily absorbed and the drug concentration in tissues usually peaked at about 12 hours after administration. The tissue:blood ratio > 0.1 in the brain and spinal cord within the first 24 hours after administration indicated that the drug-related substance had crossed the blood-brain barrier.

[0075] Its efficacy in alleviating ALS-related symptoms in vivo has been confirmed in Wobbler mice (a recognized ALS model). Administration of dazucolan for 21 days improved many aspects of the disease in these mice, including reducing forepaw atrophy, overcoming impaired performance in the rotarod test, and inhibiting neurodegeneration and inflammation.

[0076] Example 2. Pharmacokinetics and pharmacodynamics of Dazukelan in healthy volunteers

[0077] In 110 healthy male and female volunteers (18 - 60 years old; BMI 18 - 30 kg / m 2; body weight ≤ 102 kg; an adaptive-dose, double-blind, placebo-controlled study (NCT04249323, EudraCT 2019-004258-27) was conducted in a "First-in-Human" (FIH) study. This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of dazucorilant. In Part 1, healthy volunteers received single ascending doses of dazucorilant (50 - 1000 mg) (n = 63) either fed or fasted. In Part 2, healthy volunteers were given multiple doses of dazucorilant (100 - 300 mg, once daily [QD] for 14 days; n = 36). In Part 3, healthy volunteers received dazucorilant administration to establish evidence of pharmacological effects (n = 11). Additionally, in a Phase 1 randomized, partially double-blind, placebo-controlled study (NCT04994743, EudraCT 2021-002456-36), the brain permeability of dazucorilant in humans was studied in 16 healthy male volunteers (18 - 65 years old; BMI 18 - 30 kg / m 2 ; body weight ≤ 100 kg) to evaluate the PK of multiple oral doses of dazucorilant (150 mg or 300 mg QD for 14 days) in plasma and cerebrospinal fluid (CSF).

[0078] Results: Single doses of dazucorilant up to 1000 mg (fasted subjects) and 900 mg (fed subjects) were considered safe and well tolerated. Multiple doses of dazucorilant up to 300 mg QD were considered safe; multiple doses of dazucorilant up to 200 mg QD were safe and generally well tolerated. No serious or severe treatment-emergent adverse events were reported; the most common adverse events were gastrointestinal, nervous system, musculoskeletal, and connective tissue disorders. A positive effect of food was observed (1.3 to 1.7-fold increase in exposure in the fed state) (see Figure 1A and 1B ). Compared with 150 mg of dazucorilant, after oral administration of 300 mg of dazucorilant, the exposure of dazucorilant increased more than proportionally to the dose. Multiple administrations led to an approximately 2-fold increase in the amount of drug accumulated in plasma; steady-state exposure was reached within approximately 7 days (see Figure 2A and 2B ). Dazucorilant was observed to distribute into the cerebrospinal fluid, confirming brain penetration.

[0079] The first-in-human trial showed a greater-than-proportional increase in exposure and a positive effect of food

[0080] After a 3-fold increase in dose (150 mg to 450 mg, fasted), the exposure of dazucorilant (as AUC (0-inf) and C 最大值Measurements increased 4.0-fold and 3.4-fold, respectively (Table 1). After the dose was increased 2-fold further (from 450 mg to 900 mg, fed), exposures increased 2.8-fold and 2.2-fold, respectively (Table 1).

[0081] Table 1. Dazucolan dose-dependence (n = 6 per group)

[0082]

[0083]

[0084] The ANOVA model of the natural logarithm-transformed PK parameters from Part 1 of the FIH study included treatment terms fitted as fixed effects. PK parameters were normalized to the equivalent values for a 1-mg dose. AUC, area under the curve; CI, confidence interval; C 最大值 , maximum concentration; D, dose.

[0085] Compared with fasting, a significant positive food effect was observed after a high-fat breakfast, resulting in an exposure increase >2-fold (Table 2).

[0086] Table 2. Effect of food on dazucolan exposure (n = 6 per group).

[0087]

[0088] The ANOVA model of the natural logarithm-transformed PK parameters from Part 1 of the FIH study included treatment terms fitted as fixed effects. CI, confidence interval; C 最大值 , maximum concentration; AUC, area under the curve.

[0089] In the brain penetration study, the accumulation in plasma increased 2-fold after approximately 7 days and reached steady-state exposure

[0090] In the brain penetration study, after 1 week of QD dosing, the accumulation ratios of AUC (0-24) and C 最大值 (from Day 1 to Day 7) showed that the exposures of dazucolan given at 150 mg or 300 mg in the fasting state increased 1.7 to 1.9-fold. After 2 weeks of QD dosing (from Day 1 to Day 14), the exposures increased 1.6 to 2.0-fold (based on the accumulation ratios of AUC 0-24 and C 最大值 ). The accumulation ratios from Day 7 to Day 14 were between 0.9 and 1.1, indicating that the exposure of dazucolan reached steady state within 1 week of QD dosing. The steady-state exposures of 300 mg dazucolan (C 最大值 , AUC 0-24 ) were approximately 4-fold higher than those of 150 mg dazucolan (see Figure 2A ).

[0091] Dazukelan has the expected pharmacological effects

[0092] Single-dose prednisone can reduce eosinophils, lymphocytes, and osteocalcin, and increase neutrophils, which is consistent with expectations. Compared with prednisone alone, the change in AUEC of eosinophils, lymphocytes, and osteocalcin after prednisone + dazukelan (0-24) showed a statistically significant difference from the baseline (Table 3), indicating that dazukelan improved the effects of prednisone on these parameters. Similar to other SGRMs (Pivonello et al., Front Endocrinol (Lausanne). 2021; 12:662865), no significant effect of dazukelan on morning or evening cortisol or ACTH levels was observed in Part 2 of the FIH study.

[0093] Table 3. Proof of the pharmacological effects of dazukelan (n = 9 in each group).

[0094]

[0095] The linear mixed model for PD parameter estimation in Part 3 of the FIH study, including treatment fitted as a fixed effect, subject fitted as a random effect, and baseline concentration value fitted as a covariate. AUEC, area under the effect curve; cfb, change relative to the baseline; CI, confidence interval; E 最大值 , maximum change; ns, not significant.

[0096] In the brain penetration study, dazukelan was detectable in the cerebrospinal fluid of all study participants after 150 mg and 300 mg of dazukelan were administered QD for 1 week under feeding conditions. This result demonstrated the brain permeability of dazukelan in humans.

[0097] Determined the safe and well-tolerated dose of dazukelan

[0098] Single doses of dazukelan up to 1000 mg (fasting) and 900 mg (feeding) were considered safe and well-tolerated. Multiple doses of dazukelan up to 300 mg QD were considered safe; multiple doses of dazukelan up to 200 mg QD were safe and generally well-tolerated.

[0099] Conclusion: This study determined the pharmacokinetics, safety, tolerability, and pharmacological effects of dazukelan in healthy volunteers. In the study presented, 111 healthy volunteers received dazukelan. The adverse events were mild to moderate, reflecting insufficient tolerance at higher doses; no major safety hazards were found.

[0100] Example 3. A Phase 2, multicenter, randomized, double-blind, placebo-controlled study of the safety and efficacy of Dazukelan in patients with amyotrophic lateral sclerosis Figure 3

[0101] A Phase 2 study (DAZALS, NCT05407324, EudraCT 2021-005611-31) is ongoing to evaluate whether dazucorlan can benefit ALS patients by slowing functional decline.

[0102] Study description: ENCALS Risk Profile: Shows a schematic timeline of the time during which subjects in the study received dazucorlan at 150 mg / day, 300 mg / day, or placebo.

[0103] Eligibility criteria: Patients must be 18 years of age or older and have ALS (sporadic or familial). Patients with an ENCALS risk profile score greater than or equal to -6 and less than or equal to -3 are eligible to participate in the study. Patients may have received riluzole and / or edaravone treatment; however, such prior treatment is not required. If receiving riluzole and / or edaravone treatment, patients must be on a stable dose (i.e., the dose of riluzole or edaravone does not change during the study). Patients with the following conditions will be excluded: a history of clinically significant non-ALS neurological disorders; inability to swallow capsules; renal or hepatic insufficiency; low platelet count; use of non-invasive ventilation (e.g., CPAP) at any time during screening; mechanical ventilation by tracheostomy at screening; use of any form of oxygen supplementation at screening; currently using glucocorticoids; requiring regular systemic glucocorticoids; or a history of any clinically significant disease or unstable medical condition other than ALS.

[0104] Identifying eligible ALS patients: Eligible ALS patients are those in whom the disease has not progressed severely or whose disease progression is slow as assessed using the ENCALS risk profile calculator. Thus, the eligibility criteria are designed to exclude patients in the advanced disease stage or those with slow disease progression. The rate of progression of ALS is determined by multiple interdependent patient characteristics, including:

[0105] Patient information includes Patients with an ENCALS score ≥ -6 and ≤ -3 will be eligible for inclusion. The eligibility criteria do not include patients with very slow progression (long survival) and those with very rapid progression (very short survival). The ENCALS risk profile takes into account the prognostic impact of 7 patient characteristics in a single score to better assess the overall prognosis of patients when determining study eligibility (Westeneng et al., Lancet Neurol. 2018;17(5):423–433; van Eijk et al., Neurology. 2019;92(5):e 451–e460; van Eijk et al., Neurology. 2021;97(11):528–536).

[0106] ​: Screening date; Date of birth; Date of diagnosis; Date of symptom onset; El Escorial definite classification; Site of symptom onset; Presence or absence of frontotemporal dementia; Total ALSFRS-R score at screening; Vital capacity at screening; And may include other patient information.

[0107] Study design: Prior to enrollment, patients with ALS will be screened; Patients meeting the eligibility criteria will be randomly assigned to one of three study groups: placebo group, a group receiving 150 mg of dacuzolam daily, and a group receiving 300 mg of dacuzolam daily. The recruitment target is to enroll 198 patients with ALS; Patient randomization will be stratified according to the following factors: use or non-use of the ALS drugs riluzole and / or edaravone (yes / no); And the area of disease onset (bulbar / other). Plasma samples of approximately 20% of the patients will be collected at week 3 for pharmacokinetic analysis. Patients who complete the treatment period and meet the eligibility criteria for the open-label extension study (OLE) can enroll and receive dacuzolam treatment for up to 132 weeks.

[0108] Patients in each of the three groups will receive the study drug daily for 24 weeks. During the initial 24-week treatment period, patients will be contacted every 3 weeks (by phone or outpatient visit). After the 24-week treatment period, there will be a follow-up period of up to 132 weeks, a) drug-free follow-up, or b) open-label extension study period, during which patients will receive 300 mg of dacuzolam daily for up to 132 weeks. Patients will be contacted by phone.

[0109] Once every 8 to 24 weeks during the drug-free follow-up period, or once every 4, 12, or 16 weeks during the open-label extension study period (by phone or outpatient visit).

[0110] The study drug administered to patients (dacuzolam or placebo) is provided in the form of 75 mg soft capsules. The study drug will be administered orally once daily, approximately at the same time, with food and water.

[0111] The primary study endpoints included: the total score of the Revised ALS Functional Rating Scale (ALSFRS-R) (change from baseline to week 24) and safety. Secondary endpoints included: change in percentage of slow vital capacity; change in muscle strength (using a handheld dynamometer); change in quality of life (5Q-5D-5L). Other secondary endpoints included time to event, where events included death from any cause; hospitalization for ALS-related events; tracheostomy (for respiratory failure, saliva management, or both); need for respiratory support for more than 22 hours per day for 7 days. Another secondary endpoint was the Composite Assessment of Function and Survival (CAFS). Key additional endpoints included pharmacokinetic measurements; ALS biomarkers (e.g., serum neurofilament, IL-18, and / or IL-18 binding protein); and exploratory patient-reported outcome measures.

[0112] Summary: Dysregulation of cortisol levels in ALS patients, and the pro-inflammatory role of cortisol in the central nervous system, provide a strong rationale for the role of SGRMs, such as dazucorilant, in the treatment of ALS. DAZALS will be the first study to evaluate whether modulating GR with dazucorilant can reduce the neurotoxic effects of cortisol activity and benefit ALS patients by slowing functional decline (NCT05407324, EudraCT 2021-005611-31). The ENCALS risk profile score will be used to assess eligibility in order to recruit a homogeneous patient population with similar predicted prognoses.

[0113] All patents, patent publications, publications, and patent applications cited in this specification are hereby incorporated by reference in their entirety as if each such publication or patent application were specifically and individually incorporated by reference. Additionally, while the invention has been described in detail for purposes of illustration and example, it will be readily apparent to those of ordinary skill in the art that certain changes and modifications can be made without departing from the spirit or scope of the appended claims.

Claims

1. A method for treating a subject suffering from amyotrophic lateral sclerosis (ALS), the method comprising administering to the subject an effective amount of about 75 milligrams (mg) to about 500 mg of dacuzolam, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone: Wherein the administration of Dazukelan includes administering Dazukelan daily for at least 7 consecutive days, which can effectively increase the Dazukelan exposure by about 1.7 times compared to the Dazukelan exposure produced by administering the effective amount of Dazukelan on a single day. Effective for treating the ALS.

2. The method according to claim 1, wherein the dacuzolam is administered with food.

3. The method according to claim 1 or claim 2, wherein the effective amount of the dacuzolam is selected from about 75 mg, about 150 mg, about 300 mg, about 375 mg, about 450 mg, and about 500 mg of dacuzolam.

4. The method according to any one of claims 1 to 3, wherein the administration of the dacuzolam comprises daily administration of dacuzolam for at least 14 consecutive days to effectively achieve a steady-state level of dacuzolam exposure, which is at least about 1.6 times higher than the dacuzolam exposure produced by single-day administration of the effective amount of dacuzolam.

5. The method according to any one of claims 1 to 4, wherein the effective amount of the dacuzolam is contained in one or more soft capsules.

6. The method according to any one of claims 1 to 5, which further comprises administering a further therapy for ALS.

7. The method according to claim 6, wherein the further therapy for ALS comprises administering riluzole or edaravone.

8. The method according to any one of claims 1 to 7, wherein the administration of the dacuzolam comprises oral or enteral administration of dacuzolam.

9. Heteroaryl ketone-fused naphthyridane Dacuzokuran: (R)-(1-(4-Fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone: For use with food for the treatment of amyotrophic lateral sclerosis (ALS).

10. The use according to claim 9, wherein the use is for use with water and food.

11. The use according to claim 9 or claim 10, wherein the amount of the dacuzolam is selected from about 75 mg, about 150 mg, about 300 mg, about 375 mg, about 450 mg, and about 500 mg of dacuzolam.

12. Heteroarylketone-fused naphthyridinedazucorlan: (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone: Use in the manufacture of a medicament for use in combination with food for the treatment of amyotrophic lateral sclerosis (ALS).

13. The use according to claim 12, wherein the medicament is for use with water and food.

14. The use according to claim 12 or claim 13, wherein the amount of the dacuzolam is selected from about 75 mg, about 150 mg, about 300 mg, about 375 mg, about 450 mg, and about 500 mg of dacuzolam.

15. The use according to any one of claims 12 to 14, wherein the medicament comprises dacuzolam contained in soft capsules.

16. The use according to any one of claims 9 to 15, for use in combination with a further therapy for ALS.

17. The use according to claim 16, wherein the further therapy for ALS comprises using riluzole or edaravone.

18. A method for alleviating symptoms associated with amyotrophic lateral sclerosis (ALS) in a subject suffering from ALS, the method comprising administering to the subject an effective amount of about 75 milligrams (mg) to about 500 mg of dacuzolam, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone: wherein the administering of dacuzolam comprises administering dacuzolam daily for at least 7 consecutive days, which is capable of effectively increasing the dacuzolam exposure by about 1.7-fold compared to the dacuzolam exposure produced by administering the effective amount of dacuzolam on a single day, Effective for treating the ALS.

19. The method according to claim 18, wherein the dacuzolam is administered with food.

20. The method according to claim 18 or claim 19, wherein the effective amount of dacuzolam is selected from about 75 mg, about 150 mg, about 300 mg, about 375 mg, about 450 mg, and about 500 mg of dacuzolam.

21. The method according to any one of claims 18 to 20, wherein the administration of dacuzolam comprises daily administration of dacuzolam for at least 14 consecutive days to effectively achieve a steady-state level of dacuzolam exposure that is at least about 1.6 times higher than the dacuzolam exposure produced by single-day administration of the effective amount of dacuzolam.

22. The method according to any one of claims 18 to 21, wherein the effective amount of dacuzolam is contained in one or more soft capsules.

23. The method according to any one of claims 18 to 22, further comprising administering a further therapy for ALS.

24. The method according to claim 23, wherein the further therapy for ALS comprises administering riluzole or edaravone.

25. The method according to any one of claims 18 to 24, wherein the administration of dacuzolam comprises oral or enteral administration of dacuzolam.

26. The method according to any one of claims 18 to 25, wherein the symptoms associated with ALS are symptoms selected from upper limb weakness, lower limb weakness, dysarthria, and dysphagia.

27. Heteroaryl ketone-fused naphthyridine dacuzokuran: (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone: Use for use with food to alleviate symptoms associated with amyotrophic lateral sclerosis (ALS).

28. The use according to claim 27, wherein the use is in combination with water.

29. The use according to claim 27 or claim 28, wherein the amount of dacuzolam is selected from about 75 mg, about 150 mg, about 300 mg, about 375 mg, about 450 mg, and about 500 mg of dacuzolam.

30. The use according to any one of claims 27 to 29, wherein the symptoms associated with ALS are symptoms selected from upper limb weakness, lower limb weakness, dysarthria, and dysphagia.

31. Heteroarylketone-fused naphthyridinedazucorlan: (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone: Use in the manufacture of a medicament for use in combination with food to alleviate symptoms associated with amyotrophic lateral sclerosis (ALS).

32. The use according to claim 31, wherein the medicament is used in combination with water and food.

33. The use according to claim 31 or claim 32, wherein the amount of dacuzolam is selected from about 75 mg, about 150 mg, about 300 mg, about 375 mg, about 450 mg, and about 500 mg of dacuzolam.

34. The use according to any one of claims 31 to 33, for use in combination with a further therapy for ALS.

35. The use according to claim 34, wherein the further therapy for ALS comprises using riluzole or edaravone.

36. The use according to any one of claims 31 to 35, wherein the symptoms associated with ALS are symptoms selected from upper limb weakness, lower limb weakness, dysarthria, and dysphagia.

37. The use according to any one of claims 31 to 36, wherein the medicament comprises dacuzolam contained in a soft capsule.

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