Pharmaceutical compound and composition

Abstract

The disclosure refers to dantrolene prodrugs, their compositions, and methods for their use in the treatment of diseases.

Description

1 / 88 Pharmaceutical Compound and Composition Technical field

[0001] This disclosure relates to dantrolene prodrugs, their compositions, and methods for their use in the treatment of diseases. Background

[0002] Prodrugs are typically alternative forms of active drugs, reversibly modified or derived with a chemical group that renders the prodrug inactive, or confers solubility, stability, or bioavailability, or alters other properties of the active drug. Typically, the chemical group of a prodrug is cleaved from the prodrug by heat, cavitation, pressure, pH alteration, oxidation-reduction (redox), and / or enzymatic activity acting on the prodrug, thus releasing the active drug. Cleavage of the prodrug's chemical group may occur before administration of the drug to an individual, but generally occurs in vivo by enzymatic processes within the individual.

[0003] Dantrolene (1-{[5-(4-nitrophenyl)-2-furyl]methylidene-amino}imidazolidine-2,4-dione) has the structural formula (1): (1)

[0004] Dantrolene is the rescue agent of choice in the treatment of malignant hyperthermia (MH) and is widely available in most locations where anesthetics are administered. First synthesized in 1967, dantrolene was initially used in the treatment of spasms. Petition 870260038724, dated 04 / 27 / 2026, page 9 / 193 2 / 88 muscular in 1975 and subsequently received FDA approval in 1979 for the treatment of MH. Dantrolene is recognized as a powerful muscle relaxant and as a treatment for nerve spasticity. Since its initial discovery, dantrolene has been explored for the prophylaxis and treatment of other potentially fatal conditions, such as overdose of recreational drugs like ecstasy (N-methyl-3,4-methylenedioxyphenylisopropylamine), heatstroke, neuroleptic malignant syndrome, and ischemic damage to the peripheral nervous system, and may be important in the prevention of sudden infant death syndrome (SIDS).

[0005] Dantrolene is very poorly soluble in water. The low solubility of dantrolene greatly hinders its administration. For example, DANTRIUM™ is dantrolene sodium supplied in 20 mg vials that must be reconstituted with 60 mL of sterile water before intravenous administration. The recommended dose of dantrolene for the treatment of MH is 1 mg / kg to approximately 10 mg / kg. As such, an individual weighing 80 kg would require a rapid infusion of up to 2400 mL to treat MH.

[0006] In addition to its low solubility, dantrolene solutions have a high pH. The pH of DANTRIUM™ is approximately 9.5. RYANODEX®, an improved formulation of dantrolene sodium that can be reconstituted to 50 mg / mL, greatly improves the rate at which dantrolene sodium can be administered. However, reconstituted RYANODEX® also has a high pH of approximately 10.3. Due to its high pH, ​​dantrolene formulations currently cannot be administered subcutaneously or intramuscularly – only intravenously.In fact, care must be taken to avoid leakage into surrounding tissues in order to prevent necrosis. Petition 870260038724, dated 04 / 27 / 2026, page 10 / 193 3 / 88 fabric.

[0007] Although a dantrolene prodrug may be useful in addressing the drug's solubility and pH challenges, identifying a suitable prodrug moiety is complicated by several factors inherent to the dantrolene molecule. For example, it is speculated that dantrolene's low solubility is attributable to its extended aromatic system, which may be involved in hydrophobic pi-stacking behavior. Even the nitro-charged moiety of dantrolene cannot improve the compound's solubility in water.

[0008] Dantrolene includes a hydantoin moiety, which is present in other pharmaceutical compounds, such as phenytoin. However, while prodrug strategies to improve the water solubility of other hydantoin-containing compounds have been reported, it is unclear whether similar strategies can be successfully applied to dantrolene, given its unique chemical structure and physical properties.

[0009] There is a need for new dantrolene formulations that have adequate concentration and pH, making them suitable for intramuscular or subcutaneous use, as well as oral, transmucosal (e.g., intranasal), and intraosseous administration. Summary of the invention

[0010] The disclosure refers to compounds of formula I Petition 870260038724, dated 04 / 27 / 2026, page 11 / 193 4 / 88 wherein R is -P(O)(OH)2 or -P(O)(OR1)(OR2); R1 is H, C1-26 alkyl, aryl, (C1-6 alkyl)C(O)O-C1-26 alkyl, (C1)OC(O)C1-26 alkyl or (C1)OC(O)O-C1-26 alkyl; and R2 is C1-26 alkyl, aryl, (C1-6 alkyl)C(O)O-C1-26 alkyl, (C1)OC(O)C1-26 alkyl or (C1)OC(O)O-C1-26 alkyl, as well as pharmaceutically acceptable salts thereof. Pharmaceutical compositions comprising the compounds of formula I are also described, as well as methods for their use.

[0011] The disclosure also refers to compounds of the formula (II) wherein R3 is H; -C(O)-ZN(R4)(R5), -C(O)ZC(O)-OH, or -C(O)NH-Y-CH2-OC(O)-ZC(O)-OH; Z is C1-6 alkyl; Y is arylene; C1-6 alkyl; R5 is H or C1-6 alkyl; or R4 and R5 together with the nitrogen to which they are attached form a heterocycloalkyl; as well as pharmaceutically acceptable salts thereof. Pharmaceutical compositions comprising the compounds of formula II are also described, as well as methods for their use. Brief description of the figures

[0012] Figure 1 represents the peak area over time for the conversion of a dantrolene diffusion prodrug by alkaline phosphatase at 25°C.

[0013] Figure 2 represents the peak area over time for the conversion of a dantrolene disclosure prodrug (2a) by alkaline phosphatase at 25°C. Petition 870260038724, dated 04 / 27 / 2026, p. 12 / 193 5 / 88

[0014] Figure 3 represents the peak area over time for the conversion of a dantrolene-spreading prodrug by rat plasma at 22°C.

[0015] Figure 4 represents the peak area over time for the conversion of a dantrolene-spreading prodrug by rat plasma at 37°C.

[0016] Figure 5 depicts the conversion of Compound 2a to dantrolene in rat plasma. Rat plasma was incubated with 100 μg / mL of Compound 2a at 37°C. The area under the peaks of the prodrug and dantrolene in the 385 nm chromatograms is plotted against the reaction time. Circles represent the prodrug and triangles represent dantrolene.

[0017] Figure 6 represents a mean concentration of dantrolene in rat plasma from animals dosed with 7.5 mg / kg of prodrug 2a (n= 5±SEM (standard error of the mean)). Quantification by absorbance at 385 nm.

[0018] Figure 7 represents the mean concentration of dantrolene in the whole blood of rats dosed with 7.5 mg / kg of prodrug 2a (n= 5±SEM). Quantification by absorbance at 385 nm.

[0019] Figure 8 represents the mean concentration of dantrolene in rat plasma from animals dosed with 7.5 mg / kg of prodrug 2a (n= 5±SEM). Quantification by absorbance at 385 nm.

[0020] Figure 9 represents the mean concentration of dantrolene in the whole blood of rats dosed with 7.5 mg / kg of prodrug 2a (n= 5±SEM). Quantification by absorbance at 385 nm.

[0021] Figure 10 depicts the conversion of Compound 2b to dantrolene in rat plasma. The rat plasma was Petition 870260038724, dated 04 / 27 / 2026, page 13 / 193 6 / 88 incubated with 100 μg / mL of Compound 2b at 37°C. The area under the peaks of the prodrug and dantrolene in the 385 nm chromatograms is plotted against the reaction time. Circles represent the prodrug and triangles represent dantrolene.

[0022] Figure 11 represents the mean concentration of dantrolene in rat plasma from animals dosed with 10.6 mg / kg of 2b (n= 5±SEM). Quantification by absorbance at 385 nm.

[0023] Figure 12 depicts the conversion of Compound 10c to dantrolene in rat plasma. Rat plasma was incubated with 100 μg / mL of Compound 10c at 37°C. The area under the peaks of the prodrug and dantrolene in the 385 nm chromatograms is plotted against the reaction time. Circles represent the prodrug and triangles represent dantrolene.

[0024] Figure 13 depicts the conversion of Compound 12a to dantrolene in rat plasma. Rat plasma was incubated with 100 μg / mL of Compound 12a at 37°C. The area under the peaks of the prodrug and dantrolene in the 385 nm chromatograms is plotted against the reaction time. Circles represent the prodrug and triangles represent dantrolene.

[0025] Figure 14 shows the mean concentration of dantrolene in the whole blood of animals dosed with 4 mg / kg of prodrug 12a (n= 3±SEM). Quantification by absorbance at 385 nm.

[0026] Figure 15 depicts the conversion of Compound 17b to dantrolene in rat plasma. Rat plasma was incubated with 100 μg / mL of Compound 17b at 37°C. The area under the peaks of the prodrug and dantrolene in the 385 nm chromatograms is plotted against the reaction time. Circles represent the prodrug and triangles represent dantrolene. Petition 870260038724, dated 04 / 27 / 2026, page 14 / 193 7 / 88

[0027] Figure 16 depicts the conversion of Compound 22c to dantrolene in rat plasma. Rat plasma was incubated with 100 μg / mL of Compound 22c at 37°C. The area under the peaks of the prodrug and dantrolene in the 385 nm chromatograms is plotted against the reaction time. Circles represent the prodrug and triangles represent dantrolene.

[0028] Figure 17 shows the mean concentration of dantrolene in the whole blood of animals dosed with 4 mg / kg of prodrug 22c (n= 3±SEM). Quantification by absorbance at 385 nm. Detailed description of illustrative incorporations.

[0029] This disclosure can be more readily understood by reference to the following detailed description considered together with the accompanying figures and examples, which form part of this disclosure. It should be understood that this disclosure is not limited to the specific compositions or methods described and / or shown herein, and that the terminology used in this document is intended to describe particular embodiments by way of example only and is not intended to limit the disclosure claimed.

[0030] When used in the descriptive report, including the appended claims, the singular forms a, an, oea include the plural and reference to a specific numerical value includes at least that specific value, unless the context clearly shows otherwise.

[0031] When expressing a range of values, an exemplary embedding includes from a particular value and / or to another particular value. All numeric ranges are inclusive and combinable. Furthermore, reference to values ​​declared in the ranges includes each and every value within that range. Petition 870260038724, dated 04 / 27 / 2026, page 15 / 193 8 / 88 range. When values ​​are expressed as approximations, by using the term “about,” it will be understood that the particular value forms another embodiment. The term “about,” when used here referring to a measurable value such as a quantity, a time interval, and the like, means to encompass reasonable variations of the value, such as, for example, ±10% of the specified value. For example, the expression “about 50%” may include ±10% of 50, or from 45% to 55%, inclusive of 50%.

[0032] It should be understood that certain disclosure features which are, for clarity, described here in the context of separate incorporations, may also be provided in combination in a single incorporation. Conversely, several disclosure features which are, for brevity, described in the context of a single incorporation, may also be provided separately or in any subcombination.

[0033] When used here, alone or in conjunction with another term or terms, it should be understood that the phrases “method for treating” and “treatment method” may be used in such a way as to allow exchange and / or substitution with the phrase “for use in the treatment of a particular disease.”

[0034] When used herein, alone or in conjunction with another term or terms, the expression “pharmaceutically acceptable” indicates that the designated entity, such as, for example, a pharmaceutically acceptable excipient, is generally chemically and / or physically compatible with other ingredients in a composition, and / or is generally physiologically compatible with its container.

[0035] When used here, the term “pharmaceutical composition” Petition 870260038724, dated 04 / 27 / 2026, p. 16 / 193 9 / 88 refers to a prepared composition combining any of the formulations, including suspensions or dispersions, described herein with one or more pharmaceutically acceptable excipients.

[0036] “Pharmaceutically acceptable excipient” refers to a diluent, adjuvant, excipient, or vehicle with which a pharmaceutical compound is administered. A “pharmaceutically acceptable excipient” refers to a non-toxic, biologically acceptable substance that is otherwise suitable for administration to an individual, as an inert substance, added to a pharmaceutical composition or other medium used as a vehicle, carrier, or diluent to facilitate the administration of an agent and that is compatible with it. Examples of excipients are listed in, for example, Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Co. (1985).

[0037] When used herein, alone or in conjunction with another term or terms, “subject(s)”, “individual(s)” and “patient(s)” refer to mammals, including human beings. The term “human being(s)” refers to and includes children, adolescents or adults.

[0038] When used herein, whether by itself or in conjunction with another term or terms, “treats,” “treating,” “treated,” and “treatment” refers to and includes uses and outcomes of improvement, palliative and / or curative relief, or any combination thereof. In other embodiments, the methods described herein may be used prophylactically. It should be understood that “prophylaxis” or a prophylactic outcome or use does not refer to or require absolute or total prevention (i.e., 100% preventive or protective use or outcome). When used herein Petition 870260038724, dated 04 / 27 / 2026, p. 17 / 193 10 / 88 used, prophylaxis or outcome or prophylactic use refers to uses and outcomes in which administration of a compound or composition decreases or reduces the likelihood of experiencing a particular condition, symptom, disorder or disease; or delays the onset or recurrence (recurrence) of a specific condition, symptom, disorder or disease described herein; or any combination of the above.

[0039] When used herein, whether used alone or in conjunction with another term or terms, therapeutic and “therapeutically effective amount” refer to an amount of a compound or composition that: (a) treats a condition, symptom, disorder or disease described herein; (b) attenuates, improves or eliminates one or more symptoms of a particular condition, disorder or disease described herein; (c) delays the onset or relapse (recurrence) of a specific condition, symptom, disorder or disease described herein. It should be understood that the terms “therapeutic” and “therapeutically effective” encompass any of the aforementioned effects (a)-(c), whether alone or in combination with any of the others (a)-(c).

[0040] The term “C1-C6 alkyl” refers to an aliphatic ligand having 1, 2, 3, 4, 5 or 6 carbon atoms and includes, for example, -CH2-, -CH(CHs)-, -CH(CH3)-CH2- and C(CH3)2-. The term “C0 alkyl” refers to a single linkage.

[0041] The term “alkyl” refers to a straight or branched chain hydrocarbon group having from 1 to 12 carbon atoms (“C1-C12”), preferably from 1 to 6 carbon atoms (“C1-C6”), in the group. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, Petition 870260038724, dated 04 / 27 / 2026, page 18 / 193 11 / 88 tert-pentyl, hexyl, isohexyl and similar.

[0042] The term heterocycloalkyl refers to a three- to ten-membered monocyclic or bicyclic saturated ring structure containing at least one heteroatom selected from the group consisting of O, N, and S. Examples of suitable heterocycloalkyl groups include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, and the like.

[0043] The term aryl when used alone or as part of a substituent group refers to a monocyclic or bicyclic aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring. Preferred aryl moieties include phenyl and naphthyl.

[0044] The term arylene refers to a monocyclic or bicyclic aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring. Preferred arylene moieties include phenylene and naphthylene. Compounds of the disclosure may be chiral and as a result, may exist as a single enantiomer or a mixture of enantiomers. All enantiomers and mixtures thereof are contemplated by this disclosure.

[0045] Isotopic variants of the compound of formulas I and II are also within the scope of disclosure. When used herein, the term isotopic variant refers to a compound that contains proportions of isotopes in one or more of the atoms constituting such compound, in abundance greater than the natural abundance. For example, an isotopic variant of a compound may be radiolabeled, that is, it contains one or more radioactive isotopes, or it may be labeled with non-radioactive isotopes such as, for example, deuterium (2H or D), Petition 870260038724, dated 04 / 27 / 2026, p. 19 / 193 12 / 88 carbon-11 (11C), carbon-13 (13C), nitrogen-15 (15N), fluorine-18 (18F) or similar. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that, for example, any hydrogen may be 2H / D, any carbon may be 110 or 13C, any nitrogen may be 15N or any fluorine (if present) may be 18F and that the presence and positioning of such atoms may be determined within the skill of the technique.

[0046] The compounds of formulas I and II convert to dantrolene in vivo. In some respects, the compounds of formulas I and II convert to dantrolene in vivo with a half-life of about 1 second or less to about 1 minute to 90 minutes. In some respects, the compounds of formulas I and II convert to dantrolene in vivo with a half-life of less than 1 second. In other respects, the compounds of formulas I and II convert to dantrolene in vivo with a half-life of seconds, that is, with a half-life of less than one minute, for example, with a half-life of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or about 59 seconds. In other respects, the compounds of formulas I and II convert to dantrolene in vivo with a half-life of about 1 to about 5 minutes, for example, about 1, 2, 3, 4, or about 5 minutes. In other respects, the compounds of formulas I and II convert to dantrolene in vivo with a half-life of about 1 to about 10 minutes. In other respects, the compounds of formulas I and II convert to dantrolene in vivo with a Petition 870260038724, dated 04 / 27 / 2026, p. 20 / 193 13 / 88 half-life of about 5 to about 10 minutes. In some respects, compounds of formula I and II convert to dantrolene in vivo with a half-life of about 1 to 60 minutes. In some respects, compounds of formula I and II convert to dantrolene in vivo with a half-life of about 1 to 45 minutes. In some respects, compounds of formula I and II convert to dantrolene in vivo with a half-life of about 1 to 45 minutes. In some respects, compounds of formula I and II convert to dantrolene in vivo with a half-life of about 1 to 20 minutes. In some respects, the compounds of formulas I and II convert to dantrolene in vivo with a half-life of approximately 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or about 90 minutes.

[0047] The disclosure refers to dantrolene prodrugs of formula I: wherein R is -P(O)(OH)2 or -P(O)(OR1)(OR2); R1 is H, C1-26 alkyl, aryl, (C1-6 alkyl)(O)O-C1-26 alkyl, -(C1)OC(O)(C1-26 alkyl) or (C1)OC(O)O-C1-26 alkyl; and R2 is C1-26 alkyl, aryl, (C16)C(O)O-C1-26 alkyl, -(C1)OC(O)C1-26 alkyl, or (C1)OC(O)O(C1-26 alkyl); or a pharmaceutically acceptable salt thereof.

[0048] In some respects, the dantrolene prodrugs disclosed are those in which R is -P(O)(OH)2 and are of formula IA: Petition 870260038724, dated 04 / 27 / 2026, p. 21 / 193 14 / 88 (AI)

[0049] Pharmaceutically acceptable salts of compounds of formula IA are also within the scope of disclosure. Preferred salts include, for example, sodium salts of compounds of formula IA. Lithium, magnesium, calcium, and potassium salts of compounds of formula IA are also within the scope of disclosure. Alternative salt forms include ammonium, choline, and tromethamine salts. Another preferred salt of compound of formula IA is the monotromethamine salt. Another preferred salt of compound of formula IA is the ditromethamine salt. Pharmaceutically acceptable organic salts of compounds of formula IA are also within the scope of disclosure.

[0050] In some respects, the dantrolene prodrugs of disclosure are those in which R is -P(O)(OR1)(OR2) and are of formula IB:

[0051] In some respects, R1 is H. In those respects, R2 is C1-26-alkyl, aryl, (C1-6-alkyl)C(O)O-C1-26-alkyl, (C1-alkyl)OC(O)(C1-26 alkyl) or (C1)OC(O)O(C1-26 alkyl). Pharmaceutically acceptable salts of such compounds of formula IB are also within the scope of disclosure. Preferred salts Petition 870260038724, dated 04 / 27 / 2026, p. 22 / 193 15 / 88 includes, for example, sodium salts of compounds of formula IB. Other salts include lithium, magnesium, calcium, and potassium salts of compounds of formula IB. Alternative salt forms include ammonium, choline, and tromethamine salts. Pharmaceutically acceptable organic salts of compounds of formula IB are also within the scope of disclosure.

[0052] In some aspects of compounds of formula IB, R1 is H and R2 is C1-26 alkyl. For example, in some aspects, R1 is H and R2 is C1-6 alkyl. In other aspects, R1 is H and R2 is C1-12 alkyl. In other aspects, R1 is H and R2 is C13-26 alkyl. In other aspects, R1 is H and R2 is C18-26 alkyl. In other aspects, R1 is H and R2 is C20-26 alkyl. In some aspects, R1 is H and R2 is C1 alkyl. In some aspects, R1 is H and R2 is C2 alkyl. In some aspects, R1 is H and R2 is C3 alkyl. In some aspects, R1 is H and R2 is C4 alkyl. In some aspects, R1 is H and R2 is C5 alkyl. In some respects, R1 is H and R2 is C6-alkyl. In some respects, R1 is H and R2 is C7-alkyl. In some respects, R1 is H and R2 is C8-alkyl. In some respects, R1 is H and R2 is C1-alkyl. In some respects, R1 is H and R2 is C10-alkyl. In some respects, R1 is H and R2 is C11-alkyl. In some respects, R1 is H and R2 is C12-alkyl.In some respects, R1 is H and R2 is C13-alkyl. In some respects, R1 is H and R2 is C14-alkyl. In some respects, R1 is H and R2 is C15-alkyl. In some respects, R1 is H and R2 is C16-alkyl. In some respects, R1 is H and R2 is C17-alkyl. In some respects, R1 is H and R2 is C18-alkyl. In some respects, R1 is H and R2 is C19-alkyl. In some respects, R1 is H and R2 is C20-alkyl. In some respects, R1 is H and R2 is C20-alkyl. Petition 870260038724, dated 04 / 27 / 2026, page 23 / 193 16 / 88 is C21-alkyl. In some respects, R1 is H and R2 is C22-alkyl. In some respects, R1 is H and R2 is C23-alkyl. In some respects, R1 is H and R2 is C24-alkyl. In some respects, R1 is H and R2 is C25-alkyl. In some respects, R1 is H and R2 is C26-alkyl.

[0053] In some aspects of compounds of formula IB, R1 is H and R2 is aryl. For example, in some aspects of compounds of formula IB, R1 is H and R2 is phenyl.

[0054] In some aspects of compounds of formula IB, R1 is H and R2 is (C1-6 alkyl)C(O)O-C1-26 alkyl. For example, in some aspects, R1 is H and R2 is (C1 alkyl)C(O)O-C1-26 alkyl. In other aspects, R1 is H and R2 is (C2 alkyl)C(O)O-C1-26 alkyl. In other aspects, R1 is H and R2 is (C3 alkyl)C(O)O-C1-26 alkyl. In other aspects, R1 is H and R2 is (C4 alkyl)C(O)O-C1-26 alkyl. In other aspects, R1 is H and R2 is (C5 alkyl)C(O)O-C1-26 alkyl. In other aspects, R1 is H and R2 is (C6 alkyl)C(O)O-C1-26 alkyl. In other aspects, R1 is H and R2 is (C16 alkyl)C(O)O-C1-6 alkyl. In other aspects, R1 is H and R2 is (C1-6 alkyl)C(O)O-C1-12 alkyl. In other aspects, R1 is H and R2 is (C1-6 alkyl)C(O)O-C13-26 alkyl. In other aspects, R1 is H and R2 is (C1-6 alkyl)C(O)O-C18-26 alkyl. In other aspects, R1 is H and R2 is (C1-6 alkyl)C(O)O-C20-26 alkyl.

[0055] In some aspects of compounds of formula IB, R1 is H and R2 is (C1-alkyl)OC(O)(C1-26 alkyl). For example, in some aspects, R1 is H and R2 is (C1-alkyl)OC(O)(C1-6 alkyl). In other aspects, R1 is H and R2 is (C1-alkyl)OC(O)(C1-12 alkyl). In other aspects, R1 is H and R2 is (C1-alkyl)OC(O)(C13-16 alkyl). In other aspects, R1 Petition 870260038724, dated 04 / 27 / 2026, p. 24 / 193 17 / 88 is H and R2 is (alkyl of O1)00(O) (alkyl of O18-26) · In other respects, R1 is H and R2 is (alkyl of O1)00(O) (alkyl of O2026) ·

[0056] In some aspects of compounds of formula IB, R1 is H and R2 is (alkyl of 01)00(0)0(alkyl of 01-26) · For example, in some aspects, R1 is H and R2 is (alkyl of 01)00(0)0(alkyl of 01-6) · In other aspects, R1 is H and R2 is (alkyl of 01)00(0)0(alkyl of 01-12) · In some aspects, R1 is H and R2 is (alkyl of 01)00(0)0(alkyl of 013-16) · In some aspects, R1 is H and R2 is (alkyl of 01)00(0)0(alkyl of 01826) · In some aspects, R1 is H and R2 is (alkyl of 01)00(0)0(alkyl of 020-26)·

[0057] In other aspects of compounds of formula IB, R1 is -alkyl of 01-26, aryl, (alkyl of 01-6)0(0)0-alkyl of 01-26, (alkyl of 01)00(0)(alkyl of 01-26) or (alkyl of 01)00(0)0(alkyl of 01-26) and R2 is -alkyl of 01-26, aryl, (alkyl of 01-6)0(0)0-alkyl of 01-26, (alkyl of 01)00(0)(alkyl of 01-26) or (alkyl of 01)00(0)0(alkyl of 01-26)·

[0058] In some aspects of compounds of formula IB, R1 is 01-26-alkyl and R2 is 01-26-alkyl, aryl, (01-6-alkyl)0(0)0-alkyl of 01-26, (01)00(0)(01-26-alkyl) or (01)00(0)0(01-26-alkyl). For example, in these aspects, R1 may be 01-6-alkyl. In other aspects, R1 is 01-12-alkyl. In other aspects, R1 is 013-26-alkyl. In other aspects, R1 is 018-26-alkyl. In other aspects, R1 is 020-26-alkyl. In some aspects, R1 is 01-alkyl. In some aspects, R1 is an O2-alkyl group. In some respects, R1 is an O3-alkyl group. In some respects, R1 is an O4-alkyl group. In some respects, R1 is Petition 870260038724, dated 04 / 27 / 2026, page 25 / 193 18 / 88 R1 is a C5-alkyl group. In some respects, R1 is a Cg-alkyl group. In some respects, R1 is a C7-alkyl group. In some respects, R1 is a C8-alkyl group. In some respects, R1 is a C9-alkyl group. In some respects, R1 is a C10-alkyl group. In some respects, R1 is a C11-alkyl group. In some respects, R1 is a C12-alkyl group. In some respects, R1 is a C13-alkyl group. In some respects, R1 is a C14-alkyl group. In some respects, R1 is a C15-alkyl group. In some respects, R1 is a C16-alkyl group. In some respects, R1 is a C17-alkyl group. In some respects, R1 is a C18-alkyl group. In some respects, R1 is a C19-alkyl group. In some respects, R1 is a C20-alkyl group. In some respects, R1 is a C21-alkyl group. In some respects, R1 is a C22-alkyl group. In some respects, R1 is a C23-alkyl group. In some respects, R1 is a C24-alkyl group. In some respects, R1 is a C25-alkyl group. In some respects, R1 is a C26-alkyl group.

[0059] In some aspects of compounds of formula IB, R1 is aryl and R2é -alkyl of C1-26, aryl, (alkyl of C1-6)C(O)Oalkyl of C1-26, (alkyl of C1)OC(O)alkyl of C1-26Ou (alkyl of CO1-O)alkyl of CO1-O26. For example, in some aspects, R1 is phenyl and R2 is -alkyl C1-26, aryl, (alkyl C1-6)C(O)O-alkyl C1-26, (alkyl C1)OC(O)alkyl C1-26 or (alkyl C1)OC(O)alkyl C1-26).

[0060] In some aspects of compounds of formula IB, R1 is (alkyl of C1-6)C(O)O-alkyl of C1-26 and R2 is -alkyl of C1-26, aryl, -alkyl of C1-26, aryl, (alkyl of C1-6)C(O) C1) OC(O)alkyl of C1-26 or (alkyl of C1)OC(O)O(alkyl of C1-26). For example, in some respects, R1 is (C1 alkyl)C(O)O-C1-26 alkyl. In other respects, R1 is (C2 alkyl)C(O)O-C1-26 alkyl. In other respects, R1 is (C3 alkyl)C(O)O-C1-26 alkyl. In other respects, Petition 870260038724, dated 04 / 27 / 2026, page 26 / 193 19 / 88 Ri is (C4 alkyl)C(O)O-C1-26 alkyl. In other respects, R1 is (C5 alkyl)C(O)O-C1-26 alkyl. In other respects, R1 is (C6 alkyl)C(O)O-C1-26 alkyl. In other respects, R1 is (C1-6 alkyl)C(O)O-C1-6 alkyl. In other aspects, R1 is (C1-6 alkyl)C(O)O-C1-12 alkyl. In other aspects, R1 is (C1-6 alkyl)C(O)O-C13-26 alkyl. In other aspects, R1 is (C1-6 alkyl)C(O)O-C1826 alkyl. In other aspects, R1 is (C1-6 alkyl)C(O)O-C20-26 alkyl ·

[0061] In some aspects of compounds of formula IB, R1 is (C1-26 alkyl)OC(O)C1-26 alkyl and R2 is C1-26 alkyl, aryl, (C1-6 alkyl)C(O)O-C1-26 alkyl, (C1)OC(O)(C1-26 alkyl) or (C1)OC(O)O(C1-26 alkyl) · For example, in some aspects, R1 is (C1)OC(O)(C1-6 alkyl) · In other aspects, R1 is (C1)OC(O)(C1-12 alkyl) · In other aspects, R1 is (C1)OC(O)(C1-12 alkyl) C13-16)· In other aspects, R1 is (C1 alkyl)OC(O)(C18-26 alkyl)· In other aspects, R1 is (C1 alkyl)OC(O)(C20-26 alkyl)·

[0062] In some aspects of compounds of formula IB,R1 is (C1-26 alkyl)OC(O)O and R2 is C1-26 alkyl, aryl, (C1-6 alkyl)C(O)O-C1-26 alkyl, (C1-6 alkyl)C(O)-C1-26 alkyl or (C1-6 alkyl)C(O)O-C1-26 alkyl. For example, in some respects, R1 is (C1-6 alkyl). In other respects, R1 is (C1-12 alkyl)OC(O)O. In other respects, R1 is (C1-16 alkyl)OC(O)O. In other respects, R1 is (C1-26 alkyl)OC(O)O. In other respects, R1 is (C1-26 alkyl)OC(O)O. (C1 alkyl)OC(O)O(C20-26 alkyl)·

[0063] In some respects R1 is C1-26 alkyl and R2 is Petition 870260038724, dated 27 / 04 / 2026, page 27 / 193, 20 / 88 C1-26 alkyl. For example, in some aspects R1 and R2 are, independently, -C1-6 alkyl, -C1-12 alkyl, C13-26 alkyl, -C18-26 alkyl, -C20-26 alkyl, C1 alkyl, -C2 alkyl, -C3 alkyl, -C4 alkyl, -C5 alkyl, -C alkyl. C6, -C7 alkyl, -alkyl C8, -rents from C9, -rents from C10, -rents from C11, -rents from C12, -rents from C13, -rents from C14, -rents from C15, -rents from C16, -rents from C17, -rents from C18, -rents from C19, -rents from C20, -rents from C21, -rents from C22, -rent from C23, -rent from C24, -rent from C25 or rent from C26.

[0064] In some respects, R1é arila (for example, phenyla) and R2é arila (for example, phenyla).

[0065] In some aspects, R1é (C1-6 alkyla)C(O)O-C1-26 alkyla, and R2é (C1-6 alkyla)C(O)O-C1-26 alkyla. For example, in some aspects, R1 and R2 are, independently, (C1)C(O)O alkyl-C1-26 alkyl, (C2)C(O)O alkyl-C1-26 alkyl, (C3)C(O)O alkyl-C1-26 alkyl, (C4)C(O)O alkyl-C1-26 alkyl, (C5)C(O)O alkyl-C1-26 alkyl, (C6)C(O)O alkyl-C1-26 alkyl, (C1-6)C(O)O alkyl-C16 alkyl, (C1-6)C(O)O alkyl-C1-12 alkyl, (C16)C(O)O alkyl-C13-26 alkyl, (C1-6)C(O)O alkyl-C13-26 alkyl C18-26 ou (C1-6 alkyl)C(O)O-C20-26 alkyl.

[0066] In some respects, R1 is (C1)OC(O)-C1-26 alkyl and R2 is (C1)OC(O)-C1-26 alkyl. For example, in some respects, R1 and R2 are independently (C1)OC(O)-C1-6 alkyl, (C1)OC(O)-C1-12 alkyl, (C1)OC(O)-C13-16 alkyl, (C1)OC(O)-C18-26 alkyl or (C1)OC(O)-Petition 870260038724, dated 27 / 04 / 2026, page 28 / 193 21 / 88 C20-26 alkyl.

[0067] In some respects, R1 is (C1)OC(O)O-C1-26 alkyl and R2 is (C1)OC(O)O-C1-26 alkyl. For example, in some respects, R1 and R2 are independently (C1)OC(O)O-C1-6 alkyl, (C1)OC(O)O-C1-12 alkyl, (C1)OC(O)O-C13-16 alkyl, (C1)OC(O)O-C18-26 alkyl or (C1)OC(O)O-C20-26 alkyl.

[0068] Compounds of formula I, which include compounds of formula IA and IB, may be present as pharmaceutically acceptable salts, where applicable. These salts include sodium salts. Potassium, lithium, calcium, and magnesium salts are also provided. Alternative salt forms include ammonium, choline, and tromethamine salts.

[0069] Also within the scope of this disclosure are dantrolene prodrugs of formula II (II) in which R3 is H, -C(O)-ZN(R4)(R5), -C(O)ZC(O)-OH, or -C(O)-YCH2-OC(O)-ZC(O)-OH; Z is C1-6 alkyl; Y is aryl; R4 is H or C1-6 alkyl; R5 is H or C1-6 alkyl; or R4 and R5 together with the hydrogen atom to which they are attached form a heterocycloalkyl group; or pharmaceutically acceptable salts thereof.

[0070] In preferred aspects, R3 is H and the compound of formula II is a compound of formula II-A Petition 870260038724, dated 04 / 27 / 2026, p. 29 / 193 22 / 88 or a pharmaceutically produced salt thereof.

[0071] In other aspects of formula II, R3 is C(O)-ZN(R4) (R5) and the compound of formula II is a compound of formula II-B wherein Z is a C1-6 alkyl; R4 is H or a C1-6 alkyl; R5 is H or a C1-6 alkyl; or R4 and R5 together with the hydrogen atom to which they are attached form a heterocycloalkyl group; or a pharmaceutically acceptable salt thereof.

[0072] In these aspects of formula II-B, Z can be C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl or C6 alkyl. In some aspects, Z is C1-2 alkyl. In some aspects, Z is alkyl of C1.

[0073] In these aspects of formula II-B, R4 is H. In other aspects, R4 is a C1-6 alkyl, for example, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl or C6 alkyl. In preferred aspects, R4 is methyl, ethyl or isopropyl.

[0074] In these aspects of formula II-B, R5 is H. In other aspects, R5 is C1-6 alkyl, for example, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl or Petition 870260038724, dated 04 / 27 / 2026, p. 30 / 193 23 / 88 Cg alkyl. In preferred aspects, R5 is methyl, ethyl or isopropyl.

[0075] In some aspects of formula II-B, R4 is H and R5 is H. In other aspects, R4 is H and R5 is C1-6 alkyl, for example, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl or C6 alkyl. In other aspects, R4 and R5 are independently C1-6 alkyl, for example, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl or C6 alkyl.

[0076] In some of these aspects of formula II-B, R4 and R5 together with the hydrogen atom to which they are attached form a heterocycloalkyl group. Preferred heterocycloalkyl moieties include, for example, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, azetidinyl, and aziridinyl.

[0077] Preferred compounds of formula II-B include, for example

[0078] In other aspects of formula II, R3 is C(O)-ZC(O)OH and the compound of formula II is a compound of formula II-C Petition 870260038724, dated 04 / 27 / 2026, p. 31 / 193 24 / 88 wherein Z is a C1-6 alkyl; or a pharmaceutically acceptable salt thereof.

[0079] In these aspects of Formula II-C, Z may be C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl or C6 alkyl. In some aspects, Z is alkyl of C1. In some aspects, Z is C2 alkyl.

[0080] A preferred compound of formula II-C is and pharmaceutically acceptable salts thereof.

[0081] In other aspects of formula II, R3 is -C(O)-NH-YCH2-OC(O)-ZC(O)-OH and the compound of formula II is a compound of formula II-D wherein Y is arylene; and Z is C1-6 alkyl; or a pharmaceutically acceptable salt thereof.

[0082] In these aspects of formula II-D, Y can be phenylene or naphthylene, preferably phenylene.

[0083] In these aspects of formula II-D, Z can be C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl or C6 alkyl. In some aspects Z is C1-2 alkyl. In some aspects, Z is alkyl of C1. In some aspects, Z is C2 alkyl.

[0084] A preferred compound of formula II-D is Petition 870260038724, dated 04 / 27 / 2026, p. 32 / 193 25 / 88 and pharmaceutically acceptable salts thereof.

[0085] In other respects, R3 is -C(O)-OY-CH2-OC(O)-ZC(O)OH and the compound of formula II is a compound of formula II-E wherein Y is arylene; and Z is C1-6 alkyl; or a pharmaceutically acceptable salt thereof.

[0086] In these aspects of formula II-E, Y can be phenylene or naphthylene, preferably phenylene.

[0087] In these aspects of formula II-E, Z can be C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl. In some aspects Z is C1-2 alkyl. In some aspects, Z is C1 alkyl. In some aspects, Z is C2 alkyl.

[0088] The compounds of formula II, which include compounds of formula II-A, II-B, II-C, II-D and II-E, may, where applicable, be pharmaceutically acceptable salts. These salts include sodium salts. Potassium, lithium, calcium and magnesium salts are also contemplated. Alternative salt forms include ammonium, choline and tromethamine salts. Organic salts are also within the scope of the invention. Petition 870260038724, dated 04 / 27 / 2026, p. 33 / 193 26 / 88 pharmaceutically acceptable of the compounds of formula II.

[0089] The compounds of formulas I and II, which include the compounds of formulas IA, IB, II-A, II-B, II-C, II-D and IIE and pharmaceutically acceptable salts thereof, may be prepared as pharmaceutical compositions by combining the compound with a pharmaceutically acceptable excipient. In some embodiments, one or more additional pharmaceutically acceptable excipients may be selected from the group consisting of preservatives, antioxidants or mixtures thereof. In still other embodiments of the disclosure, the additional pharmaceutically acceptable excipient is a preservative such as, but not limited to, phenol, cresol, p-hydroxybenzoic ester, chlorobutanol or mixtures thereof. In still other embodiments of the disclosure, the additional pharmaceutically acceptable excipient is an antioxidant such as, but not limited to, ascorbic acid, sodium pyrosulfite, palmitic acid, butylated hydroxyanisole, butylated hydroxytoluene, tocopherols, or mixtures thereof.

[0090] The pharmaceutical compositions of the disclosure may be provided as suspensions. In other embodiments, the pharmaceutical compositions of the disclosure may be provided as solutions.

[0091] The pharmaceutical compositions of the disclosure may have the compound of the present disclosure in a concentration of about 1 mg / mL to about 400 mg / mL, for example, from 1 mg / mL to about 200 mg / mL, from 1 mg / mL to about 300 mg / mL, preferably from 5 mg / mL to about 125 mg / mL, preferably at physiological pH. In particular embodiments of the disclosure, a compound of the disclosure is Petition 870260038724, dated 04 / 27 / 2026, p. 34 / 193 27 / 88 present at a concentration greater than or equal to about 5 mg / mL. In other embodiments, a compound from the disclosure is present at a concentration of about 10 mg / mL to 25 mg / mL. In still other embodiments, a compound from the disclosure is present at a concentration of about 1 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, or 50 mg / mL. In still other embodiments, a compound of the disclosure is present at a concentration of approximately 125 mg / mL, 150 mg / mL, 175 mg / mL, 200 mg / mL, 225 mg / mL, 250 mg / mL, 275 mg / mL, 300 mg / mL, 325 mg / mL, 350 mg / mL, 375 mg / mL, or approximately 400 mg / mL.

[0092] In certain embodiments, a compound of the disclosure is present at a concentration greater than or equal to 55 mg / mL. In other embodiments, a compound of the disclosure is present at a concentration of approximately 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, 100 mg / mL, 105 mg / mL, 110 mg / mL, 115 mg / mL, 120 mg / mL or 125 mg / mL. In other embodiments, a disclosed compound is present at a concentration of approximately 75 mg / mL to 95 mg / mL, 80 mg / mL to 100 mg / mL, 90 mg / mL to 110 mg / mL, 95 mg / mL to 105 mg / mL, 95 mg / mL to 115 mg / mL, 100 mg / mL to 110 mg / mL, 110 mg / mL to 125 mg / mL, including all ranges and subranges in between.

[0093] In certain embodiments, the pharmaceutical compositions of the disclosure may further comprise a stabilizer or two or more stabilizers. In still other embodiments of the disclosure, the stabilizer is selected from the group consisting of surfactants, polymers, crosslinked polymers, buffering agents, electrolytes and non-electrolytes. In still other embodiments of the disclosure, the composition comprises a combination of two or more Petition 870260038724, dated 04 / 27 / 2026, page 35 / 193 28 / 88 Selected stabilizers from the group consisting of surfactants, polymers, crosslinked polymers, buffering agents, electrolytes and non-electrolytes. In still other embodiments of the disclosure, the stabilizer is a surfactant such as, but not limited to, poly(ethylene oxide) (PEO), a PEO derivative, polysorbate 80, polysorbate 20, poloxamer 188, polyethoxylated vegetable oils, lecithin, human serum albumin and mixtures thereof. In particular embodiments of the disclosure, the stabilizer is a polymer such as, but not limited to, polyvinylpyrrolidone (such as, but not limited to, povidone K12, povidone K17 and mixtures thereof), poly(ethylene glycol) 3350 and mixtures thereof. In other embodiments of the disclosure, the stabilizer is an electrolyte such as, but not limited to, sodium chloride, calcium chloride and mixtures thereof.In still other embodiments of the disclosure, the stabilizer is a non-electrolyte, such as, but not limited to, dextrose, glycerol, mannitol, or mixtures thereof. In other embodiments of the disclosure, the stabilizer is a cross-linked polymer such as, but not limited to, sodium carboxymethylcellulose (CMC). In some embodiments of the disclosure, the stabilizer is CMC 7LF, CMC 7MF, CMC 7HF, or mixtures thereof.

[0094] In other embodiments of the disclosure, combinations of electrolytic and non-electrolytic stabilizers may be used. In some embodiments, the combination of stabilizers may comprise two or more non-electrolytic stabilizers. In other embodiments, the combination of stabilizers may comprise two or more electrolytic stabilizers. In other embodiments, the combination of stabilizers may comprise one or more Petition 870260038724, dated 04 / 27 / 2026, page 36 / 193 29 / 88 non-electrolytic stabilizers and one or more electrolytic stabilizers. In other embodiments, the combination of stabilizers may comprise two or more of mannitol, dextrose, and sodium chloride.

[0095] In certain embodiments of the disclosure, combinations of surfactant stabilizers and polymeric stabilizers may be used. In some embodiments, the combination of stabilizers may comprise two or more surfactant stabilizers. In other embodiments, the combination of stabilizers may comprise two or more polymeric stabilizers. In still other embodiments, the combination of stabilizers may comprise one or more surfactant stabilizers and one or more polymeric stabilizers. In still other embodiments, the combination of stabilizers may comprise two or more of polysorbate 80, polysorbate 20 and poloxamer 188. In still other embodiments, the combination of stabilizers may comprise one or more of polysorbate 80, polysorbate 20 and poloxamer 188 and one or more of povidone K12, povidone K17 and poly(ethylene glycol) 3350.

[0096] In certain embodiments of the disclosure, the composition may comprise from about 0.2 to 0.7 mg / mL, 0.5 to 1 mg / mL, 1 to 5 mg / mL, 2 to 8 mg / mL, 5 to 6 mg / mL, 5 to 10 mg / mL, 8 to 12 mg / mL, 10 to 15 mg / mL, 15 to 20 mg / mL, 20 to 30 mg / mL, 30 to 40 mg / mL, 40 to 50 mg / mL, 45 to 55 mg / mL, 50 to 60 mg / mL or 60 to 75 mg / mL of one or more stabilizers and all ranges and subranges existing between them. In other incorporations of the disclosure, the composition comprises approximately 0.2 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 5.5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 Petition 870260038724, dated 04 / 27 / 2026, page 37 / 193 30 / 88 mg / mL, 12 mg / mL, 15 mg / mL, 17 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, or 75 mg / mL of one or more stabilizers.

[0097] In particular embodiments of the disclosure, the composition further comprises one or more buffering agents such as, but not limited to, NaH2PO4^H2O, NaH2PO4^2H2O, anhydrous NaH2PO4, sodium citrate, citric acid, Tris, sodium hydroxide, HCl or mixtures thereof. In certain embodiments of the disclosure, the composition comprises from about 1 mM to 20 mM of one or more buffering agents and all the ranges and subranges between them. In particular embodiments of the disclosure, the composition comprises from about 1 to 2 mM, 1 to 3 mM, 1 to 5 mM, 2 to 8 mM, 5 to 6 mM, 5 to 10 mM, 8 to 12 mM, 10 to 15 mM or 15 to 20 mM of one or more buffering agents and all the ranges and subranges between them. In other embodiments of the disclosure, the composition comprises approximately 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, or 20 mM of one or more buffering agents.

[0098] In certain embodiments of the disclosure, a pharmaceutical composition has a pH of about 3 to 10, for example, 3, 4, 5, 6, 7, 8, 9, or 10. In other embodiments of the disclosure, the composition has a pH of about 5 to 9. In other embodiments of the disclosure, the composition has a pH of about 6 to 9. In other embodiments of the disclosure, the composition has a pH of about 6 to 7. In other embodiments of the disclosure, the composition has a pH of about 6 to 8.5. In other embodiments of the disclosure, the Petition 870260038724, dated 04 / 27 / 2026, page 38 / 193 31 / 88 composition has a pH of about 7 to 8.5. In other embodiments of the disclosure, the composition has a pH of more than 7 to 8.5. In certain embodiments of the disclosure, the composition has a pH of about 6.0 to 8.0. In particular embodiments of the disclosure, the composition has a pH of about 6.0 to 7.0, 6.5 to 7.0, 6.5 to 7.5, 6.7 to 7.2, 7.0 to 7.2, 7.0 to 7.5, 7.0 to 8.0 or 7.0 to 8.5.

[0099] In certain embodiments of the disclosure, a pharmaceutical composition has an osmolarity of about 280 mOsm / L to about 310 mOsm / L, for example, about 280, 285, 290, 300, 305 or about 310 mOsm / L. In other embodiments of the disclosure, the composition has an osmolarity of about 290 mOsm / L to about 300 mOsm / L. In still other embodiments of the disclosure, the composition has an osmolarity of about 290 mOsm / L. In some embodiments, the osmolarity may be selected by using appropriate amounts of one or more stabilizers that act as tonicity agents in a composition, such as, but not limited to, the non-electrolytic stabilizers and electrolytic stabilizers described herein.In some formulations, osmolarity can be selected through the use of appropriate amounts of one or more buffering agents that act as tonicity agents in a composition, such as, but not limited to, the buffering agents described herein.

[0100] The pharmaceutical compositions of the disclosure can be administered intravenously. Alternatively, the pharmaceutical compositions of the disclosure can be administered intramuscularly. In other embodiments, the pharmaceutical compositions of the disclosure are administered via Petition 870260038724, dated 04 / 27 / 2026, page 39 / 193 32 / 88 subcutaneous. The pharmaceutical compositions of the disclosure may also be administered orally. In other embodiments, the pharmaceutical compositions of the disclosure are administered transmucosally, for example, intranasally. In other embodiments, the pharmaceutical compositions of the disclosure are administered intraosseously.

[0101] Disclosure compounds and pharmaceutical compositions may be used to treat dantrolene-responsive disorders. For example, individuals requiring treatment may be given a therapeutically effective amount of a disclosure compound, or a salt thereof. In other respects, individuals requiring treatment may be given a therapeutically effective amount of a disclosure pharmaceutical composition, or a salt thereof. In other respects, individuals requiring treatment may be exposed to a therapeutically effective amount of a disclosure compound, for example, a compound of formulas IA, IB, II-A, II-B, II-C, II-D and II-E or a pharmaceutically acceptable salt thereof. For example, individuals requiring treatment may be exposed to a therapeutically effective amount of a disclosure compound, for example, a compound of formula II-A or a pharmaceutically acceptable salt thereof.

[0102] Disorders susceptible to dantrolene include, for example, malignant hyperthermia, chronic spasticity, exertional heatstroke, cardiac arrhythmias, tachycardia, atrial fibrillation, cardiac arrest, myocardial infarction, heart failure, myocardial injury, cardiomyopathy, central nervous system disease, amyotrophic lateral sclerosis, Petition 870260038724, dated 04 / 27 / 2026, page 40 / 193 33 / 88 rhabdomyolysis, Duchenne muscular dystrophy, ataxia, detrusor overactivity, overactive bladder, seizure, epilepsy, neuroleptic malignant syndrome, human stress disorder, Alzheimer's disease, Huntington's disease, multiple sclerosis, Parkinson's disease, ischemia-reperfusion injury, neural reperfusion injury, hypoxia, cerebral aneurysm, subarachnoid hemorrhage, stroke, hyperthermia associated with drug abuse or hyperthermia associated with drug overdose.

[0103] In preferred aspects, the compounds and / or pharmaceutical compositions of the disclosure are used to treat malignant hyperthermia in an individual.

[0104] In other respects, the compounds and / or pharmaceutical compositions disclosed are used to treat chronic spasticity in an individual.

[0105] In other respects, the pharmaceutical compounds and / or compositions disclosed are used to treat exertional heatstroke in an individual.

[0106] In other respects, the pharmaceutical compounds and / or compositions disclosed are used to treat cardiac arrhythmia in an individual.

[0107] In other respects, the pharmaceutical compounds and / or compositions disclosed are used to treat tachycardia in an individual.

[0108] In other respects, the pharmaceutical compounds and / or compositions of the disclosure are used to treat atrial fibrillation in an individual.

[0109] In other respects, the pharmaceutical compounds and / or compositions of the disclosure are used to treat cardiac arrest in an individual. Petition 870260038724, dated 04 / 27 / 2026, p. 41 / 193 34 / 88

[0110] In other respects, the pharmaceutical compounds and / or compositions of the disclosure are used to treat myocardial infarction in an individual.

[0111] In other respects, the compounds and / or pharmaceutical compositions of the disclosure are used to treat heart failure in an individual.

[0112] In other respects, the compounds and / or pharmaceutical compositions of the disclosure are used to treat myocardial injury in an individual.

[0113] In other respects, the compounds and / or pharmaceutical compositions of the disclosure are used to treat cardiomyopathy in an individual.

[0114] In other respects, the pharmaceutical compounds and / or compositions of the disclosure are used to treat central core disease in an individual.

[0115] In other respects, the pharmaceutical compounds and / or compositions disclosed are used to treat amyotrophic lateral sclerosis in an individual.

[0116] In other respects, the pharmaceutical compounds and / or compositions disclosed are used to treat rhabdomyolysis in an individual.

[0117] In other respects, the pharmaceutical compounds and / or compositions of the disclosure are used to treat Duchenne muscular dystrophy in an individual.

[0118] In other respects, the pharmaceutical compounds and / or compositions disclosed are used to treat ataxia in an individual.

[0119] In other respects, the pharmaceutical compounds and / or compositions disclosed are used to treat detrusor overactivity in an individual. Petition 870260038724, dated 04 / 27 / 2026, page 42 / 193 35 / 88

[0120] In other respects, the pharmaceutical compounds and / or compositions disclosed are used to treat overactive bladder in an individual.

[0121] In other respects, the compounds and / or pharmaceutical compositions disclosed are used to treat seizures in an individual.

[0122] In other respects, the pharmaceutical compounds and / or compositions disclosed are used to treat epilepsy in an individual.

[0123] In other respects, the compounds and / or pharmaceutical compositions of the disclosure are used to treat neuroleptic malignant syndrome in an individual.

[0124] In other respects, the compounds and / or pharmaceutical compositions of the disclosure are used to treat human stress disorder in an individual.

[0125] In other respects, the compounds and / or pharmaceutical compositions disclosed are used to treat Alzheimer's disease in an individual.

[0126] In other respects, the pharmaceutical compounds and / or compositions disclosed are used to treat Huntington's disease in an individual.

[0127] In other respects, the compounds and / or pharmaceutical compositions of the disclosure are used to treat multiple sclerosis in an individual.

[0128] In other respects, the compounds and / or pharmaceutical compositions disclosed are used to treat Parkinson's disease in an individual.

[0129] In other respects, the pharmaceutical compounds and / or compositions of the disclosure are used to treat ischemia-reperfusion injury in an individual. Petition 870260038724, dated 04 / 27 / 2026, page 43 / 193 36 / 88

[0130] In other respects, the compounds and / or pharmaceutical compositions of the disclosure are used to treat neuronal reperfusion injury in an individual.

[0131] In other respects, the pharmaceutical compounds and / or compositions disclosed are used to treat hypoxia in an individual.

[0132] In other respects, the pharmaceutical compounds and / or compositions disclosed are used to treat cerebral aneurysm in an individual.

[0133] In other respects, the pharmaceutical compounds and / or compositions of the disclosure are used to treat subarachnoid hemorrhage in an individual.

[0134] In other respects, the pharmaceutical compounds and / or compositions disclosed are used to treat stroke in an individual.

[0135] In other aspects, the pharmaceutical compounds and / or compositions of the disclosure are used to treat hyperthermia associated with drug abuse (e.g., ecstasy (3,4-methylenedioxymethamphetamine) abuse) in an individual.

[0136] In other aspects, the pharmaceutical compounds and / or compositions of the disclosure are used to treat hyperthermia associated with drug overdose (e.g., ecstasy (3,4-methylenedioxymethamphetamine) overdose) in an individual.

[0137] In other respects, the compounds and / or pharmaceutical compositions of the disclosure are used to treat acetylcholine accumulation in an individual. In other respects, the compounds and / or pharmaceutical compositions of the disclosure are used to treat exposure to a neurotoxic agent, for example, exposure to neurotoxic gases (e.g., gases). Petition 870260038724, dated 04 / 27 / 2026, p. 44 / 193 37 / 88 organic phosphorus compounds such as sarin, soman, and VX) in an individual. See, for example, US Provisional Patent Application No. 62 / 554,049, filed September 5, 2017. As used herein, “neurotoxic agent” refers to compounds that affect the transmission of nerve impulses in the nervous system. Neurotoxic agents are organic phosphorus compounds, that is, they are of the formula (R)3P(O), in which each R group may be the same or different. “G” type neurotoxic agents include O-pinacolyl methylphosphonofluoride (soman, GD), N,N-dimethylphosphoramidocyanide (tabun, GA), propan-2-yl methylphosphonofluoride (sarin, GB), cyclohexyl methylphosphonofluoride (cyclosarin, GF), and 2-(dimethylamino)ethyl (GV).Type “V” neurotoxic agents include Ocyclopentyl S-(2-diethylaminoethyl)methylphosphonothiolate (EA-3148), ethyl phosphonates of (S)-(ethyl {[2-(diethylamino)ethyl]sulfonyls} such as (S)-(ethyl{[2-(diethylamino)ethyl]sulfanyl] ethyl phosphinate (VE), O,O-diethyl S-[2-(diethylamino)ethyl] phosphorothioate (VG), O-ethyl-methylphosphonothioate of S-[2-(diethylamino)ethyl] (VM), N,N-diethyl-2-(methyl-(2-methylpropoxy)phosphoryl)sulfanyl-ethanamine (VR), and ethyl ({2-[bis(propan-2-yl)amino]ethyl}sulfanyl)(methyl)phosphinate (VX). The methods described herein may be used to treat an individual exposed to a neurotoxic agent. The methods described here can also be used to treat an individual exposed to two or more neurotoxic agents.

[0138] When used here, the phrases “resulting from exposure to a neurotoxic agent” and “due to exposure to a neurotoxic agent” refer to effects that are a direct consequence of exposure to a neurotoxic agent, as well as to effects that are a secondary consequence of Petition 870260038724, dated 04 / 27 / 2026, p. 45 / 193 38 / 88 exposure to a neurotoxic agent.

[0139] In some aspects, the disclosure relates to methods for treating an individual exposed to a neurotoxic agent with a pharmaceutical composition comprising an amount of a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof. For example, in some aspects, the methods described prevent neurological damage secondary to exposure to a neurotoxic agent. In other aspects, the methods described provide neuroprotective effects after exposure to a neurotoxic agent. In other aspects, the methods described improve brain tissue damage secondary to exposure to a neurotoxic agent. In other aspects, the methods described improve brain tissue damage secondary to status epilepticus secondary to exposure to a neurotoxic agent. In other aspects, the methods described prevent neural necrosis due to exposure to a neurotoxic agent. In other aspects, the methods described improve neural necrosis due to exposure to a neurotoxic agent.In other aspects, the methods described treat intracellular calcium overload due to exposure to a neurotoxic agent. In other aspects, the methods described improve intracellular calcium overload due to exposure to a neurotoxic agent. In other aspects, the methods described prevent intracellular calcium overload due to exposure to a neurotoxic agent.

[0140] The individuals described herein may be exposed to a neurotoxic agent via inhalation. In other aspects, individuals are exposed to a neurotoxic agent via transdermal transmission of the agent. In still other aspects, individuals are exposed to a neurotoxic agent via consumption. Petition 870260038724, dated 04 / 27 / 2026, page 46 / 193 39 / 88 of a liquid or food contaminated with a neurotoxic agent. In other aspects, individuals are exposed to a neurotoxic agent via subcutaneous, intravenous, or intramuscular administration of the agent to the individual.

[0141] In some respects, the methods refer to methods for protecting an individual from neural necrosis after exposure to a neurotoxic agent. In these embodiments, a pharmaceutical composition comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof is administered to the individual after exposure to a neurotoxic agent. When used herein, the term neural necrosis protection encompasses reducing the severity of the effects of the neurotoxic agent or enhancing the effect of the neurotoxic agent or reducing neural damage resulting from exposure to the neurotoxic agent. In some respects, neural necrosis protection encompasses preventing neural necrosis in an individual who has been exposed to a neurotoxic agent.That is, individuals who are protected from neural necrosis by administration of the compounds and compositions described herein perform better on neurobehavioral tests when compared to individuals exposed to a neurotoxic agent who were not administered the compounds or compositions described.

[0142] In some incorporations, the entirety of the individual's central nervous system is protected against neural necrosis. In some incorporations, the frontoparietal cortex, hippocampus, and / or thalamus are protected against neural necrosis. In other aspects, the frontoparietal cortex will be protected against neural necrosis. In other aspects, the hippocampus is protected against neural necrosis. In other Petition 870260038724, dated 04 / 27 / 2026, page 47 / 193 40 / 88 incorporations, the thalamus is protected against neural necrosis.

[0143] The presence and extent of neural necrosis can be determined using methods known in the art, including neurobehavioral tests, radiological tests, and pathology assessment.

[0144] The disclosure also refers to methods for protecting an individual from a decrease in central nervous system function resulting from exposure to a neurotoxic agent. These methods comprise administering to the individual a pharmaceutical composition comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, after the individual has been exposed to a neurotoxic agent.

[0145] The disclosure also refers to methods for protecting an individual from central nervous system dysfunction resulting from exposure to a neurotoxic agent. These methods comprise administering to the individual a pharmaceutical composition comprising an amount of a compound of formula I described herein or of a pharmaceutically acceptable salt thereof, after the individual has been exposed to a neurotoxic agent.

[0146] The disclosure also refers to methods for treating behavioral changes in an individual resulting from exposure to a neurotoxic agent. These methods comprise administering to the individual a pharmaceutical composition comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, after the individual has been exposed to a neurotoxic agent.

[0147] When used here, protection from a decrease in central nervous system function includes decreasing the Petition 870260038724, dated 04 / 27 / 2026, page 48 / 193 41 / 88 severity of the central nervous system effects of the neurotoxic agent or improve the central nervous system effects of the neurotoxic agent or decrease the central nervous system effects of the neurotoxic agent. That is, individuals who are protected against a decrease in central nervous system function by administration of compositions containing compounds of formula I, perform better on neurobehavioral tests when compared with individuals exposed to a neurotoxic agent who were not administered the described compositions.

[0148] The disclosure also refers to methods for treating neurotoxic agent-induced seizures in an individual who has been exposed to a neurotoxic agent. In some respects, the seizures treated are status epilepticus (SE). These methods comprise administering to the individual a pharmaceutical composition comprising an amount of a compound of formula I or II or a pharmaceutically acceptable salt thereof. When used herein, the treatment of neurotoxic agent-induced seizures results in a reduction in the severity or duration of the seizures. In other respects, the treatment results in a reduction in both the severity and duration of the seizures.

[0149] The amount of compound of formula I or II or of a pharmaceutically acceptable salt thereof, which is effective in treating the individual according to any of the methods described, should be determined by a physician skilled in the art. The therapeutically effective amount may be the amount required to treat the individual in a single dose. Alternatively, the therapeutically effective amount may be the cumulative amount of dantrolene required. Petition 870260038724, dated 04 / 27 / 2026, page 49 / 193 42 / 88 to treat the individual during a chronic course of treatment.

[0150] In those embodiments in which the individual is a human being, the effective amount of the compound of formula I or II is an amount of compound equivalent to 1 mg / kg to 100 mg / kg of dantrolene, administered in one or more doses. In other aspects, the effective amount of the compound of formula I or II is an amount of compound equivalent to 1 mg / kg to about 90 mg / kg of dantrolene. In other aspects, the effective amount of the compound of formula I or II is an amount of compound equivalent to 1 mg / kg to about 80 mg / kg of dantrolene. In other aspects, the effective amount of the compound of formula I or II is an amount of compound equivalent to 1 mg / kg to about 70 mg / kg of dantrolene. In other aspects, the effective amount of the compound of formula I or II is an amount of compound equivalent to 1 mg / kg to about 60 mg / kg of dantrolene.In other respects, the effective amount of the compound of formula I or II is an amount of compound equivalent to about 50 mg / kg of dantrolene. In other respects, the effective amount of the compound of formula I or II is an amount of compound equivalent to about 40 mg / kg of dantrolene. In other respects, the effective amount of the compound of formula I or II is an amount of compound equivalent to about 30 mg / kg of dantrolene. In other respects, the effective amount of the compound of formula I or II is an amount of compound equivalent to about 20 mg / kg of dantrolene. In other respects, the effective amount of the compound of formula I or II is an amount of compound equivalent to about 5 mg / kg of dantrolene. Petition 870260038724, dated 04 / 27 / 2026, page 50 / 193 43 / 88 dantrolene. In other aspects, the effective amount of the compound of formula I or II is an amount of compound equivalent to about 10 mg / kg to about 30 mg / kg of dantrolene. In other aspects, the effective amount of the compound of formula I or II is an amount of compound equivalent to about 15 mg / kg to about 30 mg / kg of dantrolene. In other aspects, the effective amount of the compound of formula I or II is an amount of compound equivalent to about 20 mg / kg to about 30 mg / kg of dantrolene. In other aspects, the effective amount of the compound of formula I or II is an amount of compound equivalent to about 5 mg / kg to about 15 mg / kg of dantrolene. In other aspects, the effective amount of the compound of formula I or II is an amount of compound equivalent to about 5 mg / kg to about 10 mg / kg of dantrolene.In other respects, the effective amount of the compound of formula I or II is an amount of compound equivalent to about 10 mg / kg to about 20 mg / kg of dantrolene. In other respects, the effective amount of the compound of formula I or II is an amount of compound equivalent to about 2 mg / kg to about 10 mg / kg of dantrolene. In other respects, the effective amount of the compound of formula I or II is an amount of compound equivalent to about 2 mg / kg to about 6 mg / kg of dantrolene. In other respects, the effective amount of the compound of formula I or II is an amount of compound equivalent to about 15 mg / kg to about 20 mg / kg of dantrolene. In other respects, the effective amount of the compound of formula I or II is an amount of compound equivalent to about 10 mg / kg to about 100 mg / kg of dantrolene. Petition 870260038724, dated 04 / 27 / 2026, page 51 / 193 44 / 88 dantrolene. In other aspects, the effective amount of the compound of formula I or II is an amount of compound equivalent to about 20 mg / kg to about 100 mg / kg of dantrolene. In other aspects, the effective amount of the compound of formula I or II is an amount of compound equivalent to about 30 mg / kg to about 100 mg / kg of dantrolene. In other aspects, the effective amount of the compound of formula I or II is an amount of compound equivalent to about 40 mg / kg to about 100 mg / kg of dantrolene. In other aspects, the effective amount of the compound of formula I or II is an amount of compound equivalent to about 50 mg / kg to about 100 mg / kg of dantrolene. In other aspects, the effective amount of the compound of formula I or II is an amount of compound equivalent to about 50 mg / kg to 100 mg / kg of dantrolene. In other aspects, the effective amount of the compound of formula I or II is an amount of compound equivalent to 50 mg / kg to 100 mg / kg of dantrolene. In other aspects, the effective amount of the compound of formula I or II The effective amount of the compound of formula I or II is an amount of compound equivalent to 50 mg / kg to 75 mg / kg of dantrolene. In other respects, the effective amount of the compound of formula I or II is an amount of compound equivalent to 25 mg / kg to 75 mg / kg of dantrolene. In some respects, the effective amount of the compound of formula I or II is approximately equivalent to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, or approximately 34 mg / kg of dantrolene. In some respects, the effective amount of the compound of formula I or II to treat a human being is equivalent to approximately 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or approximately 100 mg / kg of dantrolene. In other respects, the effective amount of the compound of formula I or II is equivalent to approximately 1, 2, 3, 4, 5, 6, 7, 8, Petition 870260038724, dated 04 / 27 / 2026, page 52 / 193 45 / 88 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or about 100 mg / kg of dantrolene.

[0151] In some aspects of disclosure, the timing of Administration of the pharmaceutical composition comprising compound I or II or of a pharmaceutically acceptable salt thereof to an individual after exposure to a neurotoxic agent may affect the amount of protection against neural necrosis conferred to the individual.

[0152] In some aspects of disclosure, the timing of administration of the pharmaceutical composition comprising the compound of formula I or II or of a pharmaceutically acceptable salt thereof, to the individual, after exposure to a neurotoxic agent, may affect the amount of decrease in central nervous system function conferred on the individual.

[0153] In some aspects of disclosure, the timing of administration of the pharmaceutical composition comprising the compound of formula I or II or of a pharmaceutically acceptable salt thereof, to the individual, after exposure to a neurotoxic agent, may affect the treatment of neurotoxic agent-induced seizures in the individual.

[0154] With regard to the timing of administration of the pharmaceutical composition comprising compound of formula I or II or a pharmaceutically acceptable salt thereof, in some respects, the pharmaceutical composition comprising compound of formula I or II or a pharmaceutically acceptable salt of Petition 870260038724, dated 04 / 27 / 2026, p. 53 / 193 46 / 88, at least one dose is administered to the individual 24 hours or less after the individual has been exposed to the neurotoxic agent. In some aspects, the pharmaceutical composition comprising the compound of formula I or II or a pharmaceutically acceptable salt thereof, at least one dose is administered to the individual 20 hours or less after the individual has been exposed to the neurotoxic agent. In some aspects, the pharmaceutical composition comprising the compound of formula I or II or a pharmaceutically acceptable salt thereof, at least one dose is administered to the individual 16 hours or less after the individual has been exposed to the neurotoxic agent. In some aspects, the pharmaceutical composition comprising the compound of formula I or II or a pharmaceutically acceptable salt thereof, at least one dose is administered to the individual 12 hours or less after the individual has been exposed to the neurotoxic agent.In some aspects, the pharmaceutical composition comprising the compound of formula I or II or a pharmaceutically acceptable salt thereof, at least one dose is administered to the individual 8 hours or less after the individual has been exposed to the neurotoxic agent. In some aspects, the pharmaceutical composition comprising the compound of formula I or II or a pharmaceutically acceptable salt thereof, at least one dose is administered to the individual 4 hours or less after the individual has been exposed to the neurotoxic agent. In some aspects, the pharmaceutical composition comprising the compound of formula I or II or a pharmaceutically acceptable salt thereof, at least one dose is administered to the individual 2 hours or less after the individual has been exposed to the neurotoxic agent. In some aspects, the pharmaceutical composition comprising the compound of formula I or II or a salt. Petition 870260038724, dated 04 / 27 / 2026, page 54 / 193 47 / 88 pharmaceutically acceptable of the same, at least one dose is administered to the individual 1 hour or less after the individual has been exposed to the neurotoxic agent. In some aspects, the pharmaceutical composition comprising the compound of formula I or II or a pharmaceutically acceptable salt thereof, at least one dose is administered to the individual within approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or within approximately 24 hours after the individual has been exposed to the neurotoxic agent.

[0155] In some respects, the pharmaceutical composition comprising the compound of formula I or II, or a pharmaceutically acceptable salt thereof, may provide the effective amount of the compound of formula I or II in one dose. In other respects, two or more doses of the pharmaceutical composition may be required to provide the effective amount of the compound of formula I or II to the individual exposed to the neurotoxic agent. For example, 2, 3, 4, 5, 6, 7, 8, 9, or 10 doses of the pharmaceutical composition may be required to provide the effective amount of the compound of formula I or II to the individual exposed to the neurotoxic agent. These additional dosages may be administered concurrently with the first dose. In other respects, the additional dosages are temporally separated from the first dose. In those respects in which 3 or more doses are administered, each dose may be temporally separated from the administration of any other dose.Doses may be separated by an interval of 1 or more hours, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours apart. In other respects, doses may be separated by an interval of 1 or more days. Petition 870260038724, dated 04 / 27 / 2026, page 55 / 193 48 / 88

[0156] According to the disclosure, administration of compound formula I or II to an individual exposed to a neurotoxic agent is an adjunctive therapy for neurotoxic agent exposure. Individuals exposed to a neurotoxic agent may also receive one or more neurotoxic agent antidotes. One class of antidotes for neurotoxic agent exposure is that of acetylcholinesterase reactivators, for example, asoxime chloride (HI-6). Another class of antidotes for neurotoxic agent exposure is that of reverse acetylcholine receptor antagonists, for example, methylatropine nitrate. Individuals exposed to neurotoxic agents may also receive anticonvulsant medication.Exemplary anticonvulsant medications include aldehydes (e.g., paraldehyde), aromatic allylic alcohols (e.g., stiripentol), benzodiazepines (e.g., clobazam, clonazepam, clorazepate, diazepam, midazolam, lorazepam, nitrazepam, temazepam, nimetazepam), barbiturates (e.g., phenobarbital, methylphenobarbital, barbexaclone), bromides (e.g., potassium bromide), carbamates (e.g., felbamate), carboxamides (e.g., carbamazepine, oxcarbazepine, eslicarbazepine acetate), fatty acids (e.g., valproic acid, sodium valproate, divalproex sodium, vigabatrin, progabide, tiagabine), topiramate, GABA analogs (e.g., gabapentin, pregabalin), hydantoins (e.g., ethotoin, phenytoin, mephenytoin, fosphenytoin), oxazolidinediones (e.g., paramethadione, trimethadione, ethadione), propionates (e.g., beclamide), pyrimidinediones (e.g., primidone), pyrrolidines (e.g., brivaracetam, Petition 870260038724, dated 04 / 27 / 2026, p. 56 / 193 49 / 88 levitiracetam, seletracetam), succinimides (e.g., ethosuximide, phensuximide, messuximide), sulfonamides (e.g., acetazolamide, sultiame, methazolamide, zonisamide), triazines (e.g., lamotrigine), ureas (e.g., feneturide, phenacemide), valproylamides (e.g., valpromide, valnoctamide), perampanel, and combinations thereof. In some respects, the anticonvulsant drug is a benzodiazepine, e.g., midazolam. In other respects, the anticonvulsant drug is a barbiturate. In still other respects, the anticonvulsant drug is a hydantoin. In some respects, the anticonvulsant drug is paraldehyde. In other respects, the anticonvulsant drug is potassium bromide. In some respects, the anticonvulsant drug is a fatty acid. In other respects, the anticonvulsant drug is topiramate.

[0157] In those aspects in which the individual exposed to a neurotoxic agent receives an antidote, the compound of formula I or II is administered after the antidote has been administered. For example, the compound of formula I or II may be administered after the administration of the acetylcholinesterase reactivator and / or after the administration of the reverse acetylcholine receptor antagonist.

[0158] In those aspects in which the individual exposed to a neurotoxic agent receives an anticonvulsant medication, the compound of formula I or II may be administered simultaneously with the administration of the anticonvulsant medication. The compound of formula I or II may also be administered substantially simultaneously with the administration of the anticonvulsant medication, for example, approximately 5 minutes after the administration of the Petition 870260038724, dated 04 / 27 / 2026, p. 57 / 193 50 / 88 anticonvulsant medication. In other embodiments, the compound of formula I or II is administered before the administration of the anticonvulsant medication. In other embodiments, the compound of formula I or II is administered after the administration of the anticonvulsant medication.

[0159] The pharmaceutical composition comprising the compound of formula I or II or a pharmaceutically acceptable salt thereof may be administered intravenously. In other respects, the pharmaceutical composition comprising the compound of formula I or II or a pharmaceutically acceptable salt thereof may be administered transdermally. In other respects, the pharmaceutical composition comprising the compound of formula I or II or a pharmaceutically acceptable salt thereof may be administered intramuscularly. In other respects, the pharmaceutical composition comprising the compound of formula I or II or a pharmaceutically acceptable salt thereof may be administered intraosseously. In other respects, the pharmaceutical composition comprising the compound of formula I or II or a pharmaceutically acceptable salt thereof may be administered subcutaneously.

[0160] Preferred pharmaceutical compositions for use in the methods described include the compound of formula I or II or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. Preferred pharmaceutical compositions comprise the compound of formula I or II or a pharmaceutically acceptable salt thereof, mannitol, a polysorbate (e.g., polysorbate 80), a povidone (e.g., povidone K12), an optional pH adjuster (e.g., NaOH or HCl), and water.

[0161] According to the disclosure, the administration of a Petition 870260038724, dated 04 / 27 / 2026, page 58 / 193 51 / 88 compound and / or pharmaceutical composition disclosed herein will produce substantially equivalent AUC in the individual when compared with the administration of a dantrolene product listed in the reference list such as RYANODEX®. In other respects, the administration of a compound and / or pharmaceutical composition disclosed herein will produce substantially equivalent AUC in the individual when compared with that of a comparator composition. For example, in some respects, after administration to an individual, the 90% confidence intervals (CI) of the relative mean AUC(0-t) and AUC-0 of dantrolene from a disclosed pharmaceutical composition will be within the limits of 80% to 125% (e.g., 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, or 125%) of the relative mean AUC(0-t) and AUC(0-M), respectively, of dantrolene after administration of a dantrolene product listed in the reference list, for example, RYANODEX®.In some respects, after administration to an individual, the 90% confidence intervals (CI) of the relative mean AUC(0-t) and AUC-0 of dantrolene from a disclosed pharmaceutical composition will be within the limits of 80% to 125% (e.g., 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, or 125%) of the relative mean AUC^-t and AUC(0-0), respectively, of dantrolene after administration of a comparative product.

[0162] Examples are provided to illustrate some of the concepts described in this disclosure. Although each example is considered to provide specific individual embodiments of the disclosure, none of the Examples shall be considered limiting of the more general embodiments described herein. In the following examples, efforts have been made to ensure accuracy with respect to the numbers used (by Petition 870260038724, dated 04 / 27 / 2026, page 59 / 193 52 / 88 example, quantities, temperature, etc.), but some experimental error or deviation must be accounted for. Examples Example 1

[0163] Dantrolene sodium (1 eq.) was dissolved in anhydrous dimethylformamide. Reagent 3 (1 eq.) was added and the reaction mixture was stirred at 60°C in nitrogen. After 4 hours, another equivalent of reagent 3 was added and the reaction was stirred at 60°C overnight. Then, the reaction was diluted with ethyl acetate and washed twice with saturated sodium chloride. The layers were separated. The organic layers were dried over sodium sulfate and concentrated under vacuum. The crude product was purified using silica gel chromatography. The desired product was isolated with a purity of 90-95%. 1H NMR was consistent with that predicted for the desired product.

[0164] Example 1, Method A: 1a was dried overnight with P2O5. To a mixture of 1a (500 mg, 1.48 mmol) in DMF (10 mL) was added 3 (0.84 mL, 3.72 mmol) followed by NaI (245 mg, 1.63 mmol) at 0°C. The resulting mixture was stirred at room temperature for 64 hours. The mixture was diluted with EtOAc (30 mL) and brine (20 mL). The organic layer was separated, washed with water (2 x 15 mL), dried over anhydrous Na2SO4, filtered, and evaporated. The crude residue was purified by fast chromatography (twice), eluting with 0-10% MeOH / CH2Cl2 to provide the desired compound 4 (355 mg, Petition 870260038724, dated 04 / 27 / 2026, page 60 / 193 53 / 88 45%) as a yellow solid.

[0165] Example 1, Method B: 1a was dried with P2O5 overnight. To a mixture of 1a (8.0 g, 23.8 mmol) in DMF (160 mL) was added 3 (6.5 mL, 28.79 mmol) followed by NaI (4.28 g, 28.55 mmol) at room temperature. The resulting mixture was stirred at room temperature for 40 hours. The mixture was diluted with EtOAc (250 mL) and brine (60 mL). The organic layer was separated, washed with water (2 x 75 mL), dried over anhydrous Na2SO4, filtered, and evaporated. The residue was ground with CH2Cl2-hexanes to give a yellow solid (~7 g). This solid was separated by fast chromatography (twice, SiO2 deactivated), eluting with 0-10% MeOH / CH2Cl2 to provide the desired compound 4 (1.92 g, 15%) as a yellow solid. Example 2

[0166] A sample of compound 4 was treated with 1 mL of a 9 / 1 trifluoroacetic acid / water mixture for 20–30 min at room temperature. Excess TFA was immediately removed using high vacuum, and the resulting solid was collected by filtration, washed with water (5 mL), and air-dried. The starting material, reagent mixture, and final product were analyzed by LC / MS to determine if 2 reverts to dantrolene under deprotection conditions. No reversion of 2 to dantrolene was observed. 1H NMR of the product was consistent with that predicted for the desired product. Petition 870260038724, dated 04 / 27 / 2026, page 61 / 193 54 / 88

[0167] Example 2, Method A: A mixture of 4 (886 mg, 1.65 mmol) in CH2Cl2 (9 mL) TFA (9 mL) was added. The resulting mixture was stirred at room temperature for 3 hours. The solvent was evaporated in a rotary evaporator to dryness. The resulting residue was ground with hexanes for 1 hour and the yellow solid was filtered and dried to yield the desired compound 2 (660 mg, 94%). (complete dissolution) 3 mL of methanol was used to apply 1 g of Na+ ion exchange column. The compound was eluted with methanol and after lyophilization yielded 18 mg (36% recovery) of an orange solid. This material was dissolved in water and carefully titrated to pH 8.5 by adding small aliquots of 0.1 M NaOH with stirring. The solution was then lyophilized to produce the orange solid 2a. LC / MS of the sample before and after lyophilization were identical, indicating that no reversion to dantrolene occurred during ion exchange. 1H NMR of the product was consistent with that predicted for the desired product.

[0169] Example 3, Method A: To a stirred suspension of 2 (500 mg, 1.17 mmol) in water (63 mL, HPLC grade) 0.1N NaOH at room temperature was added in 650 μL aliquots immediately followed by rapid vortexing until a pH of 8.5 was reached. The solution was filtered, and the filtrate was lyophilized overnight to give the title compound 2a (530 mg, Petition 870260038724, dated 04 / 27 / 2026, p. 62 / 193 55 / 88 96%) as a yellow solid. MS (CI) m / z = 424.9 [M]+. 1H NMR (300 MHz, D2O): δ 8.08 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.59 (s, 1H), 6.98 (d, J = 3.6 Hz, 1H), 6.86 (d, J = 3.6 Hz, 1H), 5.19 (d, J = 6.0 Hz, 2H), 4.32 (s, 2H). Example 4. Conversion of 2a to dantrolene by alkaline phosphatase at 25°C Incubation with alkaline phosphatase

[0170] Prodrug 2a was incubated with purified alkaline phosphatase at 25°C. The final reagent mixture contained approximately 20 μg / mL of prodrug and 50 μU / μL of alkaline phosphatase (from calf intestine, Sigma #11097075001) in 1x PBS, pH 7.4. A control mixture containing 20 μg / mL of enzyme-free prodrug in 1x PBS, pH 7.4 was also prepared. The enzymatic reaction mixture was stored at 25°C and 10 μL aliquots were injected and analyzed by HPLC at 0.9 h, 3.2 h, 5.5 h, 7.7 h and 19.9 h. The control mixture was also stored at 25°C and 10 μL aliquots were injected and analyzed by HPLC at 1.5 h, 3.8 h, 6.6 h, 8.3 h and 20.4 h. Analysis of samples by HPLC

[0171] The analysis was performed using a Waters Alliance System 2695 equipped with a PDA detector and a Restek Ultra C18 column (5 μm, 250x4.6 mm) maintained at 25°C. Samples were analyzed using a gradient method with mobile phase A containing acetonitrile and mobile phase B containing acetonitrile / phosphate buffer at pH 6.9 at 33 / 67. The column was equilibrated from 100% mobile phase B and then held at this composition for 19 minutes. Then, mobile phase A was increased to 55% for 5 minutes. The column was washed with 55% A for 2 minutes, returned to 100% B for 2 minutes. Petition 870260038724, dated 04 / 27 / 2026, p. 63 / 193 The solution was incubated for 56 / 88 minutes, and then re-equilibrated with 100% B for 5 minutes for a total operating time of 33 minutes. 10 μL of sample was injected and the analytes were detected by UV at 375 nm. The prodrug eluted in approximately 3.1 minutes and dantrolene eluted in approximately 15.4 minutes. Changes in peak area were monitored over time to determine conversion of the prodrug to dantrolene. Peak area over time plots are shown in Figure 1 and Figure 2. Example 5. Conversion of 2a to dantrolene in rat plasma at 22°C. Plasma incubation

[0172] An in vitro experiment was performed by adding 40 μL of approximately 10 mg / mL of 2a in DMF to 360 μL of previously frozen rat plasma from male Sprague Dawley rats at 22°C. Unused plasma was stored at 22°C and 50 μL aliquots were withdrawn at 25 min, 3 h and 20 h post-disuse. The aliquots were immediately treated with 50 μL of acetonitrile and vortexed followed by centrifugation at 4000 rpm for 5 minutes at 25°C. 50 μL of supernatant was diluted 50 times in acetonitrile / phosphate buffer pH 6.9 to 33 / 67 and transferred to a glass vial for HPLC analysis. Analysis of samples by HPLC

[0173] The analysis was performed using a Waters Alliance System 2695 equipped with a PDA detector and a Restek Ultra C18 column (5 μm, 250x4.6 mm) maintained at 25°C. Samples were analyzed using a gradient method with mobile phase A containing acetonitrile and mobile phase B containing acetonitrile / phosphate buffer at pH 6.9 at 33 / 67. The column was Petition 870260038724, dated 04 / 27 / 2026, page 64 / 193 The column was equilibrated with 100% mobile phase B and then maintained at this composition for 19 minutes. Afterward, mobile phase A was increased to 55% for 5 minutes. The column was washed with 55% A for 2 minutes, returned to 100% B for 2 minutes, and then reequilibrated with 100% B for 5 minutes for a total operating time of 33 minutes. 10 μL of sample was injected and the analytes were detected by UV at 375 nm. The prodrug eluted in approximately 3.1 minutes and dantrolene eluted in approximately 15.4 minutes. Changes in peak area were monitored over time to determine conversion of the prodrug to dantrolene. See Figure 3. Example 6. Conversion of 2a to dantrolene in plasma at 37°C Plasma incubation

[0174] An in vitro experiment was performed by adding 60 μL of approximately 10 mg / mL of prodrug in DMF to 690 μL of previously frozen rat plasma from male Sprague Dawley rats at 37°C. Unused plasma was stored at 37°C and 50 μL aliquots were withdrawn at 5 min, 10 min, 20 min, 30 min, 40 min, 50 min, 60 min, 100 min, 2.5 h, 3.5 h, 4 h, 5 h, and 6.5 h post-disuse. Aliquots were immediately treated with 50 μL of acetonitrile and vortexed, followed by centrifugation at 4000 rpm for 5 minutes at 25°C. 50 μL of the supernatant was transferred to a glass vial for HPLC analysis. Analysis of samples by HPLC

[0175] The analysis was performed using a Waters Alliance System 2695 equipped with a PDA detector and a Restek Ultra C18 column (5 μm, 250x4.6 mm) maintained at 25°C. Samples were analyzed using a mobile phase gradient method. Petition 870260038724, dated 04 / 27 / 2026, page 65 / 193 58 / 88 Mobile phase A contained 0.1% trifluoroacetic acid in water, and mobile phase B contained 0.1% trifluoroacetic acid in acetonitrile at a flow rate of 1.0 mL / min. The column was equilibrated with 67% mobile phase A / 33% mobile phase B and then maintained at this composition for 19 minutes. Then, mobile phase B was increased to 70% for 5 minutes. The column was washed with 70% B for 2 minutes, returned to 33% B for 2 minutes, and then reequilibrated with 33% B for 15 minutes for a total operating time of 47 minutes. 5 μL of sample was injected, and the analytes were detected by UV at 375 nm. The prodrug eluted in approximately 6.5 minutes, and dantrolene eluted in approximately 18.5 minutes. Changes in peak area were monitored over time to determine conversion of the prodrug to dantrolene. The graph of prodrug peak area over time is shown in Figure 4. Example 7. Bioavailability of dantrolene after 2a administration to rats. Methods. [017 6] Compound 2a is formulated at 8 mg / mL in 5% aqueous mannitol (as a tonicity modifier) ​​at pH 8.0. The formulation is administered IV, SC, or IM to cannulated Harlan Sprague Dawley rats (3 rats / group) from Envigo RMS, Inc. (Indianapolis, IN). Each group receives 7.5 mg / kg of 2a, which is equal to 5 mg / kg of dantrolene equivalents (DE). Blood (0.1 mL) is collected via a jugular vein catheter at 0, 0.033 (IV only), 0.083, 0.167, 0.33, 0.66, 1, 3, 6, and 9 hours. Immediately after collection, 0.1 mL of whole blood is added to 0.3 mL of acetonitrile to quench the prodrug bioconversion reaction. The samples are then placed... Petition 870260038724, dated 04 / 27 / 2026, page 66 / 193 59 / 88 on moist ice until centrifugation to remove the precipitate. The precipitated whole blood matrix is ​​analyzed for 2α, dantrolene, and dantrolene metabolite 5-OH using a Phenomenex Synergi 4pm Polar RP 80 Å, 75x2mm column in a Waters Acquity UPLC system attached to an Applied Biosystems / MDS Sciex API 6500 LC / MS / MS system. Samples are quantified based on standardized curves prepared for each analyte in the precipitated whole blood matrix.

[0177] Similarly, plasma concentrations of dantrolene over time are measured after intravenous administration of RYANODEX® to rats at a dose of 5 mg / kg. Since RYANODEX® is dantrolene sodium 3,5-hydrate, this is equivalent to a dose of 3.9 mg / kg of dantrolene on a molar basis (i.e., 3.9 mg / kg of dantrolene equivalents (DE)).

[0178] The area under the curve (AUC) is calculated using the trapezoidal rule by the SigmaPlot 12.5 software. Results

[0179] Administration of 2a to rats via IV, IM and SC will result in rapid appearance of dantrolene in the blood. Example 8. Bioavailability of dantrolene after administration of diffusion compounds in rats. Methods.

[0180] The compounds for dissemination are formulated in 5% aqueous mannitol (as a tonicity modifier). The formulation is administered IV, SC, or IM to cannulated Harlan Sprague Dawley rats (3 rats / group) from Envigo RMS, Inc. (Indianapolis, IN). Each group receives an amount equivalent to 5 mg / kg of dantrolene equivalents (DE). Whole blood (0.1 mL) is collected via a jugular vein catheter at 0, 0.033 (IV only), 0.083, 0.167, 0.33, 0.66, Petition 870260038724, dated 04 / 27 / 2026, page 67 / 193 60 / 88 1, 3, 6, and 9 hours. Immediately after collection, 0.1 mL of whole blood is added to 0.3 mL of acetonitrile to quench the prodrug bioconversion reaction. Samples are then placed on moist ice until centrifugation to remove the precipitate. The precipitated whole blood matrix is ​​analyzed for the initial prodrug, dantrolene, and dantrolene 5-OH metabolite using a Phenomenex Synergi 4pm Polar RP 80 Å, 75x2 mm column in a Waters Acquity UPLC system attached to an Applied Biosystems / MDS Sciex API 6500 LC / MS / MS system. Samples are quantified based on standardized curves prepared for each analyte in the precipitated whole blood matrix.

[0181] Similarly, plasma concentrations of dantrolene over time are measured after intravenous administration of RYANODEX® to rats at a dose of 5 mg / kg. Since RYANODEX® is dantrolene sodium 3,5-hydrate, this is equivalent to a dose of 3.9 mg / kg of dantrolene on a molar basis (i.e., 3.9 mg / kg of dantrolene equivalents (DE)).

[0182] The area under the curve (AUC) is calculated using the trapezoidal rule by the SigmaPlot 12.5 software. Results

[0183] Administration of diffusion compounds in rats via IV, IM and SC routes will result in rapid appearance of dantrolene in the blood. Example 9 Study overview

[0184] The aim of the study is to determine whether a disclosure compound (e.g., compound 2a) has neuroprotective effects in a mammalian survival model, e.g., dogs, pigs, rabbits, rodents (e.g., rats, Petition 870260038724, dated 04 / 27 / 2026, page 68 / 193 61 / 88 mice, guinea pigs) and primates (e.g., monkeys, chimpanzees). An exemplary model is a survival model of GD (soman) and rats.

[0185] Single doses of the disclosure compound will be administered after the onset of seizures induced by neurotoxic agents. For example, single doses of the compound equivalent to 1 mg / kg to 30 mg / kg of dantrolene (e.g., 10 mg / kg or 30 mg / kg) are administered. The disclosure compound may be administered intravenously, subcutaneously, intramuscularly, transdermally, or intraosseously. For example, the dose may be administered intravenously.

[0186] Survival may be facilitated by treatment with an antidote to the neurotoxic agent. For example, asoxime chloride (HI-6) may be administered before exposure to the neurotoxic agent, for example, thirty minutes before subcutaneous (SQ) injection of soman, methylatropine nitrate one minute after SQ injection of soman, and midazolam twenty minutes after the onset of soman-induced seizures that reach a Racine score of at least 3.

[0187] The controls include a group of untreated animals and another group that will receive sterile water after the onset of seizures induced by a neurotoxic agent (e.g., 50 minutes after the onset of seizures induced by a neurotoxic agent).

[0188] A series of neurobehavioral tests are performed over a period of time, for example, approximately 28 days after exposure to a single dose of a neurotoxic agent. On the day after the test period (e.g., day 29), all animals are sacrificed under anesthesia, for example, by exsanguination and intracardiac perfusion. Collection Petition 870260038724, dated 04 / 27 / 2026, page 69 / 193 62 / 88 if the brain of each animal is collected for microscopic neuropathological examination, and if the heart of each animal is collected for possible pathological examination. Materials

[0189] Soman (GD) - diluted with sodium chloride to 0.9%. Soman is an organophosphorus neurotoxic agent that deactivates acetylcholine esterase (AChE) by forming an adduct with the enzyme. • Chemical name: Methyl pinacolyl phosphonofluoride • Formula: C7Hi6FO2P • Molecular weight: 182.17 • MRIGlobal Lot #: GD090415-DOC-1 • Primary standard ID: 13972-49-3 • Purity: 100% • Storage conditions: <4 °C

[0190] HI-6: Chemical name: [(E)—[l—[(4—carbamoyl-pyridin-1-io-l-yl)methoxymethyl] pyridin-2-ylidene] methyl]-oxoazanium methanesulfonate (asoxime chloride) Structure: OH NH. Formula: Ci4Hi6C12N4O3 Molecular weight: 359.207

[0191] Methyl atropine nitrate: Chemical name: (8,8-dimethyl-8-azoniabicyclo[3.2.1]octan-3-yl) 3-hydroxy-2phenylpropanoate nitrate Petition 870260038724, dated 04 / 27 / 2026, page 70 / 193 63 / 88 Structure: ^N+ Formula: Ci8H26N2O6 Molecular weight: 366.414

[0192] Midazolam: Chemical name: 8-chloro-6- (2-fluoro-phenyl)l-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine Structure: Formula: C18H13CIFN3 Molecular weight: 325.771 Doses

[0193] HI-6, soman, methyl atropine nitrate and midazolam: Single doses of HI-6 (IP, 125 mg / kg); soman (SC, 154 μg / kg, 1.4 x LD50), methyl atropine nitrate (IM, 2 mg / kg); and midazolam (IM, 2 mg / kg) may be selected. This regimen is expected to induce seizures that achieve a Racine score of at least 3 and an acceptable number of survivors for follow-up study.

[0194] Disclosure compounds: It can be administered Petition 870260038724, dated 04 / 27 / 2026, page 71 / 193 64 / 88 any compound disclosed or a pharmaceutically acceptable salt thereof described herein. A preferred compound is compound 2a. Dosage preparation

[0195] In those experiments using GD, GD is prepared in 0.9% sodium chloride cooled on ice according to SOP MRI-5821 Preparation of Standards and Samples from Research Development and Testing Evaluation (RDTE) Dilute Solutions. Racine Scale 1 = immobilization and fixed gaze 2 = head shaking, wet dog trembling 3 = forelimb clonus 4 = bilateral forelimb clonus 5 = Bilateral clonus of the forelimb, creation and loss of balance. Neurobehavioral tests

[0196] Brain areas damaged by soman exposure may include the hippocampus and the entorhinal, frontal, and parietal cortices. These areas contain neural structures and circuits for learning, memory formation, information processing, and other cognitive processes. To assess the potential neuroprotective effects of the disclosure compound, animals are evaluated using a series of behavioral tests that require learning, memory, sensorimotor integration, and adaptive responses. Examples of such tests include: (1) Sucrose preference test and (2) Forced swim test. Sucrose preference test Petition 870260038724, dated 04 / 27 / 2026, page 72 / 193 65 / 88

[0197] The sucrose preference test (SPT) utilizes the natural inclination of rats to prefer sugar water over plain water. It is an established test for measuring pleasure-seeking behavior (hedonia) or lack thereof (anhedonia) and requires animals to adapt to changes in the left-versus-right placement of bottles containing tap water and water with 1% sucrose.

[0198] Rats were housed individually with ad libitum access to food and water (a single water bottle in each cage) prior to the SPT. For the acclimation portion of the SPT, 2 water bottles were introduced into each rat's home cage for 5-6 days. The water bottles were fitted with clamp tubes to minimize leakage and were weighed approximately every 24 hours. After the acclimation phase, one water bottle was filled with approximately 200 mL of 1% aqueous sucrose solution and the other water bottle with approximately 200 mL of tap water. The left / right placement of the bottles was then switched and the amount of fluid remaining was again recorded twenty-four hours later. The amount (mL) of sucrose solution consumed was expressed as a percentage of the total volume of fluid consumed (sucrose water plus water) in each of the two 24-hour periods and compared between groups and days. Forced swimming test

[0199] The forced swim test (FST) was developed in the late 1970s by Porsolt as a quick way to track the effectiveness of antidepressant medications in rodents. The increased immobility that occurs at the end of the 5-minute FST in untreated (normal) rodents was Petition 870260038724, dated 04 / 27 / 2026, page 73 / 193 66 / 88 interpreted to reflect “behavioral despair,” and its reversal with antidepressant drugs correlated with the antidepressant efficacy of these agents in people. However, the validity of this test construct has been questioned for several reasons, including: (1) the acute effects of antidepressants are tested in the FST, whereas in clinically depressed patients, medication requires 4–6 weeks for clinical improvement; (2) the dependent variable in the FST is the animal’s acute response to the test and not an animal characteristic; and (3) the interpretation of fluctuating behavior as “behavioral despair” is anthropomorphic. It is now believed that the progressive immobility observed in untreated rats reflects an adaptive response to the acute stress of being placed in a container with no possibility of escape.

[0200] In the FST, swimming activity and immobility were measured in a cylindrical chamber (46 cm high x 30 cm in diameter) filled with water (30 cm high, 25°C). Thermometers were used to ensure that the water temperature was constant at 24-26°C for all animals. Two swimming sessions were conducted, one as an initial 15-minute “pre-test,” followed 24 hours later by a second 5-minute “test.” The test sessions were video-recorded. Time spent actively swimming and time spent immobile were scored for each minute of the FST. Neuropathology

[0201] The 7 brain sections of each animal were evaluated microscopically using a 6-point semi-quantitative scoring system. Microscopic lesions were classified on a 6-point scale: Petition 870260038724, dated 04 / 27 / 2026, page 74 / 193 67 / 88 0 = normal 1 = 1-5 cells affected per 40X microscopic field 2 = ​​6-20 cells affected per 40X microscopic field 3 = 21-50 cells affected per 40X microscopic field 4 = 50%-80% of cells affected by a 40X microscopic field 5 = >80% of cells affected by a 40X microscopic field. Example 10. Preparation of 2b

[0202] To a stirred suspension of 2 (100 mg, 0.23 mmol) in water (12 mL, HPLC grade) Tris (5.57 mg, 0.47 mmol) dissolved in water (5 mL) was added dropwise at room temperature. The pH of the final solution was 6.6. The solution was filtered and the filtrate was lyophilized overnight to give the title compound 2b (150 mg, 95%) as a yellow solid. MS (CI) m / z = 424.9 [M] + . 1H NMR (300 MHz, DMSOd6): δ 8.24 (m, 2H), 7.93 (m, 2H), 7.73 (m, 1H), 7.12 (m, 1H), 6.97 (m, 1H), 5.20 (m, 2H), 4.40 (m, 2H), 3.63 (m, 15 H). Example 11 Petition 870260038724, dated 04 / 27 / 2026, p. 75 / 193 68 / 88

[0203] Step 1: 1a was dried overnight with P2O5. Glacial acetic acid (340 μL, 5.95 mmol) at room temperature was added to a mixture of 1a (1.0 g, 2.97 mmol) in DMF (20 mL). The mixture was stirred overnight at room temperature. The mixture was poured over crushed ice, the solid was filtered and washed with water. The resulting wet solid was dried over anhydrous P2O5 to obtain the desired compound 7 (920 mg, 98%) as a yellow solid.

[0204] Step 2: Formalin (4.35 mL, 57.45 mmol, 37% formaldehyde in water) was added to a suspension of 7 (1.35 g, 4.29 mmol) in water (45 mL), followed by K2CO3 (51 mg, 0.37 mmol). The mixture was stirred at room temperature for 24 hours. The reactant mixture was filtered, and the yellow solid was washed with 3% aqueous formaldehyde and air-dried for 24 hours to give the desired compound 9 (1.2 g, 82%).

[0205] Step 3: To a solution of 9 (615 mg, 1.78 mmol) in DMF / acetone (45 mL, 15 / 25 mL) PCl3 (1.2 mL, 13.71 mmol) was slowly added at 0°C. The reactant mixture was stirred for 10 min at 0°C and for 2 hours at room temperature. Then, the mixture was poured over crushed ice and the resulting yellow solid was filtered, washed with water (3 x 50 mL) and dried under vacuum in P2O5 for 16 hours to give the desired compound 6 (600 mg, 92%). 1H NMR (300 MHz, DMSO-d6): δ 8.33 (d, J = 8.5 Hz, 2H), 8.03 (d, J = 8.8 Hz, 2H), 7.87 (s, 1H), 7.48 (d, J = 3.3 Hz, 1H), 7.11 (d, J = 3.6 Hz, 1H), Petition 870260038724, dated 04 / 27 / 2026, p. 76 / 193 69 / 88 5.42 (s, 2H), 4.53 (s, 2H). Example 12

[0206] Step 1: 1a was dried with P2O5 overnight. To a mixture of 1a (1.0 g, 2.97 mmol) in DMF (20 mL) glacial acetic acid (340 μL, 5.95 mmol) was added at room temperature. The mixture was stirred overnight at room temperature. The resulting solid was dried with ground ice, the mixture was poured over anhydrous P2O5 to obtain the desired compound 7 (920 mg, 98%) as a yellow solid.

[0207] Step 2: Formalin (0.29 mL, 3.83 mmol, 37% formaldehyde in water) was added to a suspension of 7 (90 mg, 0.28 mmol) followed by K2CO3 (3.4 mg, 0.02 mmol). The mixture was stirred at room temperature for 24 hours. The reactant mixture was filtered, and the yellow solid was washed with 3% aqueous formaldehyde and air-dried for 24 hours to give the desired compound 9 (86 mg, 88%). MS (CI) m / z = 343 [M]. 1H NMR (300 MHz, DMSO-d6): δ 8.32 (d, J = 9.0 Hz, 2H), 8.03 (d, J = 9.1 Hz, 2H), 7.83 (s, 1H), 7.47 (d, J = 3.6 Hz, 1H), 7.08 (d, J = 3.6 Hz, 1H), 6.52 (t, 1H), 4.85 (d, J = 7.1 Hz, 2H), 4.45 (s, 2H). Example 13 Petition 870260038724, dated 04 / 27 / 2026, p. 77 / 193 70 / 88 Stage 2

[0208] Step 1: Anhydrous DMF (0.8 mL, 10.33 mmol) was dissolved in tetrahydrofuran (13 mL). This solution was added dropwise to a stirred solution of thionyl chloride (0.75 mL, 10.33 mmol) dissolved in tetrahydrofuran and cooled in an ice bath. After complete addition and 30 minutes in ice, the ice bath was removed and N-hydroxysuccinimide (832 mg, 7.23 mmol) was added (which dissolved completely) followed immediately by the addition of solid pre-pulverized morpholine acetic acid (1.0 g, 6.88 mmol). The morpholine acetic acid dissolved slowly to a homogeneous solution that quickly became cloudy. The reaction was left under vigorous stirring overnight at room temperature. The white solid was washed with tetrahydrofuran and vacuum dried to yield the desired compound 11 (1.6 g, 96%) as a white solid.

[0209] Step 2: To a solution of 9 (660 mg, 1.92 mmol) and 11 Petition 870260038724, dated 04 / 27 / 2026, page 78 / 193 71 / 88 (928 mg, 3.83 mmol) in anhydrous DMF (12 mL) was added to triethylamine (0.39 mL, 2.8 mmol). The resulting mixture was stirred overnight at 60°C. The reactant mixture was cooled to room temperature and purified by reversed-phase column chromatography, and the fractions containing the product were lyophilized to give the crude compound with 50% purity. This crude product was further purified by preparative HPLC using acetonitrile-water. Lyophilization of pure fractions gave the titer 10 compound (100 mg, 10%) as a yellow solid.

[0210] Step 3: To a stirred solution of 10 (75 mg, 0.16 mmol) in anhydrous 1,4-dioxane (4 mL) was added HCl (0.3 mL, 4N in 1,4-dioxane) at room temperature and the resulting mixture was stirred for 2 hours. The solvents were evaporated in a rotary evaporator to dryness. The resulting residue was dissolved in water and lyophilized overnight to yield 10c (75 mg, 94%).

[0211] MS (CI) m / z = 472.1 [M]+. NMR of 1H (300 MHz, DMSOd6): δ 8.33 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 9.1 Hz, 2H), 7.89 (s, 1H), 7.49 (d, J = 3.6 Hz, 7, =1H), 1H), 5.60 (s, 2H), 4.54 (s, 2H), 3.32–3.81 (m, 10H). NMR de1H (300 MHz, D2O): δ 8.17 (d, J = 8.5 Hz, 2H), 7.81 (d, J = 8.8 Hz, 2H), 7.60 (s, 1H), 6.93-7.02 (m, 1H, 79.88 (s)m 2H), 4.39 (s, 2H), 4.26 (s, 2H), 3.90–4.09 (m, 4H), 3.30–3.52 (m, 4H). Example 14 O ,ν\^Λ\ -O \ V / Οχ ^\\ n Petition 870260038724, dated 4 / 27 / 2026, p. 79 / 193 72 / 88 cr horse2ci Stage-1 Stage-3 Stage-4 12a

[0212] Step 1: A mixture of K2CO3(4.0 g, 28.94 mmol) and TBAHSO4 (240 mg, 0.70 mmol) in water (8 mL) was added to 13 (2.0 g, 11.48 mmol) in CH2Cl2 (8 mL) at 0°C. The resulting mixture was stirred for 20 minutes at 0°C before adding 14 (1.3 mL, 12.85 mmol) and stirring again for 3 hours. The organic layer was separated and washed with water (2 x 5 mL) and saturated aqueous brine (5 mL). The CH2Cl2 layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by fast chromatography eluting with 0-100% EtOAc / hexanes to give the desired compound 15 (2.2 g, 86%) as a colorless gum.

[0213] Step 2: 1a was dried overnight with P2O5. To a mixture of 15 (2.2 g, 987 mmol) in DMF (35 mL) 1a (1.66 g, 4.93 mmol) at room temperature was added. The resulting mixture was stirred at room temperature for 20 hours. The mixture was diluted with EtOAc (50 mL) and washed with water (2 x 25 mL) and saturated aqueous brine (15 mL). The EtOAc layer was dried over anhydrous Na2SO4, filtered, and evaporated under vacuum. The crude residue was purified by fast chromatography eluting with 0-100% EtOAc / CH2Cl2 (twice) followed by trituration with CH2Cl2-hexanes to give the desired compound 16 (500 mg, 20%) as a yellow solid. Petition 870260038724, dated 04 / 27 / 2026, page 80 / 193 73 / 88

[0214] Step 3: To a mixture of 16 (340 mg, 0.68 mmol) in CH2Cl2 (18 mL) TFA (1.8 mL) was added. The resulting mixture was stirred overnight at room temperature. The solvents were evaporated in a rotary evaporator to dryness. The resulting residue was ground with hexanes for 1 hour and the yellow solid was filtered and dried to yield the desired compound 12 (300 mg, 99%).

[0215] Step 4: To a stirred suspension of 6 (260 mg, 0.58 mmol) in water (36 mL, HPLC grade) was added 0.1N NaOH (5.85 mL, 0.58 mmol) at room temperature in 400 μL aliquots followed immediately by rapid vortexing. The pH of the final solution was 6.73. The solution was filtered, and the filtrate was lyophilized overnight to give the title compound 12a (150 mg, 55%) as a yellow solid. MS (CI) m / z = 445.1 [M] + . 1H NMR (300 MHz, DMSO-d6): δ 8.34 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.8 Hz, 2H), 7.87 (s, 1H), 7.49 (d, J = 3.6 Hz, 1H), 7.11 (d, J = 3.8 Hz, 1H), 5.43 (s, 2H), 4.51 (s, 2H), 2.40 (m, 2H), 2.15 (m, 2H). Petition 870260038724, dated 04 / 27 / 2026, p. 81 / 193 74 / 88 Stage 2

[0216] Step 1: To a solution of compound 9 (500 mg, 1.45 mmol) in anhydrous DMF (10 mL) was added compound 18 (488 mg, 1.85 mmol) in DMF (2 mL) followed by TEA (0.3 mL, 2.2 mmol). The resulting mixture was stirred for 16 hours at room temperature. The mixture was diluted with EtOAc (50 mL) and washed with water (2 x 15 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude product was purified twice by fast chromatography eluting with 0-10% MeOH / CH2Cl2 to obtain the desired compound 19 (350 g, 40%) as a yellow solid.

[0217] Step 2: To a solution of compound 19 (200 mg, 0.32 mmol) in MeOH / 1,4-dioxane (1 / 1.6 mL) was added p-toluenesulfonic acid monohydrate (63 mg, 0.32 mmol). The clear solution was stirred for 16 hours at room temperature. The solvents were evaporated in a rotary evaporator to dryness. The residue was purified by Petition 870260038724, dated 04 / 27 / 2026, page 82 / 193 75 / 88 rapid chromatography eluting with 0-10% MeOH / CH2Cl2 to obtain the desired compound 20 (125 g, 77%) as a yellow solid.

[0218] Step 3: To a solution of compound 20 (120 mg, 0.24 mmol) and compound 21 (26.4 mg, 0.26 mmol) in m-xylene / 1,4-dioxane (1 / 1.16 mL) was added p-toluenesulfonic acid monohydrate (15 mg, 0.07 mmol) and 4 Å molecular sieves (100 mg). The resulting mixture was refluxed for 16 hours. The reagent mixture was cooled to room temperature, diluted with 1,4-dioxane (30 mL) and filtered. The filtrate was evaporated and the crude residue was purified twice by fast chromatography eluting with 0-10% MeOH / CH2Cl2 to give the desired compound 17 (16 mg, 11%) as a yellow solid.

[0219] Step 4: To a stirred suspension of 17 (5 mg, 8.4 μmol) in water (3 mL, HPLC grade) 0.1N Tris (90 μL, 8.9 μmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 3 hours. The solution was filtered and the filtrate was lyophilized overnight to give the title compound 17b (6 mg, 100%) as a yellow solid. MS (CI) m / z = 594.1 [M]+. 1H NMR (300 MHz, DMSO-dg): δ 9.96 (brs, 1H), 8.34 (d, J = 8.8 Hz,2H), 8.05 (d, J = 8.5 Hz, 2H), 7.89 (s, 1H), 7.5 (d, J = 3.2 Hz, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 3.5 Hz, 1H), 5.57 (s, 2H), 4.99 (s, 2H), 4.55 (s, 2H), 3.23-3.32 (m, 9H), 2.33-2.36 (m, 4H). Example 16 Petition 870260038724, dated 04 / 27 / 2026, p. 83 / 193 76 / 88 HO HN-Boc Stage 1

[0220] Step 1: To a mixture of 23 (2.5 g, 14.28 mmol) in DMF (30 mL) was added to triethylamine (3.4 mL, 24.93 mmol) followed by 24 (3.92 mL, 53.9 mmol) at room temperature. The resulting mixture was stirred at room temperature for hours. The mixture was diluted with EtOAc (100 mL) and water (50 mL). The EtOAc layer was washed with water (2 x 25 mL), 5% NaHCO3 (25 mL), and saturated aqueous brine (15 mL). The EtOAc layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude residue was purified by fast chromatography eluting with 0-100% EtOAc / hexanes to give the desired compound 25 (657 mg, 21%) as a colorless oil.

[0221] Step 2: 1a was dried with P2O5 overnight. To a mixture of 1a (647 mg, 1.92 mmol) in DMF (12 mL) 25 (647 mg, 2.89 mmol) at room temperature was added. The resulting mixture was stirred at room temperature for 110 hours. The mixture was diluted with EtOAc (40 mL) and washed. Petition 870260038724, dated 04 / 27 / 2026, page 84 / 193 77 / 88 with water (2 x 15 mL) and saturated aqueous brine (15 mL). The EtOAc layer was dried with anhydrous Na2SO4, filtered, and evaporated under vacuum. The crude residue was purified by fast chromatography eluting with 0-100% EtOAc / CH2Cl2 to give the desired compound 26 (260 mg, 27%) as a yellow solid.

[0222] Step 3: To a stirred solution of 26 (210 mg, 0.41 mmol) in anhydrous 1,4-dioxane (4 mL) was added HCl (4 mL, 4N in 1,4-dioxane) at room temperature, and the resulting mixture was stirred overnight. The solvents were evaporated in a rotary evaporator to dryness. The resulting residue was ground with hexanes for 1 hour and the yellow solid was filtered and dried to yield the compound with title 22c (153 mg, 83%). MS (CI) m / z = 402.1 [M] + . 1H NMR (300 MHz, DMSO-de): δ 8.47 (brs, 3H), 8.34 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.8 Hz, 2H), 7.91 (s, 1H), 7.50 (d, J = 3.6 Hz, 1H), 7.12 (d, J = 3.6 Hz, 1H), 5.61 (s, 2H), 4.56 (s, 2H), 3.85 (s, 2H). Example 17. General UPLC methods and materials

[0223] LC-MS analysis was performed using an Agilent Infinity 1290 ultra-high-performance liquid chromatography system equipped with an Agilent Zorbax Eclipse Plus C18 column (2.1 x 50 mm, 1.8 μm). Elution was monitored at 210 nm and 385 nm using a diode array detector. Mobile phase A was water with 0.1% (v / v) trifluoroacetic acid and mobile phase B was acetonitrile with 0.1% trifluoroacetic acid. For each sample, 10 UL were injected and elution was performed using a linear gradient that started at 25% B and increased to 43% B over 4 minutes at a flow rate of 0.5 mL / min. The liquid chromatography system was Petition 870260038724, dated 04 / 27 / 2026, p. 85 / 193 78 / 88 coupled to an Agilent 6420 mass spectrometer. Standardized HPEC curves for concentration measurement

[0224] Approximately 1 mg of the compound of interest was weighed using 25% acetonitrile (in water, v / v). A 10-fold dilution was prepared using 25% acetonitrile of the prodrug to provide a solution with a concentration of 100 μg / mL. A series of 2-fold dilutions were performed using 25% acetonitrile to obtain solutions with concentrations of 50, 25, 12.5, and 6.26 μg / mL. For each sample, 10 μE was analyzed using the equipment and gradients described in the General Methods and Materials section of UPLC. The standard curve for concentration was generated by manually integrating the 385 nm chromatograms and plotting the peak area as a function of concentration. Pharmacokinetic analysis

[0225] At each time point, 400 μE of blood was collected in a K2EDTA tube and then placed on ice before centrifugation. After centrifugation, 100 μE of plasma was combined with 300 μE of acetonitrile before centrifugation to remove precipitated material. Samples were analyzed using the gradient described in the General Methods and Materials section of UPEC. For each experiment, a dantrolene standard curve was created by dissolving 3.8 mg of DANTRIUM in 14.9 mE of 50% (v / v) methanol in water. The DANTRIUM was diluted in the precipitated rat blood / acetonitrile supernatant at a 1 / 3 ratio to generate samples for the standard curve. The standard curve ranged from 5000 to 5 ng / mE. Dantrolene was monitored by absorbance at 385 nm using the diode array detector and the mass spectrometer's multiple reaction monitoring functionality. Petition 870260038724, dated 04 / 27 / 2026, page 86 / 193 79 / 88 Reconversion of Compound 2a in Plasma and Pharmacokinetics

[0226] To measure the conversion of Compound 2a to dantrolene in rat plasma, 1 mg of Compound 2a was dissolved to a concentration of 1 mg / mL in water. A 100 μL aliquot of Compound 2a was combined with 900 μL of plasma taken from Sprague Dawley rats. The plasma reaction was then placed in a water bath at 37°C. The initial concentration of Compound 2a in the plasma was 100 μg / mL. An initial sample was prepared by immediately removing 100 μL from the plasma reaction, which was mixed with 100 μL of acetonitrile to quench the reaction, causing precipitation. The insoluble material was pelletized by centrifugation at 15000 rpm for 5 minutes at 25°C. LC-MS analysis was performed by injecting 10 μL, and samples were eluted using the equipment and gradient described in the General Methods and Materials section of UPLC. Additional samples were prepared after 10, 30, 45, 60, 120, 180, and 240 minutes.The loss of test compound and increase in dantrolene were quantified by manual integration of peaks in 385 nm chromatograms (Figure 5). The half-life of Compound 2a under these conditions was obtained by fitting an exponential function to the data. The half-life of Compound 2a was 82 minutes. A negative control was also performed using phosphate-buffered brine instead of rat plasma, and no conversion was observed.

[0227] The plasma pharmacokinetics of dantrolene after administration of Compound 2a in live rats was analyzed by assays in Sprague-Dawley rats with cannulated veins, and by analyzing the plasma for dantrolene using LC-MS (Figure 6 and Table 1). Assay, sample collection, and analysis were Petition 870260038724, dated 04 / 27 / 2026, page 87 / 193 80 / 88 performed by MPI research. Intravenous doses were administered via jugular vein cannula. Intramuscular doses were administered by injecting half the dose into the large muscle mass of the left hind limb and the other half into the right hind limb. There were five rats in each test group. Compound 2a was dissolved to 8 mg / mL in sterile filtered aqueous 5% mannitol (weight / volume) to provide a dose level of 7.5 mg / kg and a dose volume of 0.94 mL / kg. Plasma was collected before administration and at 0.033, 0.083, 0.167, 0.33, 0.66, 1, 2, 3, 6, and 9 hours after administration.

[0228] In each experiment, only traces of 2a were observed after administration of the compound via IV, IM, or SC. Consequently, only the dantrolene concentration was monitored for pharmacokinetic measurement. Table 1. Bioavailability of dantrolene after administration of compound 2a, intravenously and intramuscularly. Route of administration AUC (ng*h / mL) AUC ^g*h / mL) % bioavailability IV 52148 5.2148 100 IM 40565 4.0565 77.8

[0229] In a second analysis, whole blood pharmacokinetics of Compound 2a were performed in live rats (Figure 7 and Table 2). Each test group included three rats. Compound 2a was dissolved to 8 mg / mL in sterile filtered aqueous 5% mannitol (weight / volume) to provide a dose level of 7.5 mg / kg and a dose volume of 0.94 mL / kg. Plasma was collected before administration and at 0.033, 0.083, 0.167, 0.33, 0.66, 1, 2, 3, 6, and 9 hours after administration. Whole blood samples were diluted 4-fold in acetonitrile and centrifuged to remove precipitate. Petition 870260038724, dated 04 / 27 / 2026, page 88 / 193 81 / 88 Table 2. Whole blood bioavailability of dantrolene after intravenous and intramuscular administration of compound 2a. Route of administration AUC (ng*h / mL) AUC ^g*h / mL) % bioavailability IV 47528 4.7528 100 IM 45297 4.5297 95.3

[0230] Another pharmacokinetic analysis of compound 2a was performed in live rats (Figures 8 and 9, and Table 3). Each test group had five rats. Compound 2a was dissolved to 8 mg / mL in sterile filtered aqueous 5% mannitol (weight / volume) to provide a dose level of 7.5 mg / kg and a dose volume of 0.94 mL / kg. Blood was collected before administration and at 0.033, 0.083, 0.167, 0.33, 0.66, 1, 2, 3, 6, and 9 hours after administration. Blood samples were diluted 4 times in acetonitrile and centrifuged to remove precipitate. Plasma samples were obtained by placing blood in K2EDTA tubes and then centrifuging. The resulting plasma was then aspirated and diluted 4 times in acetonitrile before another round of centrifugation to remove the precipitated material. Table 3. Bioavailability of dantrolene after administration of compound 2a via intravenous, intramuscular, and subcutaneous routes. Route of administration AUC (ng*h / mL) AUC ^g*h / mL) % bioavailability IVa 41906 4.1906 100 IMa 33861 3.3861 80.8 SCa 26388 2.6388 64.0 IVb 40298 4.0298 100 IMb 22857 2.2857 56.7 SCb 20019 2.0019 49.7 aWhole blood analysis. bPlasma analysis. Reconversion of compound 2b in plasma and pharmacokinetics Petition 870260038724, dated 04 / 27 / 2026, page 89 / 193 82 / 88

[0231] To measure the conversion of compound 2B to dantrolene in rat plasma, 1 mg of compound 2B was dissolved to 1 mg / mL in water. A 100 μL aliquot of compound 2B was combined with 900 μL of plasma taken from Sprague Dawley rats. The plasma reaction was then placed in a water bath at 37°C. The initial concentration of compound 2B in the plasma was 100 μL. An initial sample was prepared by immediately removing 100 μL from the plasma reaction and mixing it with 100 μL of acetonitrile to quench the reaction, which caused precipitation. The insoluble material was pelletized by centrifugation at 15000 rpm for 5 minutes at 25°C. A sample for LC-MS analysis was prepared by combining 75 μL of the supernatant with 75 μL of water. LC-MS analysis was performed by injecting 10 μL, and the samples were eluted using the equipment and gradients described in the General Methods and Materials section of ULPC. Additional samples were prepared after 15, 30, 45, 60, 120, 180, and 240 minutes.The loss of compound 2 and the increase in dantrolene were quantified by manual integration of peaks in the 385 nm chromatograms (Figure 10). The half-life of compound 2b under these conditions was obtained by fitting an exponential function to the data. The half-life of compound 2b was 77 minutes. A negative control using phosphate-buffered brine instead of rat plasma was also performed, and no conversion was observed.

[0232] The pharmacokinetics of dantrolene after administration of compound 2b to live rats was also tested by dosing intravenously cannulated Sprague-Dawley rats and analyzing the blood for dantrolene using LC-MS (Figure 11 and Table 4). Dosing, sample collection, and analysis were performed by Petition 870260038724, dated 04 / 27 / 2026, pp. 90 / 193 83 / 88 MPI research. Intravenous doses were administered via jugular vein cannula. Intramuscular doses were administered by injecting half the dose into the large muscle mass of the left hind limb and the other half into the right hind limb. There were five rats in each test group. Compound 2B was dissolved to 11.4 mg / mL in sterile filtered aqueous 5% mannitol (weight / volume) to provide a dose level of 10.6 mg / kg and a dose volume of 0.94 mL / kg. Plasma was collected before administration and at 0.033, 0.083, 0.167, 0.33, 0.66, 1, 2, 3, 6, and 9 days after administration. Table 4. Plasma bioavailability of dantrolene after intravenous and intramuscular administration of compound 2b. Route of administration AUC (ng*h / mL) AUC ^g*h / mL) % bioavailability IV 55748 5.5749 100 IM 41947 4.1947 75.2 Example 18. Reconversion of compound 10c into plasma

[0233] To measure the conversion of 10c to dantrolene in rat plasma, 0.9 mg of 10c was dissolved to 1 mg / mL in water. A 100 μL aliquot of 10c was combined with plasma taken from Sprague Dawley rats. The plasma reaction was then placed in a water bath at 37°C. The initial concentration of 10c in the plasma was 100 μL / mL. An initial sample was prepared by immediately removing 100 μL from the plasma reaction and mixing it with 100 μL of acetonitrile to quench the reaction, which caused precipitation. The insoluble material was pelletized by centrifugation at 15000 rpm for 5 minutes at 25°C. A sample was prepared for LC-MS analysis by combining 75 μL of the supernatant with 75 μL of water. The analysis Petition 870260038724, dated 04 / 27 / 2026, pp. 91 / 193 84 / 88 LC-MS was performed by injecting 10 μE, and samples were eluted using the equipment and gradient described in the General Methods and Materials section of UPLC. Additional samples were prepared after 10, 20, 35, 45, and 60 minutes. The loss of 10c and the increase in dantrolene were quantified by manual integration of peaks on the 385 nm chromatograms. The half-life of 10c under these conditions was obtained by fitting an exponential function to the data. In the first 10 minutes of incubation with plasma, 10c was completely converted to dantrolene. The half-life was estimated to be 1.9 minutes. A negative control was also performed where phosphate-buffered brine was used instead of rat plasma, and low conversion to dantrolene was observed. The half-life of 10°C in phosphate-buffered brine was 294 minutes. See Figure 12. Example 19. Plasma conversion of compound 12a and pharmacokinetics

[0234] To measure the conversion of 12a to dantrolene in rat plasma, a 1 mg / mL solution of 12a in water was prepared. A 100 μE aliquot of 12a was combined with plasma taken from Sprague Dawley rats. The plasma reaction was then placed in a water bath at 37°C. The initial concentration of 12a in the plasma was 100 μg / mL. An initial sample was prepared by immediately removing 100 μE from the plasma reaction and mixing it with 100 μE of acetonitrile to quench the reaction, which caused precipitation. The insoluble material was pelletized by centrifugation at 15000 rpm for 5 minutes at 25°C. A sample was prepared for LC-MS analysis by combining 75 μE of the supernatant with 75 μE of water. EC-MS analysis was performed by injecting 10 μE, and the samples were... Petition 870260038724, dated 04 / 27 / 2026, pp. 92 / 193 85 / 88 eluted using the equipment and gradient described in the General Methods and Materials Section of UPLC. Additional samples were prepared after 10, 20, 35, 45, 60, 75, and 150 minutes. The loss of 12α and the increase in dantrolene were quantified by manual integration of peaks on 385 nm chromatograms (Figure 13). The half-life of 12α under these conditions was obtained by fitting an exponential function to the data. The calculated half-life was 12.2 minutes. A negative control using phosphate-buffered brine instead of rat plasma was also performed, and the half-life was greater than 150 minutes.

[0235] The pharmacokinetic properties of 12a were analyzed in the same manner as for 22c, except that the compound was dissolved to 5 mg / mL in 5% mannitol to provide a dose level of 4 mg / kg and a dose volume of 0.8 mL / kg (Figure 14). Example 20. Plasma conversion of compound 17b

[0236] To generate a standard curve to calculate the concentration of 17b, we dissolved 1 mg of compound in 200 μL of dimethylformamide to obtain a solution with a concentration of 5 mg / mL. The 5 mg / mL solution was diluted 5 times in water and then centrifuged at 15000 rpm for 5 minutes at 25°C. The supernatant was used to make a 10-fold dilution in 25% acetonitrile water to provide a solution with a concentration of 100 μg / mL. A series of 2-fold dilutions were performed using 25% acetonitrile to obtain solutions with concentrations of 50, 25, 12.5, and 6.25 μg / mL. These solutions were analyzed as described in the General Methods and Materials Section of UPLC, except that the gradient was extended to terminate in 90% acetonitrile after 14.4 minutes. Petition 870260038724, dated 04 / 27 / 2026, pp. 93 / 193 86 / 88

[0237] To measure the conversion of 17b to dantrolene in rat plasma, a 1 mg / mL solution of 17b in water was prepared. A 100 μL aliquot of 17b was combined with plasma taken from Sprague Dawley rats. The plasma reaction was then placed in a water bath at 37°C. The initial concentration of 17b in the plasma was 100 μg / mL. An initial sample was prepared by immediately removing 100 μL from the plasma reaction and mixing it with 100 μL of acetonitrile to quench the reaction, which caused precipitation. The insoluble material was pelletized by centrifugation at 15000 rpm for 5 minutes at 25°C. A sample for LC-MS analysis was prepared by combining 75 μL of the supernatant with 75 μL of water. LC-MS analysis was performed by injecting 10 μL, and samples were eluted using the equipment described in the General Methods and Materials section of UPLC and the extended method described in the previous paragraph. Additional samples were prepared after 15, 30, 45, 60, 180, 240, and 300 minutes.The loss of 17b and increase in dantrolene were quantified by manual integration of peaks in 385 nm chromatograms (Figure 15). The half-life of 17b under these conditions was obtained by fitting an exponential function to the data. The calculated half-life was 94.5 minutes. A negative control using phosphate-buffered brine instead of rat plasma was also performed, and the estimated half-life was 447 minutes. Example 21. Plasma conversion of compound 22c and pharmacokinetics

[0238] To measure the conversion of 22c to dantrolene in rat plasma, a 1 mg / mL solution of 22c in water was prepared. A 100 μL aliquot of 22c was combined with 900 μL of plasma taken from Sprague Dawley rats. The plasma reaction was Petition 870260038724, dated 04 / 27 / 2026, pp. 94 / 193 87 / 88 was then placed in a water bath at 37°C. The initial concentration of 22C in the plasma was 100 μg / mL. An initial sample was prepared by immediately removing 100 μL from the plasma reaction and mixing it with 100 μL of acetonitrile to quench the reaction, which caused precipitation. The insoluble material was pelletized by centrifugation at 15000 rpm for 5 minutes at 25°C. A sample for LC-MS analysis was prepared by combining 7.5 μL of the supernatant with 7.5 μL of water. LC-MS analysis was performed by injecting 10 μL, and the samples were eluted using the equipment and gradient described in the General Methods and Materials Section of UPLC. Additional samples were prepared after 10, 20, 35, 45, 60, 75, and 150 minutes. The loss of 22c and the increase in dantrolene were quantified by manual integration of peaks in 385 nm chromatograms (Figure 16). The half-life of 22c under these conditions was obtained by fitting an exponential function to the data.Within the first 10 minutes of incubation, 22c plasma had been completely converted to dantrolene. The calculated half-life was 3.2 minutes. A negative control using phosphate-buffered brine instead of rat plasma was also performed, and 85% reconversion was observed after 150 minutes.

[0239] The pharmacokinetics of 22c in live rats were tested by dosing cannulated Sprague-Dawley rats intravenously and analyzing the blood for dantrolene using LC-MS (Figure 17). Intravenous doses were administered via jugular vein cannula. Subcutaneous doses were administered by injection between the skin and underlying tissue layers in the left hind limb of each animal. Intramuscular doses were administered by injecting half the dose into the large mass Petition 870260038724, dated 04 / 27 / 2026, pp. 95 / 193 88 / 88 of the dose was administered to the left hind limb muscle and the other half to the right hind limb. There were three rats in each test group. 22c was dissolved to 3 mg / mL in sterile filtered 5% aqueous mannitol (weight / volume) with 10% DMSO to provide a dose level of 4 mg / kg and a dose volume of 1.33 mL / kg. Blood was collected before administration and 0.167, 0.33, 0.66, and 1.33 hours after administration. At each time point, 100 μL of blood was collected in a vial loaded with 300 μL of acetonitrile. Blood samples were centrifuged to pellet any insoluble material. Supernatants were flash-frozen and stored on dry ice. The samples were analyzed using the methods in the General Methods and Materials sections of UPLC and Pharmacokinetic Analysis. Petition 870260038724, dated 04 / 27 / 2026, pp. 96 / 193

Claims

1 / 3 CLAIMS 1. Compound, characterized in that it has formula I: wherein R is: -P(O)(OH)2 or -P(O)(OR1)(OR2); R1 is H, C1-26 alkyl; and R2 is C1-26 alkyl; or - a pharmaceutically acceptable salt thereof.

2. Compound according to claim 1, characterized in that R is -P(O)(OH)2.

3. Compound according to claim 1, characterized in that R is -P(O)(OR1)(OR2).

4. Compound according to claim 3, characterized in that R1 is H.

5. Compound according to claim 3, characterized in that R1 is a C1-26 alkyl group.

6. A compound, according to any one of claims 1 to 5, characterized in that it is in the form of a pharmaceutically acceptable salt.

7. Pharmaceutical composition, characterized by comprising a compound, as defined in any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

8. Compound, according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized by the fact that it is used in the preparation of a Petition 870260038724, dated 04 / 27 / 2026, page 97 / 193 2 / 3 medicine useful in the treatment of a dantrolene-responsive disorder.

9. A compound according to claim 16, characterized in that the disorder is malignant hyperthermia, chronic spasticity, exertional heatstroke, cardiac arrhythmias, tachycardia, atrial fibrillation, cardiac arrest, myocardial infarction, heart failure, myocardial injury, cardiomyopathy, central nervous system disease, amyotrophic lateral sclerosis, rhabdomyolysis, Duchenne muscular dystrophy, ataxia, detrusor overactivity, overactive bladder, seizure, epilepsy, neuroleptic malignant syndrome, human stress disorder, Alzheimer's disease, Huntington's disease, multiple sclerosis, Parkinson's disease, ischemia-reperfusion injury, neural reperfusion injury, hypoxia, cerebral aneurysm, subarachnoid hemorrhage, stroke, hyperthermia associated with drug abuse, hyperthermia associated with drug overdose, exposure to neurotoxic agents, exposure to neurotoxic gases, or accumulation of acetylcholine.

10. Compound, according to any one of claims 8 or 9, characterized in that the compound is in a form for intravenous use.

11. Compound, according to any one of claims 8 or 9, characterized in that the compound is in a form for intramuscular use.

12. Compound, according to any one of claims 8 or 9, characterized in that the compound is in a form for oral use.

13. Compound, according to any one of claims 8 or 9, characterized in that the compound is in a form for subcutaneous use.

14. Compound, according to any one of claims 8 or 9, characterized in that the compound is in a form for intranasal use.

15. Compound, according to any one of claims 8 or 9, characterized in that the compound is in a form for intraosseous use.

16. Compound, according to claim 1, characterized in that it is compound 2b: Petition 870260038724, dated 04 / 27 / 2026, p. 99 / 193

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