Deuterated blarcamesine, process of preparation, pharmaceutical compositions comprising same, and use thereof

Abstract

The present invention relates to deuterated Blarcamesine, a hydrochloride salt of the deuterated Blarcamesine compound, processes of preparation thereof, a pharmaceutical composition comprising deuterated Blarcamesine, and a use of deuterated Blarcamesine and a pharmaceutical composition thereof for the treatment of a condition or disorder.

Description

[0001] DEUTERATED BLARCAMESINE, PROCESS OF PREPARATION, PHARMACEUTICAL COMPOSITIONS COMPRISING SAME, AND USE THEREOF

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to Indian Provisional Patent Application number 202441055842, filed on 22 July 2024, which is hereby incorporated by reference herein in its entirety.

[0004] TECHNICAL FIELD OF THE INVENTION

[0005] The present invention in general relates to the field of pharmaceutical chemistry. Particularly, it relates to deuterated Blarcamesine, its salts, processes of preparation thereof, a pharmaceutical composition comprising deuterated Blarcamesine, and a use of deuterated Blarcamesine and a pharmaceutical composition thereof for the treatment of a condition or disorder. More particularly, the present invention relates to deuterated Blarcamesine and a hydrochloride salt thereof, and their preparation, a pharmaceutical composition comprising them, and a use of them for the treatment a condition or disorder.

[0006] BACKGROUND OF THE INVENTION

[0007] Blarcamesine, is chemically known as / V, / V-dimethyl-2,2-diphenyltetrahydrofuran-3-methanamine and is represented by the following structure:

[0008] Blarcamesine (ANAVEX2-73) is designed as a sigma-1 receptor agonist and muscarinic agonist. These receptors play crucial roles in various neurological processes, including neurotransmission, neuroprotection, and neuroplasticity. By targeting these receptors, Blarcamesine aims to modulate signalling pathways implicated in neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, Rett syndrome and other central nervous system (CNS) disorders. Currently Blarcamesine and its hydrochloride salt are in phase Ilb / phase III trials for Alzheimer's disease and Rett syndrome; phase Ila trials for Parkinson's disease; phase I trials for epilepsy; and are undergoing preclinical trials for amyotrophic lateral sclerosis and stroke.

[0009] Therapeutically, Blarcamesine and its analogs (such as ANAVEX 1-41 and ANAVEX 19-144) are effective in potentially slowing down or even reversing the progression of neurodegenerative diseases. Its mechanism of action suggests potential benefits in improving cognitive function, reducing neuroinflammation, and protecting neurons from degeneration. Further, Blarcamesine showed highly favorable safety profile and dose-dependency, with minimal side effects and dosage-dependent improvements in cognitive abilities and daily functioning, measured by tests like MMSE (Mini-Mental State Examination) and ADCS-ADL (Alzheimer’s Disease Cooperative Study- Activities of Daily Living) respectively. Blarcamesine is also potentially useful for treating other diseases or conditions (for example, Huntington disease) due to its ability to activate sigma- 1 receptor, and anti-apoptotic and anti-oxidant properties. Recently, Blarcamesine has been given the “Orphan Drug” designation from the U.S. FDA for Fragile X syndrome. However, the pharmacokinetic profile of Blarcamesine (T1 / 2 = 8.56 hours) indicates rapid metabolism of the drug, resulting in the production of demethylated Blarcamesine metabolite. This rapid metabolism necessitates frequent or increased dosing to maintain sufficiently high plasma levels of the drug, which would otherwise be highly effective in treating diseases. This requirement for frequent / increased dosing can lead to several treatment challenges, such as poor patient compliance, more pronounced side effects at higher doses, and increased treatment costs.

[0010] Therefore, there is a need to provide new drugs that effectively treat one or more above-mentioned conditions or disorders with improved metabolic stability, efficacy and / or safety.

[0011] SUMMARY OF THE INVENTION

[0012] Accordingly, the present invention provides deuterated Blarcamesine, hydrochloride salt of the compound deuterated Blarcamesine, as well as processes for their preparation, pharmaceutical compositions thereof, and uses and methods for the treatment of certain conditions or disorders. The conditions or disorders include Neurodegenerative and Neurodevelopmental disorders such as Alzheimer’s disease, Parkinson’s disease dementia, Rett syndrome, Huntington disease and Fragile X syndrome.

[0013] In an aspect, deuterated Blarcamesine is a potential compound that improves the pharmacokinetic properties compared to non-deuterated Blarcamesine. In a further aspect, deuterated Blarcamesine enhances metabolic stability, drug efficacy, safety, and / or exhibit reduced drug-drug interactions compared to non-deuterated Blarcamesine. In another aspect, deuterated Blarcamesine crosses the blood brain barrier and accumulates in brain exhibiting effect in treatment of neurodegenerative diseases. In certain aspects, modulation of the dosage of the deuterated Blarcamesine enables to achieve improved therapeutic efficacy while minimizing or avoiding adverse or toxic effects in brain.

[0014] In another aspect, the present invention provides a deuterated Blarcamesine compound of Formula

[0015] II: or a pharmaceutically acceptable salt, a crystal, a co-crystal, a polymorph, a hydrate, a solvate, a prodrug, an A- ox ide, a bioisostere, or a stereoisomer thereof.

[0016] In another aspect, the present invention provides a hydrochloride salt of the compound of Formula II

[0017] In yet another aspect, the present invention provides a crystalline form of the hydrochloride salt of the compound of Formula II.

[0018] In another aspect, the present invention provides a pharmaceutical composition comprising a deuterated Blarcamesine compound provide herein, or a pharmaceutically acceptable salt, a crystal, a co-crystal, a polymorph, a hydrate, a solvate, a prodrug, an A- ox ide, a bioisostere, or a stereoisomer thereof, and a pharmaceutically acceptable carrier. Also provided is a use of a deuterated Blarcamesine compound as described or provided herein, or a pharmaceutically acceptable salt, a crystal, a co-crystal, a polymorph, a hydrate, a solvate, a prodrug, an A-oxide, a bioisostere, or a stereoisomer thereof; or a pharmaceutical composition as described herein, for treating a condition or disorder in a subject in need thereof. In some aspects, provided is a use of a deuterated Blarcamesine compound as described herein, or a pharmaceutically acceptable salt, a crystal, a co-crystal, a polymorph, a hydrate, a solvate, a prodrug, an A-oxide, a bioisostere, or a stereoisomer thereof; or a pharmaceutical composition as described herein in the manufacture of a medicament for treating a condition or disorder in a subject in need thereof.

[0019] Further, in an aspect, the present invention provides a process for preparation of the compound of Formula II, wherein the process comprises reacting a compound of Formula III with dimethyl-de- amine (compound of Formula IV) or its salt to obtain a compound of Formula II. The said process is represented as follows:

[0020] Scheme 1 wherein L is hydroxyl, or a suitable leaving group.

[0021] In yet another aspect, the present invention provides a process for preparation of a crystalline form of the hydrochloride salt of the compound of Formula II, comprising the steps of: a) reacting a compound of Formula II with hydrogen chloride in a solvent to obtain a reaction mixture comprising hydrochloride salt of the compound of Formula II; b) optionally stirring the mixture; and c) isolating the crystalline form of the hydrochloride salt of the compound of Formula II. The present invention also provides a method for treatment or prophylaxis a condition or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a deuterated Blarcamesine as described herein, or a pharmaceutically acceptable salt, a crystal, a co-crystal, a polymorph, a hydrate, a solvate, a prodrug, an / V- ox ide, a bioisostere, or a stereoisomer thereof; or a pharmaceutical composition as described herein. The condition or disorder includes Neurodegenerative and Neurodevelopmental disorders such as Alzheimer’s disease, Parkinson’s disease dementia, Rett syndrome, Huntington disease and Fragile X syndrome.

[0022] BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure- 1 illustrates the 'H nuclear magnetic resonance (NMR) spectrum of the compound of Formula II prepared according to Example 1.

[0024] Figure-2 illustrates the powder X-ray diffraction (PXRD) pattern of the compound of Formula II prepared according to Example 1.

[0025] Figure-3 illustrates the thermogravimetric differential thermal analysis (TG / DTA) thermogram of the compound of Formula II prepared according to Example 1.

[0026] Figure-4 illustrates the 'H nuclear magnetic resonance (NMR) spectrum of the hydrochloride salt of compound of Formula II prepared according to Example 2.

[0027] Figure-5 illustrates powder X-ray diffraction (PXRD) pattern of the hydrochloride salt of compound of Formula II prepared according to Example 2.

[0028] Figure-6 illustrates the thermogravimetric differential thermal analysis (TG / DTA) thermogram of the hydrochloride salt of compound of Formula II prepared according to Example 2.

[0029] DETAILED DESCRIPTION OF THE INVENTION

[0030] At the very outset of the detailed description, it may be understood that the ensuing description only illustrates a particular form of this invention. However, such a particular form is only exemplary embodiment, and without intending to imply any limitation on the scope of this invention. Accordingly, the description is to be understood as an exemplary embodiment and teaching of invention and not intended to be taken restrictively.

[0031] It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the present disclosure.

[0032] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the methods. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the methods, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the methods.

[0033] Certain ranges are presented herein with numerical values being preceded by the term “about.” The term “about” is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In determining whether a number is near to or approximately a specifically recited number, the near or approximating unrecited number may be a number which, in the context in which it is presented, provides the substantial equivalent of the specifically recited number. In an embodiment, “about” can mean within one or more standard deviations, or within ± 30%, 25%, 20%, 15%, 10% or 5% of the stated value. For example, "about 10" may be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.

[0034] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described. The articles "a" and "an" are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0035] As used herein, the term “comprises” or “comprising” is generally used in the sense of include, that is to say permitting the presence of one or more features or components. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range “between” two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

[0036] The term “deuterated Blarcamesine " refers to the drug Blarcamesine, where one or more of the hydrogen atoms in the molecule (Blarcamesine) are replaced with deuterium atoms. Deuterium may be substituted for hydrogen at one or more, or all, of the available positions in Blarcamesine or a salt thereof, including positions on the phenyl ring, the tetrahydrofuran ring, the alkyl (methylene) group, and the A,A-dimethylamino group of Blarcamesine, either individually or in any combination.

[0037] The term “excipient(s)” is used to describe an inert substance that is added to a pharmaceutical composition to make it easier to administer the active ingredient. This can include a range of substances, such as surfactants, tonicity agents, pH adjusters, buffers, preservatives, vehicles, vegetable oils, and polyethylene glycols.

[0038] The term “formulation” or “composition” refers to a pharmaceutical formulation of deuterated Blarcamesine described herein with a pharmaceutically acceptable carrier and / or excipient. The terms “formulation” or “composition” may be used interchangeably.

[0039] The term “pharmaceutically acceptable carrier” refers to a substance that is used as a carrier, vehicle, adjuvant, or solvent in the formulation of a drug, but does not cause significant irritation to the body or interfere with the biological activity of the drug. The terms “vehicle”, “solvent” and “solvent system” refer to the same component(s), and the said terms can be used interchangeably. The term “subject” includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).

[0040] Each embodiment is provided by way of explanation of the invention and not by way of limitation of the invention. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made to the compounds, and methods described herein without departing from the scope or spirit of the invention. For instance, features illustrated or described as part of one embodiment can be applied to another embodiment to yield a still further embodiment. Thus, it is intended that the present invention includes such modifications and variations and their equivalents.

[0041] All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25 °C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise.

[0042] Other objects, feature, and aspects of the present invention are disclosed in or are obvious from, the following detailed description. It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments only and is not to be construed as limiting the broader aspects of the present invention.

[0043] In an embodiment, the present invention provides deuterated Blarcamesine. The deuterated Blarcamesine may be in the form of a free base, a pharmaceutically acceptable salt, a crystal, a cocrystal, a polymorph, a hydrate, a solvate, a prodrug, an A-oxide, a bioisostere, or a stereoisomer thereof. The deuterated Blarcamesine may contain up to about 50% deuterium or more at any specific hydrogen atom. In an embodiment, it may contain up to about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% deuterium at any specific hydrogen atom.

[0044] In a further embodiment, the present invention provides a compound of Formula II:

[0045]

[0046] In an embodiment, the present invention provides a compound of Formula II characterized by a NMR spectrum as depicted in Figure- 1.

[0047] In an embodiment, the present invention provides a crystalline form of a compound of Formula II. The crystalline form of the compound of Formula II is characterized by a powder X-ray diffraction (PXRD) pattern substantially as depicted in Figure-2 and / or a thermogravimetric differential thermal analysis (TG / DTA) thermogram substantially as depicted in Figure-3. In certain embodiments, the crystalline form of the compound of Formula II is characterized by a PXRD pattern substantially as depicted in Figure-2 and a TG / DTA thermogram substantially as depicted in Figure-3.

[0048] The phrase “substantially as depicted in”, or “substantially as shown in”, when used in reference to an PXRD pattern, or TG / DTA thermogram, refers to data that may not be exactly identical to those illustrated herein, but that would be recognized by a person skilled in the art as being within acceptable experimental deviation.

[0049] In an embodiment, the crystalline form of the compound of Formula II is characterized by a PXRD pattern comprising peaks at 5.25, 11.63, 15.47, 19.03, and 21.85 degrees 2-theta ± 0.2 degrees 2- theta.

[0050] In an embodiment, the crystalline form of the compound of Formula II is characterized by a PXRD pattern comprising peaks at 5.25, 11.63, 15.47, 19.03, and 21.85 degrees 2-theta ± 0.2 degrees 2- theta, and also having any one, two, three, four or five additional peaks selected from 5.85, 6.97, 10.42, 13.96, 16.89, 23.52, and 25.59 degrees 2-theta ± 0.2 degrees 2-theta.

[0051] In a further embodiment, the crystalline form of the compound of Formula II exhibits an PXRD pattern characterized by at least two, three, four, five, six, or seven of the most intense 2-theta diffraction peaks corresponding to those shown in Figure-2. It is recognized that relative peak intensities may vary due to factors such as sample handling, mounting method, and the specific equipment or analytical conditions employed. Therefore, the reported peak positions for polymorphic Form I are considered to allow for a margin of ±0.2 degrees 2-theta to account for typical experimental variations.

[0052] In an embodiment, the crystalline form of the compound of Formula II is anhydrous, as determined by TGA. In an embodiment, the crystalline form of the compound of Formula II contains up to about 0.5% w / w residual solvent content.

[0053] In another aspect, the present invention provides a hydrochloride salt of the compound of Formula II characterized by a NMR spectrum as shown in Figure 4.

[0054] In an embodiment, the present invention provides a crystalline form of the hydrochloride salt of the compound of Formula II. The crystalline form of the hydrochloride salt of the compound of Formula II is characterized by a PXRD pattern substantially as shown in Figure 5 and / or a thermogravimetric differential thermal analysis (TG / DTA) thermogram as shown in Figure 6.

[0055] In an embodiment, the crystalline form of the hydrochloride salt of the compound of Formula II is characterized by a powder X-ray diffraction pattern comprising peaks at 6.25, 13.87, 15.86, 18.94, and 21.27 degrees 2-theta ± 0.2 degrees 2-theta.

[0056] In another embodiment, the crystalline form of the hydrochloride salt of the compound of Formula II is characterized by a powder X-ray diffraction pattern comprising peaks at 6.25, 13.87, 15.86, 18.94, and 21.27 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 11.60, 12.55, 20.20, 23.01, 23.27, 26.80, and 29.53 degrees 2-theta ± 0.2 degrees 2-theta.

[0057] In another embodiment, the crystalline form of the hydrochloride salt of the compound of Formula II is anhydrous as determined by TGA. In an embodiment, the crystalline form of the hydrochloride salt of the compound of Formula II may contain up to about 0.5% w / w residual solvent content. Deuterated Blarcamesine improves the pharmacokinetic properties compared to non-deuterated Blarcamesine. In an embodiment, deuterated Blarcamesine enhances metabolic stability, drug efficacy, safety, and / or exhibit reduced drug-drug interactions compared to non-deuterated Blarcamesine. The deuterated Blarcamesine crosses the blood brain barrier and accumulates in brain exhibiting effect in treatment of neurodegenerative diseases. Modulating the dosage of the deuterated Blarcamesine, ensures to achieve improved therapeutic efficacy while reducing the unwanted toxic effects in brain.

[0058] In an embodiment, the present invention provides a process for preparing a deuterated Blarcamesine compound of Formula II: or a pharmaceutically acceptable salt, a crystal, a co-crystal, a polymorph, a hydrate, a solvate, a prodrug, an / V-oxide, a bioisostere, or a stereoisomer thereof; wherein the process comprises reacting a compound of Formula III, HI with dimethyl-de-amine (compound of Formula

[0059] IV) or its salt; wherein L is hydroxyl or a suitable leaving group. The above process is schematically represented as follows: Examples of a suitable leaving group include, but are not limited to, halogen and sulfonate. The sulfonate can be an alkyl sulfonate (such as methanesulfonate (mesylate) and trifluoromethanesulfonate (triflate)) or an aryl sulfonate (such as benzenesulfonate (besylate), p- toluenesulfonate (tosylate) and / ?-nitrobenzenesulfonate (nosylate)). In some embodiments, the sulfonate is an alkyl sulfonate. In further embodiments, the sulfonate is trifluoromethanesulfonate.

[0060] In an embodiment, L is a halogen selected from a group consisting of chlorine, bromine and iodine. In some embodiments, L is a halogen selected from a group consisting of chlorine, bromine and iodine. In another embodiment, L is a sulfonate selected from a group consisting of alkyl sulfonates comprising methanesulfonate or mesylate and trifluoromethanesulfonate or triflate; and aryl sulfonates comprising benzenesulfonate or besylate, / ?-toluenesulfonate or tosylate and p- nitrobenzenesulfonate or nosylate.

[0061] In an embodiment, when L is hydroxy, the hydroxy may be converted to corresponding leaving group, such as sulfonate or halogen, according to the methods known in the art. Then the resulting sulfonate or halide compound may be reacted with the compound of Formula TV or its salt to obtain the compound of Formula II. In an embodiment, the sulfonate or halide compound may either be isolated or reacted in situ.

[0062] In an embodiment, the reaction of the compound of Formula III with dimethyl-de-amine (compound of Formula IV) is carried out in the presence of a solvent. The solvent incudes, but is not limited to, an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, dimethoxy ethane, di-tert-butyl ether, diglyme, dimethoxymethane, dipropyl ether, dibutyl ether or the like; an alcohol such as methanol, ethanol, ethylene glycol, 1 -propanol, 2-propanol, 2-methoxy ethanol, 1 -butanol, 2-butanol, / .s -butyl alcohol, tert- butyl alcohol, glycerol or the like; a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, chlorobenzene or the like; an aromatic hydrocarbon such as toluene, xylene, ethylbenzene or the like; an aliphatic hydrocarbon such as hexane, heptane, cyclohexane or the like; a nitrile such as acetonitrile, propionitrile or the like; an ester such as methyl acetate, ethyl acetate or the like; a polar aprotic solvent such as V, / V-dimethylformamide, dimethylsulphoxide, N,N- dimethylacetamide or the like; water and mixtures thereof. In an embodiment, the process comprises reacting the compound of Formula III with dimethylde-amine (compound of Formula IV) in the presence of a base. The base includes, but is not limited to, an inorganic base such as alkali metal or alkaline earth metal carbonate, hydrogen carbonate, hydroxide and carboxylate, e.g., potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium acetate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium acetate, lithium carbonate, lithium hydrogen carbonate, lithium hydroxide, lithium acetate, cesium carbonate, barium hydroxide, calcium hydroxide, magnesium hydroxide, or the like; and an organic base, such as triethylamine, diisopropylethylamine, l,8-Diazabicyclo[5.4.0]undec-7- ene (DBU), pyridine, 2,6-dimethylpyridine, / V, / V-dimethylaminopyridine, tetramethylguanidine (TMG), l,5-diazabicyclo(4.3.0)non-5-ene (DBN) or mixtures thereof.

[0063] In an embodiment, the process comprises reacting the compound of Formula III with dimethylde-amine (compound of Formula IV) in the presence of a catalyst and a phase transfer reagent. The catalyst includes, but is not limited to, an alkali metal halide such as potassium iodide, sodium iodide or the like; and the phase transfer reagent includes, but is not limited to, tetrabutylammonium bromide, triethylbenzylammonium chloride, tributylphosphonium bromide, 18-crown-6 or the like.

[0064] In an embodiment, the reaction between compound of Formula III and compound of Formula TV is carried out in a solvent, in the presence of a base, a catalyst, and a phase transfer reagent. The solvent, base, catalyst, and phase transfer reagent are same as defined above.

[0065] In an embodiment, the process of any of the preceding embodiments is carried out at a temperature ranging from about 0°C to the boiling point of the solvent. The time required for the reaction widely varies, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. In an embodiment, the process is carried out for a time ranging from about 1 hour to about 24 hours or more.

[0066] In an embodiment, the process further comprises isolating the compound of Formula II. The isolation technique includes, but are not limited to, decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like. In an embodiment, the process optionally comprises washing the compound of Formula II with a solvent.

[0067] In another embodiment, the present invention provides a process for preparing a crystalline form of the hydrochloride salt of the compound of Formula II, comprising the steps of: a) reacting a compound of Formula II with hydrogen chloride in a solvent to obtain a reaction mixture; b) optionally stirring the mixture; and c) isolating the crystalline form of the hydrochloride salt of the compound of Formula II from the reaction mixture.

[0068] In an embodiment, step (a) comprises:

[0069] (i) providing a mixture of compound of Formula II in a suitable solvent;

[0070] (ii) combining the mixture with hydrogen chloride gas or a solution of hydrogen chloride in a suitable solvent; or by

[0071] (iii) providing a solution of hydrogen chloride in a suitable solvent, and adding a compound of Formula II or its solution in a suitable solvent into the hydrogen chloride solution.

[0072] In an embodiment, the solvent in step (a), or in steps (i)-(iii), includes, but is not limited to, an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, methyl tert-butyl ether, 1 ,4-dioxane, dimethoxyethane, di-tert-butyl ether, diglyme, dimethoxymethane, dipropyl ether, dibutyl ether or the like; an alcohol such as methanol, ethanol, ethylene glycol, 1 -propanol, 2-propanol, 2- methoxy ethanol, 1 -butanol, 2-butanol, / .w-butyl alcohol, tert-butyl alcohol, glycerol or the like; a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, chlorobenzene or the like; an aromatic hydrocarbon such as toluene, xylene, ethylbenzene or the like; an aliphatic hydrocarbon such as hexane, heptane, cyclohexane or the like; a nitrile such as acetonitrile, propionitrile or the like; an ester such as methyl acetate, ethyl acetate or the like; a polar aprotic solvent such as / V, / V-dimethylformamide, dimethylsulphoxide, N,N- dimethylacetamide or the like; water and mixtures thereof. In an embodiment, the stirring in step (b) is carried out at a temperature of about -10°C to about 40°C, or about -5°C to about 10°C. In an embodiment, the stirring in step (b) is carried out for a suitable time. In an embodiment, the stirring is carried out for about 5 minutes to about 2 hours, or for about 30 min to about 1 hour.

[0073] In an embodiment, the isolation in step (c) can be carried out using conventional techniques known in the art or by any procedure disclosed in the present application. Examples of isolation techniques include, but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, concentrating, cooling, stirring, shaking, combining with an anti-solvent, adding seed crystals, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, or the like. In an embodiment, the isolation is carried out at atmospheric pressure or under reduced pressure.

[0074] The solid that is obtained carries a small proportion of occluded mother liquor containing a higher percentage of impurities. In an embodiment, the solid obtained after isolation is optionally washed with a solvent to wash out the mother liquor. Suitable solvents for washing include, but are not limited to, an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,4-di oxane, dimethoxy ethane, di-tert-butyl ether, diglyme, dimethoxymethane, dipropyl ether, dibutyl ether or the like; an alcohol such as methanol, ethanol, 1 -propanol, 2-propanol, 2- methoxy ethanol, 1 -butanol, 2-butanol, iso-butyl alcohol, tert- butyl alcohol or the like; an ester such as methyl acetate, ethyl acetate or the like; and mixtures thereof. The choice of solvent may depend on the solubility characteristics of the solid and the components of the mother liquor.

[0075] In an embodiment, the solid is optionally dried in a vacuum oven at a temperature of about 20 °C to about 80 °C, or about 40 °C to about 45 °C. In another embodiment, the drying is carried out over a period of about 1 hour to about 24 hours, or about 2 hours to about 10 hours.

[0076] The present invention also provides a pharmaceutical composition comprising the deuterium Blarcamesine described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable carrier. In an embodiment, the present invention provides a pharmaceutical composition comprising the compound of Formula II, or a hydrochloride salt thereof, one or more pharmaceutically acceptable polymer, and one or more pharmaceutically acceptable excipients. In an embodiment, the composition optionally comprises an additional therapeutic agent selected from the group comprising Rivastigmine, Rasagiline, Huperzine A, Propentofylline, Baclofen, Carbidopa, Amantadine, Sertraline, Citalopram, Tetrabenazine, Trofinetide, Valproic acid, Ethosuximide, Gabapentin, Donepezil.

[0077] In an embodiment, the pharmaceutical composition is an amorphous solid dispersion (ASD) comprising the compound of Formula II, or a hydrochloride salt thereof, one or more pharmaceutically acceptable polymer, and one or more pharmaceutically acceptable excipients. Examples of pharmaceutically acceptable polymers include, but are not limited to, celluloses (e.g., carboxymethylcelluloses, methylcelluloses, hydroxypropylcelluloses, hydroxypropylmethylcelluloses); polysaccharides, heteropolysaccharides (pectins); poloxamers; poloxamines; ethylene vinyl acetates; polyethylene glycols; dextrans; polyvinylpyrrolidones; chitosans; polyvinylalcohols; propylene glycols; polyvinylacetates; phosphatidylcholines (lecithins); polylactic acid; polyhydroxybutyric acid; polyethylene glycol-polylactic acid (PEG- PLA), polyethylene glycol-polyhydroxybutyric acid (PEG-PHB), polyvinylpyrrolidone- polyvinylalcohol (PVP-PVA), cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, hydroxymethylcellulose ethyl phthalate, hydroxypropylmethylcellulose phthalate, eudragit, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethyl acetate maleate, hydroxypropylmethyl trimellitate, carboxymethylethylcellulose, polyvinyl butyrate phthalate, polyvinyl alcohol acetate phthalate, methacrylic acid / ethyl acrylate copolymer, and methacrylic acid / methyl methacrylate copolymer, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethyl acetate maleate and hydroxypropylmethyl trimellitate.

[0078] A pharmaceutically acceptable carrier refers to any non-toxic compound or group of compounds that do not compromise or significantly reduce the pharmacological effectiveness of the therapeutic agent with which it is formulated. These carriers or vehicles can include any standard solid, liquid, or gaseous carriers known in the pharmaceutical industry. The choice of carrier depends on the intended route of administration for the pharmaceutical composition. The route is determined by healthcare professionals based on convenience, the health and condition of the patient, and the location and stage of the condition being treated. Possible routes of administration include, but are not limited to, buccal, direct local injection, inhalation, intra-arterial injection, intradermal injection, intramuscular injection, intraperitoneal injection, intrathecal injection, intravenous injection, nasal, oral, rectal, subcutaneous injection, sublingual, topical, transdermal, transmucosal, and vaginal. Administration can also be via transfusion or infusion, using implants, implanted pumps, external pumps, or any other known device.

[0079] Consequently, pharmaceutical compositions can take various forms, such as tablets, capsules, caplets, lozenges, dragees, pills, granules, oral solutions, powders for dilution or inhalation, vapors, gases, sterile solutions for injection or infusion, transdermal patches, buccal patches, inserts, implants, rectal or vaginal suppositories, creams, lotions, oils, ointments, topical coverings (e.g., wound dressings), suspensions, emulsions, and lipid vesicles.

[0080] Any pharmaceutically acceptable carrier may be used with the invention, including those known in the industry. Examples materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non- toxic compatible substances employed in pharmaceutical formulations.

[0081] The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition may be formulated as tablets, pills, powders, granules, capsules, suspensions, liquids for internal use, emulsions, syrups, aerosols, or sterile injectable solutions. Depending on the intended use, the composition can be administered to a subject by any of a number of routes of administration including, for example orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin or as an eye drop). The compound may also be formulated for inhalation. In yet another embodiment, a compound may be simply dissolved or suspended in sterile water.

[0082] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredients, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0083] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product.

[0084] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0085] The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated and like factors well known in the medical arts.

[0086] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By "therapeutically effective amount" is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound and, if desired, another type of therapeutic agent being administered with the compound of the disclosure. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).

[0087] In general, a suitable daily dose of an active compound used in the compositions and methods of the disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0088] If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In yet another embodiment of the present disclosure, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.

[0089] Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, coating agents, release agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0090] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alphatocopherol and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.

[0091] In an embodiment, the present invention provides a use of a deuterated Blarcamesine compound of Formula II or a pharmaceutically acceptable salt, a crystal, a co-crystal, a polymorph, a hydrate, a solvate, a prodrug, an A-oxide, a bioisostere, or a stereoisomer thereof; or a pharmaceutical composition comprising the deuterated Blarcamesine as described herein for treating a condition or disorder in a subject in need thereof. In some embodiments, the present invention provides use of deuterated Blarcamesine or a pharmaceutical composition comprising the deuterated Blarcamesine as described herein in the manufacture of a medicament for treating a condition or disorder in a subject in need thereof. In some embodiments, the deuterated Blarcamesine compound of Formula II is a hydrochloride salt of Formula II. In a further embodiment, the present invention provides deuterated Blarcamesine or a pharmaceutical composition comprising the deuterated Blarcamesine as described herein for use in the treatment of condition or disorder. The conditions or disorders include Neurodegenerative and Neurodevelopmental disorders such as Alzheimer’s disease, Parkinson’s disease dementia, Rett syndrome, Huntington disease and Fragile X syndrome.

[0092] In an embodiment, the present invention provides a deuterated Blarcamesine compound as a hydrochloride salt; or a pharmaceutical composition as an oral formulation of the hydrochloride salt of deuterated Blarcamesine compound; for use in the treatment or prophylaxis of a condition or disorder which is Neurodegenerative and Neurodevelopmental. In some embodiments, the condition or disorder is selected from Alzheimer’s disease, Parkinson’s disease dementia, Rett syndrome, Huntington disease and Fragile X syndrome.

[0093] In another embodiment, the present invention provides a deuterated Blarcamesine compound as hydrochloride salt; or a pharmaceutical composition as an oral formulation of the hydrochloride salt of deuterated Blarcamesine compound; for use as a medicament.

[0094] The present invention further provides a method for the treatment or prophylaxis of a condition or disorder in a subject in need thereof. The method comprises administering to the subject a therapeutically effective amount of a deuterated Blarcamesine or a pharmaceutical composition of the present invention. In certain embodiments, the condition or disorder refers to a disease condition that is benefited by administering Blarcamesine. In some embodiments, the deuterated Blarcamesine compound of Formula II is a hydrochloride salt of Formula II. Examples of such a disorder include, but is not limited to, Neurodegenerative and Neurodevelopmental disorders such as Alzheimer’s disease, Parkinson’s disease dementia, Rett syndrome, Huntington disease and / or Fragile X syndrome. The Possible routes of administration include, but are not limited to, oral, buccal, direct local injection, inhalation, intra-arterial injection, intradermal injection, intramuscular injection, intraperitoneal injection, intrathecal injection, intravenous injection, nasal, rectal, subcutaneous injection, sublingual, topical, transdermal, transmucosal, and vaginal. Administration can also be via transfusion or infusion, using implants, implanted pumps, external pumps, or any other known device.

[0095] In an embodiment, the method for the treatment or prophylaxis of a condition or disorder comprises optionally administering an additional therapeutic agent selected from the group comprising Rivastigmine, Rasagiline, Huperzine A, Propentofylline, Baclofen, Carbidopa, Amantadine, Sertraline, Citalopram, Tetrabenazine, Trofinetide, Valproic acid, Ethosuximide, Gabapentin, Donepezil. In an embodiment, the additional therapeutic agent is administered prior to, concurrently with, or subsequently to the administration of the compound of Formula II or a hydrochloride salt thereof; or the composition comprising the compound of Formula II or a hydrochloride salt thereof. In an embodiment, the additional therapeutic agent is administered prior to the administration of the compound of Formula II or a hydrochloride salt thereof; or the composition comprising the compound of Formula II or a hydrochloride salt thereof. In a further embodiment, the additional therapeutic agent is administered concurrently with the administration of the compound of Formula II or a hydrochloride salt thereof; or the composition comprising the compound of Formula II or a hydrochloride salt thereof. In yet another embodiment, the additional therapeutic agent is administered subsequent to the administration of the compound of Formula II or hydrochloride salt thereof; or the composition comprising the compound of Formula II or a hydrochloride salt thereof. In some embodiments, the condition or disorder is Neurodegenerative and Neurodevelopmental. In some embodiments, the condition or disorder is selected from Alzheimer’s disease, Parkinson’s disease dementia, Rett syndrome, Huntington disease and Fragile X syndrome.

[0096] The present invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present disclosure and are not intended to limit the present disclosure in any way.

[0097] Examples

[0098] Example 1: Synthesis of N-((2,2-diphenyltetrahydrofuran-3-yl)methyl)-N-(methyl- < / ,)niethanamine-< / , (compound of Formula II)

[0099] 2,6-lutidine (3.43 mL) was added to a solution of (2,2-diphenyltetrahydrofuran-3-yl)methanol

[0100] [compound of formula HI wherein L is hydroxyl (OH); 5.0 g] in CH2CI2 (250 mL), maintained at -10 °C under nitrogen atmosphere. The resulting mixture was stirred at -10 °C for 10 minutes before being treated with trifluoromethanesulfonic anhydride (4.98 mb) at the same temperature. The obtained reaction mixture was stirred for an additional 2 hours while being maintained below -10 °C. Thereafter, it was concentrated under reduced pressure below 20 °C to afford an oily substance, which was dissolved in diethyl ether (175 mL). The obtained solution was washed with cold water (100 mL) and the organic layer separated. The separated aqueous layer was extracted with diethyl ether (2 x 50 mL). The separated organic layers were combined, washed with cold water (100 mL), dried over Na2SO4, and concentrated under reduced pressure below 20 °C to obtain (2,2-diphenyltetrahydrofuran-3-yl)methyl trifluoromethanesulfonate [compound of formula III wherein L is trifluoromethanesulfonate (OTf); 7.2 g] as a white solid, which was used in the subsequent reaction without any further purification.

[0101] The crude trifluoromethanesulfonate thus obtained was dissolved in dry THF (100 mL) and cooled to 0°C. Dimethyl-de-amine hydrochloride (hydrochloride salt compound of formula TV, 2.06 g), followed by DIPEA (10.56 mL), were added to the solution maintained at 0 °C. The obtained reaction mixture was then allowed to warm to room temperature and stirred for 16-18 hours. Thereafter, the reaction mixture was concentrated under reduced pressure at 40-45 °C. The obtained concentrate was diluted with diethyl ether (100 mL) and washed with water (50 mL). The organic layer was separated, and the separated aqueous layer was extracted with diethyl ether (2 x 50 mL). The separated organic layers were combined, washed successively with water (75 mL) and brine (75 mL), dried over Na2SO4 and concentrated under reduced pressure below 25 °C to afford a brown syrup (11.7 g).

[0102] A part of the obtained brown syrup (5.85 g) was purified by column chromatography using silica gel (100-200 mesh) and 2% MeOH-EtOAc. The fractions, containing the pure product, were combined and concentrated under reduced pressure at 40-45 °C. The obtained solid (0.720 g) was dissolved in DCM (10 mL) and washed with aqueous NaHCCh solution (2 x 10 mL). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure at 40-45 °C to obtain the title compound (0.520 g). Purity by HPLC: 97.20 %.

[0103] 'H NMR (400Mz, DMSO-rf6): 5 7.59 - 7.54 (m, 2H), 7.37 - 7.28 (m, 4H), 7.26 - 7.17 (m, 3H), 7.16 - 7.10 (m, 1H), 4.10 - 4.02 (m, 1H), 3.72 - 3.65 (m, 1H), 3.20 - 3.13 (m, 1H), 2.12 - 2.04 (m, 1H), 1.85 - 1.73 (m, 3H). Example 2: Synthesis of N-((2,2-diphenyltetrahydrofuran-3-yl)methyl)-N-(methyl- < / ,)niethanamine-<7, hydrochloride (hydrochloride salt compound of Formula II)

[0104] HCI in dioxane, EtOAc

[0105] 0-5 °C, 30 min

[0106] 5.85 g of the brown syrup, obtained in Example 1, was taken in EtOAc (7.60 mL). The resulting mixture was cooled to 0-5 °C and while being maintained at the same temperature, treated with 7.60 mL of 4.0 M hydrochloric acid in 1,4-di oxane. The obtained reaction mixture was stirred at 0-5 °C for 30 minutes and concentrated under reduced pressure at 40-45 °C. The resulting brown syrup was taken in diisopropyl ether (5.85 mL) and gently scratched with a spatula for 5 minutes. The supernatant diisopropyl ether layer was decanted off. The residue, thus obtained, was subjected to one more repetition of scratching in diisopropyl ether, followed by decantation of the supernatant diisopropyl ether layer. The obtained off-white solid was taken in EtOAc (11.7 mL) and heated at 70 °C for 1 hour. The obtained solution was then cooled to room temperature and the precipitated solids were filtered under suction. The obtained wet cake was washed with EtOAc (3.0 mL) and dried under reduced pressure at 40-45 °C for 1 hour to obtain the title compound (0.460 g) as a white crystalline solid. Purity by HPLC: 99.76 %.

[0107] 'H NMR (400Mz, DMSO-rfs): 5 10.67 (brs, 1H), 7.65 - 7.60 (m, 2H), 7.45 - 7.40 (m, 2H), 7.37 - 7.28 (m, 4H), 7.25 - 7.16 (m, 2H), 4.20 - 4.12 (m, 1H), 3.79 - 3.73 (m, 1H), 3.63 - 3.56 (m, 1H), 2.78 - 2.65 (m, 2H), 2.42 - 2.35 (m, 1H), 1.97 - 1.88 (m, 1H).

[0108] Example 3: Comparative Pharmacokinetic Profiling of Blarcamesine Hydrochloride and Deuterated Blarcamesine Hydrochloride in a Zebrafish Model

[0109] A pharmacokinetic (PK) study was conducted to compare the kinetic profiles of Blarcamesine hydrochloride and deuterated Blarcamesine hydrochloride. The objective of this study was to observe potential differences in the pharmacokinetics of these two compounds in both blood and brain tissue. Methodology.

[0110] A two-hour PK study was performed with both compounds administered orally at a dose of 30 mg / kg body weight in zebrafish. During the study, it was observed that deuterated Blarcamesine induced signs of excitotoxicity, including epilepsy-like behavior, and resulted in the mortality of 3 out of 10 zebrafish subjects. Following this observation, the brain and whole blood lysates of the zebrafish were analyzed using an HPLC-based method for pharmacokinetic analysis.

[0111] Results'. The pharmacokinetic analysis revealed interesting findings regarding the concentrations of Blarcamesine hydrochloride and deuterated Blarcamesine hydrochloride in blood and brain. The results were as follows:

[0112] • Blarcamesine HC1: o Blood: Not Determined (ND) o Brain: 0.61 ppm

[0113] • Deuterated Blarcamesine HC1: o Blood: 0.38 ppm o Brain: 1.07 ppm

[0114] These results indicated that deuterated Blarcamesine hydrochloride exhibited higher concentrations in both blood and brain tissue compared to Blarcamesine hydrochloride, with notably higher accumulation in the brain.

[0115] Given the observed excitotoxicity in the initial study, a second round of experiments was conducted with a new batch of drugs after confirming the purity of the compounds. In this followup study, the dose was reduced to 20 mg / kg, and again, the compounds were administered orally. This time, no mortality or excitotoxicity was observed in the zebrafish.

[0116] At the 2-hour PK time point, it was observed that deuterated Blarcamesine hydrochloride had higher concentrations in the brain compared to Blarcamesine hydrochloride, though the concentrations in the blood were not detectable. The PK data for the reduced dosage was as follows:

[0117] • Blarcamesine HC1: o Blood: ND o Brain: 0.10 ppm

[0118] • Deuterated Blarcamesine HC1: o Blood: ND o Brain: 0.28 ppm

[0119] These findings further confirmed that deuterated Blarcamesine hydrochloride has a tendency to accumulate more in the brain than Blarcamesine hydrochloride, while blood concentrations of both compounds were not detected in this study.

[0120] Conclusion".

[0121] The pharmacokinetic analysis of Blarcamesine hydrochloride and deuterated Blarcamesine hydrochloride revealed notable differences in their distribution between blood and brain, deuterated Blarcamesine hydrochloride demonstrated superior brain penetration, exhibiting higher concentrations in the brain compared to Blarcamesine hydrochloride, suggesting a preferential accumulation in brain tissue. The initial study with a higher dose of deuterated Blarcamesine hydrochloride showed excitotoxicity and mortality in zebrafish, raising concerns about safety. However, in the subsequent study, where the dose was reduced, no excitotoxicity or mortality were observed, indicating that optimizing the dose helped mitigate these effects.

[0122] The pharmacokinetic analysis of Blarcamesine hydrochloride and deuterated Blarcamesine hydrochloride revealed notable differences in their distribution between blood and brain, deuterated Blarcamesine hydrochloride demonstrated superior brain penetration, exhibiting higher concentrations in the brain compared to Blarcamesine hydrochloride, inferring a preferential accumulation in brain tissue and hence an enhanced efficacy.

Claims

We claim,1. A deuterated Blarcamesine compound of Formula II:or a pharmaceutically acceptable salt, a crystal, a co-crystal, a polymorph, a hydrate, a solvate, a prodrug, an A-oxide, a bioisostere, or a stereoisomer thereof.

2. The compound as claimed in claim 1, wherein the compound is crystalline characterized by a powder X-ray diffraction (PXRD) pattern comprising peaks at 5.25, 11.63, 15.47, 19.03, and 21.85 degrees 2-theta ± 0.2 degrees 2-theta.

3. The compound as claimed in claim 2, wherein the compound is crystalline form of compound of Formula II characterized by a PXRD pattern comprising peaks at 5.25, 11.63, 15.47, 19.03, and 21.85 degrees 2-theta ± 0.2 degrees 2-theta, and comprising any one, two, three, four or five additional peaks selected from 5.85, 6.97, 10.42, 13.96, 16.89, 23.52, and 25.59 degrees 2-theta ± 0.2 degrees 2-theta.

4. The compound as claimed in claim 2, wherein the crystalline form of the compound of Formula II is anhydrous or contains up to about 0.5% w / w residual solvent content.

5. The compound as claimed in claim 1, wherein the compound is a hydrochloride salt of the compound of Formula II.

6. The compound as claimed in claim 5, wherein the compound is a crystalline form of the hydrochloride salt of the compound of Formula II characterized by a PXRD pattern comprising peaks at 6.25, 13.87, 15.86, 18.94, and 21.27 degrees 2-theta ± 0.2 degrees 2- theta.

7. The compound as claimed in claim 6, wherein the compound is a crystalline form of the hydrochloride salt of the compound of Formula II characterized by a powder X-ray diffraction pattern having peaks at 6.25, 13.87, 15.86, 18.94, and 21.27 degrees 2-theta ± 0.2 degrees 2-theta, and having any one, two, three, four or five additional peaks selected from 11.60, 12.55, 20.20, 23.01, 23.27, 26.80, and 29.53 degrees 2-theta ± 0.2 degrees 2- theta.

8. The compound as claimed in claim 5, wherein the crystalline form of the hydrochloride salt of Formula II is anhydrous or contains up to about 0.5% w / w residual solvent content.

9. A process for preparing a deuterated Blarcamesine compound of Formula II:or a pharmaceutically acceptable salt, a crystal, a co-crystal, a polymorph, a hydrate, a solvate, a prodrug, an / V-oxide, a bioisostere, or a stereoisomer thereof; the process comprises reacting a compound of Formula III with a compound of Formula IV or a salt thereof;wherein L is hydroxyl or a leaving group.

10. The process as claimed in claim 9, wherein the leaving group is a halogen or a sulfonate.

11. The process as claimed in claim 10, wherein the sulfonate is an alkyl sulfonate, or an aryl sulfonate.

12. The process as claimed in claim 9, wherein the compound of Formula III is reacted with the compound of Formula IV in presence of a solvent.

13. The process as claimed in claim 12, wherein the solvent is selected from the group comprising an ether, an alcohol, a halogenated hydrocarbon, an aromatic hydrocarbon, an aliphatic hydrocarbon, a nitrile, an ester, a polar aprotic solvent, water and mixtures thereof.

14. The process as claimed in claim 9, wherein the compound of Formula III is reacted with the compound of Formula IV in presence of a base.

15. The process as claimed in claim 14, wherein the base is selected from the group comprising an inorganic base, an organic base, and mixtures thereof.

16. The process as claimed in claim 9, wherein the compound of Formula III is reacted with the compound of Formula IV in presence of a catalyst and a phase transfer reagent.

17. The process as claimed in claim 16, wherein the catalyst is an alkali metal halide; and the phase transfer reagent is selected from the group comprising tetrabutylammonium bromide, triethylbenzylammonium chloride, tributylphosphonium bromide, and 18-crown- 6.

18. The process as claimed in claim 9, wherein the compound of Formula III is reacted with the compound of Formula IV at a temperature ranging from about 0°C to about boiling point of the solvent for a time ranging from about 1 hour to 24 hours or more.

19. A process for preparing a crystalline form of the hydrochloride salt of the compound of Formula II, wherein the process comprises: a) reacting a compound of Formula II with hydrogen chloride in a solvent to obtain a reaction mixture; b) optionally stirring the mixture; and c) isolating the crystalline form of the hydrochloride salt of the compound of Formula II from the reaction mixture.

20. The process as claimed in claim 19, wherein the stirring in step (b) is carried out at a temperature of about -10°C to about 40°C for about 5 minutes to about 2 hours.

21. A pharmaceutical composition comprising a deuterated Blarcamesine compound as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt, a crystal, a cocrystal, a polymorph, a hydrate, a solvate, a prodrug, an A- ox ide, a bioisostere, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.

22. The pharmaceutical composition as claimed in claim 21, wherein the composition further comprises an additional therapeutic agent selected from the group comprising Rivastigmine, Rasagiline, Huperzine A, Propentofylline, Baclofen, Carbidopa, Amantadine, Sertraline, Citalopram, Tetrabenazine, Trofinetide, Valproic acid, Ethosuximide, Gabapentin, and Donepezil.

23. Use of a deuterated Blarcamesine compound as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt, a crystal, a co-crystal, a polymorph, a hydrate, a solvate, a prodrug, an A-oxide, a bioisostere, or a stereoisomer thereof; or a pharmaceutical composition as claimed in any one claims 21 to 22, for treating a condition or disorder in a subject in need thereof.

24. Use of a deuterated Blarcamesine compound as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt, a crystal, a co-crystal, a polymorph, a hydrate, a solvate, a prodrug, an A-oxide, a bioisostere, or a stereoisomer thereof; or a pharmaceuticalcomposition as claimed in any one of claims 21 to 22 in the manufacture of a medicament for treating a condition or disorder in a subject in need thereof.

25. The use as claimed in claim 23 or claim 24, wherein the condition or disorder is a neurodegenerative disorder or a neurodevelopmental disorder selected from Alzheimer’s disease, Parkinson’s disease dementia, Rett syndrome, Huntington disease and Fragile X syndrome.

26. A compound as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt, a crystal, a co-crystal, a polymorph, a hydrate, a solvate, a prodrug, an A-oxide, a bioisostere, or a stereoisomer thereof; or a pharmaceutical composition as claimed in any one of claims 21 to 22; for use in the treatment or prophylaxis of a neurodegenerative disorder or a neurodevelopmental disorder selected from Alzheimer’s disease, Parkinson’s disease dementia, Rett syndrome, Huntington disease and Fragile X syndrome.

27. A compound as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt, a crystal, a co-crystal, a polymorph, a hydrate, a solvate, a prodrug, an A-oxide, a bioisostere, or a stereoisomer thereof; or a pharmaceutical composition as claimed in any one of claims 21 to 22; for use as a medicament.

28. A method for treatment or prophylaxis of a condition or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a deuterated Blarcamesine compound as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt, a crystal, a co-crystal, a polymorph, a hydrate, a solvate, a prodrug, an A-oxide, a bioisostere, or a stereoisomer thereof; or a pharmaceutical composition as claimed in any one of claims 21 to 22.

29. The method as claimed in claim 28, wherein the method comprises optionally administering an additional therapeutic agent selected from the group comprising Rivastigmine, Rasagiline, Huperzine A, Propentofylline, Baclofen, Carbidopa, Amantadine, Sertraline, Citalopram, Tetrabenazine, Trofinetide, Valproic acid,Ethosuximide, Gabapentin, Donepezil, wherein the additional therapeutic agent is administered prior to, concurrently with, or subsequently to the administration of the deuterated Blarcamesine compound.

30. The method as claimed in claim 28 or claim 29, wherein the condition or disorder is a neurodegenerative disorder or a neurodevelopmental disorder selected from Alzheimer’s disease, Parkinson’s disease dementia, Rett syndrome, Huntington disease and Fragile X syndrome.

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