Solid forms of posiphen d-tartrate and processes of preparation thereof

Abstract

Solid forms of (3aR)-l, 3a, 8-trimethyl-l, 2, 3, 3a, 8, 8a-hexahydropyrrolo (2, 3-b) indol- 5-yl phenyl-carbamate tartrate, including (3aR)-l, 3a, 8-trimethyl-l, 2, 3, 3a, 8, 8a- hexahydropyrrolo (2, 3-b) indol-5-yl phenyl-carbamate tartrate (posiphen D-tartrate Form A), (3aR)-l, 3a, 8-trimethyl-l, 2, 3, 3a, 8, 8a-hexahydropyrrolo (2, 3-b) indol-5-yl phenyl-carbamate tartrate dihydrate (posiphen D-tartrate Form B) and methods of preparing the same are disclosed.

Description

SOLID FORMS OF POSIPHEN D-TARTRATE AND PROCESSES OF PREPARATION THEREOFRELATED APPLICATIONS AND INCORPORATION BY REFERENCE

[0001] This application claims benefit of and priority from U.S. provisional patent application Serial No. 63 / 656,876, filed June 6, 2024.

[0002] Reference is made to U.S. provisional patent application Serial Nos. 63 / 580,011, filed September 1, 2023, and 63 / 509,356, filed June 21, 2023, the contents of which are hereby incorporated by reference in its entirety. Reference is also made to U.S. patent application Serial Nos. 10 / 042,586, filed January 9, 2002, now U.S. Patent No. 6,495,700, 10 / 415,765, filed February 6, 2004, now U.S. Patent No. 7,153,882, 10 / 593, 179, filed October 4 9, 2005, now U.S. PatentNo. 7,625,942, 12 / 357,115, filed January 21, 2009, now U.S. Patent No. 7,786,162, 12 / 841,888, filed July 22, 2010, now U.S. Patent No. 8,258,172, 13 / 041,211, filed March 4, 2011, now abandoned, 15 / 751,337, filed February 8, 2018, which is pending, 15 / 450,937, filed March 6, 2017, now U.S. Patent No. 10,383,851, 16 / 994,881, filed August 17, 2020, now U.S. Patent No. 11,400,075, 16 / 994,881, filed August 17, 2020, now U.S. PatentNo. 11,382,893, 16 / 994,921, filed August 17, 2020, now U.S. Patent No. 1 1,376,238, 16 / 827,194, filed March 23, 2020, now U.S. Patent No. 11,596,621.

[0003] The foregoing applications, and all documents cited therein or during their prosecution (“appln cited documents”) and all documents cited or referenced in the appln cited documents, and all documents cited or referenced herein (“herein cited documents”), and all documents cited or referenced in herein cited documents, together with any manufacturer’s instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.FIELD OF THE INVENTION

[0004] The invention relates to solid forms of posiphen, in particular, posiphen D-tartrate, methods of synthesis, preparation, and characterization, pharmaceutical compositions comprisingthe novel solid forms, and methods of treating and / or preventing various conditions by administering the novel solid forms.BACKGROUND OF THE INVENTION

[0005] The solid form (i.e., the crystalline or amorphous form) of a pharmaceutical compound can be important relative to its pharmacological properties and development as a viable active pharmaceutical ingredient (“API”).

[0006] Pharmaceutical products are often formulated from crystalline compounds because crystalline materials may provide higher levels of purity and resistance to physical and chemical instabilities under ambient conditions, relative to amorphous forms. Crystalline forms of a compound may in some cases, offer advantages over amorphous forms, such as improved solubility, stability, processing improvements, etc., and different crystalline forms (e.g. polymorphs of the compound) may offer greater or lesser advantages over one another. However, crystalline forms of a compound are not predictable, and in fact, are not always possible. It is a well-accepted principle that the formation of a new polymorphic or crystalline form (e.g. a new crystalline salt form) of a compound is totally unpredictable, and until a particular polymorph is prepared, there is no way to know whether it might exist, how to prepare it, or what its properties might be. Bernstein, J. Polymorphism in Molecular Crystals. New York: Oxford University Press, 9 (2002).

[0007] Unlike a crystalline solid, which has an orderly array of unit cells in three dimensions, amorphous forms lack long-range order because molecular packing is more random. As a result, amorphous organic compounds tend to have different properties than their crystalline counterparts. For example, amorphous compounds often have greater solubility than crystalline forms of the same compound. Thus, by way of example only, in pharmaceutical formulations whose crystalline forms are poorly soluble, amorphous forms may present attractive formulation options. As such, amorphous APIs may be used to improve physical and chemical properties of drugs, such as, for example, dissolution and bioavailability.

[0008] Solid forms of a compound, including both crystalline and amorphous forms, are of particular interest to the pharmaceutical industry, for example to those involved in the development of suitable dosage forms, if the solid form of the API (e.g. the crystalline polymorphic form or amorphous form) is not held constant during clinical or stability studies, the exact dosage formused or studied may not be comparable from one lot to another. In addition, regulatory agencies require solid form characterization and control of the API for approval.

[0009] Posiphen D-tartrate, (3aR)-l, 3a, 8-trimethyl-l, 2, 3, 3a, 8, 8a-hexahydropyrrolo (2, 3- b) indol-5-yl phenyl-carbamate tartrate, the D-tartaric acid salt of posiphen, has the following structure shown below. Posiphen is useful for treating and / or preventing a variety of conditions, such as, for example, combating neurodegenerative diseases such as Alzheimer's disease and disorders associated with abnormal production of amyloid precursor protein such as dementia. Examples of neurotoxic aggregating proteins include, but are not limited to, amyloid precursor protein (APP / A0), super oxide dismutase (SOD1), alpha-synuclein (SNCA), NAC, prion protein (PrP), huntingtin (HTT), microtubule associated protein (MAPT / Tau), TDP43, and C9orf72.

[0010] Accordingly, there is a need in the art to identify novel solid forms of posiphen D- tartrate, particularly those having advantageous chemical and / or physical properties. This invention answers those needs by providing novel solid forms of posiphen D-tartrate, including forms having improved properties.SUMMARY OF THE INVENTION

[0011] In accordance with various embodiments of the invention and after extensive experimentation, this disclosure provides novel and nonobvious crystalline forms of posiphen, including the two forms referred to herein as Forms A and B.

[0012] In accordance with various embodiments of the invention and after extensive experimentation, this disclosure provides processes of preparing novel and nonobvious crystalline forms of posiphen, including the two forms referred to herein as Forms A and B.

[0013] The invention in various embodiments also relates to pharmaceutical compositions and formulations comprising the novel crystalline forms, and methods of treating and / or preventing various conditions by administering the novel crystalline forms.

[0014] According to one aspect of the present invention, the present invention provides substantially pure (3aR)-l, 3a, 8-trimethyl-l, 2, 3, 3a, 8, 8a-hexahydropyrrolo (2, 3-b) indol-5-yl phenyl-carbamate tartrate dihydrate, or posiphen D-tartrate Form B that has little or no detectable impurities as shown in the data herein, by the analyses reported herein (e.g., Q-NMR and / headspace gas chromatography and / or HPLC and / or chiral HPLC), or posiphen D-tartrate Form B having a purity of greater than 99.5%, or having a purity of greater than 99.6%, or having a purity of greater than 99.7%, or having a purity of greater than 99.8%, advantageously as determined by one or more analyses reported herein (e.g., Q-NMR and / headspace gas chromatography and / or HPLC and / or chiral HPLC).

[0015] According to another aspect of the present invention, the present invention provides a process of preparing (+)-posiphen (Compound 10) comprising the steps of a) preparing a free base of Compound 8, wherein Compound 8 has the structure:and cleaving an ether of the free base to form Compound 9:wherein R’ is an alkyl group, A is an acid, and wherein Compound 8 is an acid salt of acid A; and b) converting Compound 9 to Compound 10: N.Ph

[0016] According to another aspect of the invention, the present invention provides for a process for producing (3aR)-l, 3a, 8-trimethyl-l, 2, 3, 3a, 8, 8a-hexahydropyrrolo (2, 3-b) indol- 5-yl phenyl-carbamate tartrate dihydrate (posiphen D-tartrate Form B), which has the formula:comprising a step c) of converting Compound 10 to posiphen D-tartrate Form B; wherein the posiphen D-tartrate Form B produced by the process has a purity of greater than 99.5% as determined by FLPLC.

[0017] In one embodiment, the posiphen D-tartrate Form B produced by the process as herein described is characterized by an X-ray powder diffraction pattern having characteristic peaks at 5.16, 8.56, 10.3, 11.24, 13.14, 13.48, 14.66, 15.24, 15.44, 15.76, 16.18, 16.54, 17.48, 17.94, 18.08, 19.72, 20.62, 20.76, 21.22, 21.5, 22.2, 22.54, 23.46, 24.4, 24.72, 26.4, 26.86, 27.14, 27.48, 27.7, 28.52, 28.74, 29.14, 29.96, 30.68, 31.14, 32.3, 33.26, 35.44, 37.24, and 37.74 in 20.

[0018] In one embodiment, the posiphen D-tartrate Form B has characteristics consistent with those described in Table 16 and / or FIG. 3 and / or as prepared according to the process as herein described and / or claimed and / or according to Example 2.

[0019] In one embodiment, the posiphen D-tartrate Form B produced by the process as herein described has a purity of greater than 99.6%, or having a purity of greater than 99.7%, or having a purity of greater than 99.8%, or having a purity of greater than 99.9% as determined by HPLC.

[0020] In one embodiment, the posiphen D-tartrate Form B produced by the process as herein described comprises two or fewer impurity peaks as determined by HPLC and / or no impurity peak greater than 0.2% as determined by HPLC.

[0021] In one embodiment, step a) comprises forming a free base of Compound 8 and reacting the free base with BBn to cleave an ether of the free base according to the following reaction scheme:

[0022] In one embodiment, the base is potassium carbonate.

[0023] In some embodiments, A is dibenzoyl-L-tartaric acid, (-)-di-p-toluoyl-L-tartaric acid, or L-malic acid. In one embodiment, R’ is an ethyl group, A is L-malic acid, and wherein Compound 8 is (+)-eserethole L-malate.

[0024] In one embodiment, step b) comprises reacting Compound 9 with 1, 1’- carbonyldiimidazole (CDI) to form an intermediate Compound 10-INT1 having the formula:and reacting Compound 10-INT1 with aniline to produce Compound 10 according to the following reaction scheme:

[0025] In one embodiment, step c) comprises reacting Compound 10 with D-tartaric acid to form posiphen D-tartrate Form B.

[0026] In one embodiment, step c) proceeds according to the following reaction scheme:and comprises the steps: c-i) reacting a solution of Compound 10 in ethanol with an aqueous solution of D-tartaric acid; and c-ii) adding a seed of posiphen D-tartrate Form B in a solution of methyl tert-butyl ether to the solution of Compound 10 and D-tartaric acid to form posiphen D-tartrate Form B.

[0027] In another aspect according to the present invention, the present invention provides for a process for producing Compound 8, comprising the steps of: i) aminating a Compound 0 having the general formula:wherein R is an alkyl and X is a halogen; with methylamine to form Compound 1, which has the structure:ii) reacting Compound 1 with an acylating agent having a leaving group L to form an intermediate Compound 2 having the structure:iii) cyclizing the intermediate Compound 2 to form Compound 3, which has the structure:iv) alkylating the hydroxyl group of Compound 3 with an alkylating agent to obtain Compound 4, which has the structure:wherein R’ is an alkyl and may be the same or different as the alkyl of Compound 0 of step i); v) performing an allylation reaction Compound 4 with an allyl compound to obtain Compound 5, which has the structure:vi) hydroxylating Compound 5 to form a vicinal diol and oxidatively cleaving said vicinal diol to obtain Compound 6 having the structure:vii) reacting Compound 6 with methylamine to form an imine and reducing said imine to obtain an intermediate Compound 7 having the structure:viii) obtaining Compound 8 by reducing the ketone of intermediate Compound 7, forming an acid salt of acid A, and performing a cycloaddition reaction:wherein Compound 8 has an optical purity greater than 99% as determined by chiral chromatography.

[0028] In one embodiment, alkylating step iv) comprises the step of simultaneously flowing a solution of Compound 3 dissolved in a solvent, a solution of the alkylating agent dissolved in a solvent, and an aqueous solution of a base through one or more microreactors; wherein the solution of Compound 3, the solution of the alkylating agent, and the solution of the base simultaneously contact each other; and wherein each microreactor is arranged in series and in fluid connection with each other.

[0029] In one embodiment, the alkylating agent of alkylating step iv) is diethyl sulfate.

[0030] In one embodiment, step v) of performing the allylation reaction comprises reacting Compound 4 with the allyl compound and a chiral phase transfer catalyst.

[0031] In one embodiment, the phase transfer catalyst comprises a cinchona alkaloid having the structure:wherein Ar is a monocyclic or polycyclic aryl or heteroaryl group whose carbon atoms may be substituted with a group R3;X is a halogen; each of R2and R3independently represents zero, mono, or up to a maximum allowed substitutions to its associated ring; each of R1, R2, and R3is independently a hydrogen or a substituent comprising deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, arylalkyl, alkoxy, aryloxy, amino, silyl, germyl, boryl, selenyl, alkenyl, cycloalkenyl, heteroalkenyl, alkynyl, aryl, heteroaryl, acyl, carboxylic acid, ether, ester, nitrile, isonitrile, sulfanyl, sulfinyl, sulfonyl, phosphino, or combinations thereof; and any two substituents can be joined or fused together to form a ring.

[0032] In one embodiment, the cinchona alkaloid comprises:

[0033] In one embodiment, the cinchona alkaloid is

[0034] In one embodiment, Compound 5 as obtained in step v) has an optical purity greater than 70%, or an optical purity greater than 71%, or an optical purity greater than 72%, or an optical purity greater than 73%, or an optical purity greater than 74%, or an optical purity of about 75% as determined by chiral chromatography.

[0035] In one embodiment, in step i), R is methyl and X is bromine.

[0036] In one embodiment, R and R’ are different from each other.

[0037] In one embodiment, Compound 0 is 4-bromoanisole, and step i) comprises aminating the 4-bromoanisole with methylamine in the presence of Q12O according to the following reaction scheme to obtain Compound 1A:

[0038] In one embodiment, step ii) comprises reacting Compound 1 A with 2-bromopropionyl bromide to obtain intermediate Compound 2A according to the following reaction scheme:

[0039] In one embodiment, step iii) comprises cyclizing the intermediate Compound 2 A to obtain Compound 3 A according to the following reaction scheme:In one embodiment, the intermediateCompound 2A is not isolated and / or purified and used directly in cyclizing step iii).

[0040] In one embodiment, step iv) comprises alkylating the hydroxyl group of Compound 3A with the alkylating agent, wherein the alkylating agent is diethyl sulfate, to obtain Compound 4A according to the following reaction scheme:

[0041] In one embodiment, step v) comprises performing the allylation reaction on Compound 4A to obtain Compound 5A according to the following reaction scheme:

[0042] In one embodiment step v) occurs in the presence of a chiral phase transfer catalyst.

[0043] In one embodiment, the chiral phase transfer catalyst comprises a a cinchona alkaloid having the structure:wherein Ar is a monocyclic or polycyclic aryl or heteroaryl group whose carbon atoms may be substituted with a group R3;X is a halogen; each of R2and R3independently represents zero, mono, or up to a maximum allowed substitutions to its associated ring; each of R1, R2, and R3is independently a hydrogen or a substituent comprising deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, arylalkyl, alkoxy, aryloxy, amino, silyl, germyl, boryl, selenyl, alkenyl, cycloalkenyl, heteroalkenyl, alkynyl, aryl, heteroaryl, acyl, carboxylic acid, ether, ester, nitrile, isonitrile, sulfanyl, sulfinyl, sulfonyl, phosphino, or combinations thereof; and any two substituents can be joined or fused together to form a ring.

[0044] In one embodiment, the cinchona alkaloid comprises:

[0045] In one embodiment, the cinchona alkaloid is

[0046] In one embodiment, step vi) comprises hydroxylating Compound 5A to form the vicinal diol and oxidatively cleaving said vicinal diol to obtain Compound 6A according to the following reaction scheme:

[0047] In one embodiment, step vii) comprises reacting Compound 6A with methylamine to form an imine and reducing the imine to form intermediate Compound 7A. In one embodiment, step vii) occurs according to the following reaction scheme:

[0048] In one embodiment, step viii) comprises reducing intermediate Compound 7A, performing cycloaddition, and forming a salt with L-malic acid to obtain Compound 8 A according to the following reaction scheme:wherein Compound 8A is (+)-eserethole L-malate.

[0049] According to another aspect of the present invention, the present invention provides a process of preparing (3aR)-l, 3a, 8-trimethyl-l, 2, 3, 3a, 8, 8a-hexahydropyrrolo (2, 3-b) indol-5- yl phenyl-carbamate tartrate (posiphen D-tartrate Form A), which has the formula:the process comprising a step cl) of converting Compound 10 to posiphen D-tartrate Form A; wherein the posiphen D-tartrate Form A produced by the process has a purity of greater than 99.5% as determined by HPLC.

[0050] In one embodiment, step cl) comprises reacting Compound 10 with D-tartaric acid to form posiphen D-tartrate Form A.

[0051] In one embodiment, the posiphen D-tartrate Form A produced by the process as herein described is characterized by an X-ray powder diffraction pattern having characteristic peaks at4.2, 8.5, 11.6, 11.8, 12.0, 12.8, 13.5, 14.4, 14.6, 14.9, 15.0, 15.2, 15.4, 16.2, 16.5, 17.0, 17.3, 17.9, 18.3, 18.6, 19.4, 19.6, 20.0, 20.4, 20.8, 21.0, 21.3, 21.8, 23.1, 23.6, 23.8, 24.2, 24.4, 24.8, 25.0,25.2, 25.6, 25.8, 26.9, 27.9, 28.0, 28.4, 29.0, 29.5, 30.0, 30.4, 30.7, 31.3, 31.6, 32.3, 32.6, 33.0, 34.6, 35.0, 35.7, 36.8, 37.7, and 38.6 in 20.

[0052] In one embodiment, the posiphen D-tartrate Form A has characteristics consistent with those described in Table 15 and / or FIG. 2 and / or as prepared according to the process as herein described and / or claimed and / or according to Example 4.

[0053] In one embodiment, the posiphen D-tartrate produced by the process as herein described has a purity of greater than 99.6%, or having a purity of greater than 99.7%, or having a purity of greater than 99.8%, or having a purity of greater than 99.9% as determined by HPLC.

[0054] According to another aspect of the present invention, the present invention provides for a pharmaceutical formulation comprising the (3aR)-l, 3a, 8-trimethyl-l, 2, 3, 3a, 8, 8a- hexahydropyrrolo (2, 3-b) indol-5-yl phenyl-carbamate tartrate dihydrate (posiphen D-tartrate Form B) having been prepared by the process as herein described whereby the posiphen D-tartrate Form B has a purity of greater than 99.5%, or having a purity of greater than 99.6%, or having a purity of greater than 99.7%, or having a purity of greater than 99.8%, advantageously as determined by one or more analyses reported herein (e.g., Q-NMR and / headspace gas chromatography and / or HPLC and / or chiral HPLC) and a pharmaceutically acceptable carrier.

[0055] According to another aspect of the present invention, the present invention provides a method of treating a neurological disorder in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition comprising posiphen D-tartrate Form B having been prepared by the methods disclosed herein that has little or no detectable impurities as shown in the data herein, by the analyses reported herein (e.g., Q-NMR and / headspace gas chromatography and / or HPLC and / or chiral HPLC), or posiphen D-tartrate Form B having a purity of greater than 99.5%, or having a purity of greater than 99.6%, or having a purity of greater than 99.7%, or having a purity of greater than 99.8%, advantageously as determined by one or more analyses reported herein (e.g., Q-NMR and / headspace gas chromatography and / or HPLC and / or chiral HPLC), and a pharmaceutically acceptable carrier; wherein the neurological disorder comprises:a chronic neurodegeneration, wherein the chronic neurodegeneration comprises Alzheimer’s disease, frontotemporal dementia, chronic traumatic encephalopathy, tauopathies, Parkinson’s and alpha-synucleopathies, prion disease, transmissible spongiform encephalopathies (TSE), Down Syndrome, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, or other dementias and neurodegenerative disorders which present as misfolding, aggregation and accumulation of proteins in the brain, resulting in axonal transport impairment, inflammation, and eventual cell death; or an acute neurodegeneration, wherein the acute neurodegeneration comprises traumatic brain injury, stroke, acute brain injury induced by brain ischemia, acute brain injury induced by insufficient oxygen supply to the brain, acute brain injury induced by anoxia or hypoxia, micro infarcts, acute brain injury induced by concussion, post-operative cognitive decline resulting from anesthesia or surgery-induced inflammation, acute brain injury induced by drowning, acute brain injury associated with whip lash, acute brain injury associated with bicycle crashes, acute brain injury associated with automobile accidents, shaken baby syndrome, acute brain injury induced by falling, acute brain injury associated with physical impact of the head, or acute angle-closure glaucoma; or a neuropsychiatric indication, wherein the neuropsychiatric indication comprises depression, schizophrenia, dementia, Alzheimer’s disease, anxiety, or substance abuse disorder; or a mental illness, wherein the mental illness comprises autism, attention deficithyperactivity disorder, bipolar disorder, depression and major depressive disorder, behavioral problems, posttraumatic stress disorder or schizophrenia.

[0056] In one embodiment, the neurological disorder is a chronic neurodegeneration.

[0057] In another embodiment, the chronic neurodegeneration comprises Alzheimer’s disease, frontotemporal dementia, chronic traumatic encephalopathy, tauopathies, Parkinson’s and alpha- synucleopathies, prion disease, transmissible spongiform encephalopathies (TSE), Down Syndrome, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, or other dementias and neurodegenerative disorders which present as misfolding, aggregation and accumulation of proteins in the brain, resulting in axonal transport impairment, inflammation, and eventual cell death.

[0058] In another embodiment, the neurological disorder is an acute neurodegeneration.

[0059] In another embodiment, the acute neurodegeneration comprises traumatic brain injury, stroke, acute brain injury induced by brain ischemia, acute brain injury induced by insufficient oxygen supply to the brain, acute brain injury induced by anoxia or hypoxia, micro infarcts, acute brain injury induced by concussion, post-operative cognitive decline resulting from anesthesia or surgery-induced inflammation, acute brain injury induced by drowning, acute brain injury associated with whip lash, acute brain injury associated with bicycle crashes, acute brain injury associated with automobile accidents, shaken baby syndrome, acute brain injury induced by falling, acute brain injury associated with physical impact of the head, or acute angle-closure glaucoma.

[0060] In another embodiment, the neurological disorder is a neuropsychiatric indication.

[0061] In another embodiment, the wherein the neuropsychiatric indication comprises depression, schizophrenia, dementia, Alzheimer’s disease, anxiety, or substance abuse disorder.

[0062] In another embodiment, the neurological disorder is a mental illness.

[0063] In another embodiment, the mental illness is wherein the mental illness comprises autism, attention deficit-hyperactivity disorder, bipolar disorder, depression and major depressive disorder, behavioral problems, posttraumatic stress disorder or schizophrenia.

[0064] In one embodiment, the method for treating the neurological disorder provides for a dosage of posiphen D-tartrate Form B from about 0.1 mg / kg to about 100 mg / kg of body weight.

[0065] In another embodiment, the method for treating neurological disorder provides for a dosage of posiphen D-tartrate Form B from about 1 mg / kg to about 20 mg / kg of body weight.

[0066] In one embodiment, the method provides for daily administration to the subject.

[0067] In another embodiment, the method provides for a single daily administration to the subject.

[0068] In another embodiment, the subject is human.

[0069] In another embodiment, the administering is oral administration.

[0070] Accordingly, it is an object of the invention not to encompass within the invention any previously known product, process of making the product, or method of using the product such that Applicants reserve the right and hereby disclose a disclaimer of any previously known product, process, or method. It is further noted that the invention does not intend to encompass within the scope of the invention any product, process, or making of the product or method of using the product, which does not meet the written description and enablement requirements of the USPTO(35 U.S.C. §112(a)) or the EPO (Article 83 of the EPC), such that Applicants reserve the right and hereby disclose a disclaimer of any previously described product, process of making the product, or method of using the product. It may be advantageous in the practice of the invention to be in compliance with Art. 53(c) EPC and Rule 28(b) and (c) EPC. All rights to explicitly disclaim any embodiments that are the subject of any granted patent(s) of applicant in the lineage of this application or in any other lineage or in any prior filed application of any third party is explicitly reserved. Nothing herein is to be construed as a promise.

[0071] It is noted that in this disclosure and particularly in the claims and / or paragraphs, terms such as “comprises”, “comprised”, “comprising” and the like can have the meaning attributed to it in U.S. Patent law; e.g., they can mean “includes”, “included”, “including”, and the like; and that terms such as “consisting essentially of’ and “consists essentially of’ have the meaning ascribed to them in U.S. Patent law, e.g., they allow for elements not explicitly recited, but exclude elements that are found in the prior art or that affect a basic or novel characteristic of the invention.

[0072] These and other embodiments are disclosed or are obvious from and encompassed by the following Detailed Description.BRIEF DESCRIPTION OF THE DRAWINGS

[0073] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0074] FIG. 1 shows an exemplary reaction scheme to obtain posiphen D-tartrate Form B starting from 4-bromoanisole.

[0075] FIG. 2 shows a PXRD trace of Form A.

[0076] FIG. 3 shows a PXRD trace of Form B.

[0077] The following detailed description, given by way of example, but not intended to limit the invention solely to the specific embodiments described, may best be understood in conjunction with the accompanying drawings.DETAILED DESCRIPTION OF THE INVENTION

[0078] In various embodiments, the invention relates to novel and nonobvious crystalline Forms A and B of posiphen D-tartrate. Exemplary methods of preparing these solid forms are found in the examples below.

[0079] Posiphen D-tartrate Form B is a dihydrate whereas posiphen D-tartate Form A is an anhydrate. As shown in the below characterization of posiphen D-tartrate Form A and posiphen D-tartrate Form B, the anhydrate posiphen D-tartrate Form A does not take up water in the solid state and form the corresponding dihydrate of posiphen D-tartrate Form B. On the other hand, posiphen D-tartrate Form B does not lose water when dried at typical manufacturing conditions. Therefore, posiphen D-tartrate Form A and posiphen D-tartrate Form B do not readily interconvert from anhydrate to dihydrate and are distinct and separate compounds that have separate and distinct crystalline phases. Conversion of Form A to Form B was observed at low pH after 24 hours.

[0080] Posiphen inhibits the synthesis of neurotoxic aggregating proteins, which have been implicated in mental illness and neurodegenerative and neurological diseases and disorders. Neurotoxic aggregating proteins, which, due to misfolding, aggregation and accumulation, impair axonal transport, cause inflammation, and kill nerve cells. Examples of neurotoxic aggregating proteins include, but are not limited to, amyloid precursor protein (APP / AP), super oxide dismutase (SOD1), alpha-synuclein (SNCA), NAC, prion protein (PrP), huntingtin (HTT), microtubule associated protein (MAPT / Tau), TDP43, and C9orf72.

[0081] Neurological disorders can include chronic neurodegeneration. Examples of chronic neurodegeneration include, but are not limited to Alzheimer’s disease, frontotemporal dementia, chronic traumatic encephalopathy, tauopathies, Parkinson’s and alpha-synucleopathies, prion disease, Down Syndrome, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis and other dementias and neurodegenerative disorders which present as misfolding, aggregation and accumulation of proteins in the brain, resulting in axonal transport impairment, inflammation, and eventual cell death.

[0082] For example, in Alzheimer's disease (AD), a progressive neurodegenerative condition leading to loss of memory, the major pathological hallmarks are characterized by the appearance of senile plaques which are primarily composed of A(3 and neurofibrillary tangle aggregates (Selkoe, 1997; Roberson and Harrell, 1997). Ap, a 40-42 residue peptide, is derived from a larger protein, PAPP (695-770 amino acids), whose biological functions remain to be fully determined but whose pathological role may be separated on the basis of its final proteolysed form (Checler, 1995; Selkoe, 1997). PAPP derivatives are generated by three enzymatic activities termed a-, P-, and y- secretases, to produce different protein fragments that are either neuroprotective oramyloidogenic. An aspartyl protease with P-secretase like properties has been identified (Hussaain et al., 1999; Sinha et al., 1999; Vassar et al., 1999; Yan et al., 1999), that may serve as a therapeutic marker. However, its value as a target for drug development is complicated by its location within two membranes (plasma and Golgi apparatus). Furthermore, the role of alternative compensatory activities remains unclear. Indeed, a second enzyme, Thimet oligopeptidase, was found capable of P-secretase activity in transfected COS cells (Koike et al., 1999). A major pharmaceutical industry focus has been to look for agents that reduce amyloidogenic processing using compounds that can manipulate PAPP to produce non-amyloidogenic by-products. However, it is important to note that the role of alternative PAPP fragments in AD is unclear.

[0083] Regarding regulatory mechanisms involved in PAPP processing, environmental agents have been demonstrated to accelerate PAPP turnover into its pathological Ap form (Selkoe, 1997). Furthermore, the cellular surrounding of neurons, particularly astrocytes and microglia, are additional and non-neuronal sources of PAPP (Funato et al., 1998; Akiyama et al., 2000). Thus, amyloid plaque occurrence is often associated with enlarged microglia, which produce interleuken-1 (IL-1), a potent mediator of astroglial proliferation and PAPP production (Akiyama et al., 2000). The fact that IL-1 can influence this process suggests that signaling pathways induced by cytokines are interconnected with PAPP metabolism. Another example of receptor-signaling association and PAPP homeostasis is demonstrated through the activation of muscarinic ml and m3 receptors which modify PAPP synthesis and processing through MAP kinase dependent and independent pathways (Felder et al., 1993; Nitsch et al., 1992 and 1994). Reductions in muscarinic receptors, as in AD, may alter PAPP metabolism and result in subsequent Ap deposition. Cholinergic system impairment has been reversed with moderate success by the use of anticholinesterases (Greig et al., 1995; Brossi et al., 1996), the only approved drugs for AD treatment.

[0084] Anticholinesterases dramatically improves cognitive performance in rodents and is in clinical trials (Greig et al., 1995; Patel et al., 1998). Studies of rats with forebrain cholinergic lesions that are known to dramatically increase PAPP in cholinergic projection areas have shown that anticholinesterases can protect against this and additionally, reduce PAPP production in naive animals (Haroutunian et al., 1997). Both PAPP processing and cholinesterase activity are affected in the AD brain (Bronfman et al., 1996). The anticholinesterase, tacrine, has been shown todecrease 0APP and Ap in neuronal cells in vitro (Lahiri et al., 1998). Current studies have focused on the molecular changes induced by compounds such as posiphen.

[0085] Neurological disorders can also include acute neurodegeneration. Examples of acute neurodegeneration include, but are not limited to traumatic brain injury, stroke, acute brain injury induced by brain ischemia, acute brain injury induced by insufficient oxygen supply to the brain, acute brain injury induced by anoxia or hypoxia, micro infarcts, acute brain injury induced by concussion, post-operative cognitive decline resulting from anesthesia or surgery-induced inflammation, acute brain injury induced by drowning, acute brain injury associated with whip lash, acute brain injury associated with bicycle crashes, acute brain injury associated with automobile accidents, shaken baby syndrome, acute brain injury induced by falling, acute brain injury associated with physical impact of the head, and acute angle-closure glaucoma.

[0086] Neurological disorders can also include neuropsychiatric indications. Examples of neuropsychiatric indications include, but are not limited to depression, schizophrenia, dementia, Alzheimer’s disease, anxiety, and substance abuse disorder.

[0087] Neurological disorders can also include mental illness. Impaired neuronal communication, axonal transport, and abnormal levels of neurotoxic aggregating proteins have been implicated in mental illness. Examples of mental illnesses include, but are not limited to autism, attention deficit-hyperactivity disorder, bipolar disorder, depression and major depressive disorder, behavioral problems, posttraumatic stress disorder and schizophrenia.

[0088] It is the cholinergic action of anticholinesterases that provides the compounds their ability to improve cognitive performance in both animal models and humans. Likewise, it is the cholinergic action that is also dose limiting for these same compounds (nausea, sweating, GI effects) (Becker et al., 1991). Conversely, the (+)-enanti omers are unable to inhibit either acetylcholinesterase (AChE., EC 3.1.1.7.) or butyryl cholinesterase (BChE., EC 3.1.1.8.), and hence have no cholinergic action. The (+)-enantiomers are also unnatural isomers and thus, need to be synthesized. Synthetic procedures provide a mixture of (+)- and (-)- forms that require early separation into optically pure forms to eventually obtain the final products. The preparation and pharmacologic activity of posiphen D-tartrate are described in, for example, U.S. Pat. Nos. 6,495,700, 7,153,882, 7,625,942, 7,786,162, 8,258,172, 10,383,851, 11,376,238, 11,382,893, 11,400,075, 11,596,621, WO 2003 / 059909, Yu, et al. Antiinflamm. Antiallergy Agents Med. Chem. 2012; 12(2): 117-128, Kuo et al. Am. J. Neurodegener. Dis. 2019; 8(1): 1-15, Maccecchini et al.,J. Neurol. Neurosurg. Psychiatry 2012; 83:894-902, all of which are incorporated herein by reference.

[0089] While therapeutic efficacy is a primary concern for a therapeutic agent such as posiphen D-tartrate, as discussed above, the solid form of a pharmaceutical drug candidate is also important. For example, each solid form of a drug candidate can have different solid state (physical and chemical) properties. The differences in physical properties exhibited by a different solid form of an API, such as a polymorph of the original compound, can affect pharmaceutical parameters such as storage stability, compressibility and density, all of which may be important in formulation and product manufacturing, and solubility and dissolution rates, which may be important factors in determining bioavailability. Because these practical physical properties can be influenced by the solid form of the API, they can significantly impact the selection of a compound as an API, the ultimate pharmaceutical dosage form, the optimization of manufacturing processes, and absorption in the body. Moreover, finding the most adequate form for further drug development can reduce the time and the cost of that development. It may also be beneficial to identify and characterize additional crystal forms so that they may be recognized if they appear during drug development and / or manufacturing.

[0090] Obtaining pure solid forms, then, can be extremely useful in drug development, as it generally permits better characterization of the drug candidate's chemical and physical properties. Crystalline forms often have more favorable chemical and physical properties than amorphous forms of the same compound. As such, one or more crystalline forms may possess more favorable pharmacology than amorphous forms or be easier to process, or may have better storage stability.

[0091] The present invention provides processes for obtaining posiphen D-tartrate Form B in high yields and high purity. Advantages of the present process include accessing Form B from precursor compounds of high purity and high optical purity. These processes help to improve the overall purity of the Form B polymorph.

[0092] Posiphen D-tartrate Form B has the formula:and is a D-tartrate dihydrate salt of posiphen.

[0093] Accordingly, described herein are processes of obtaining posiphen, which may undergo subsequent conversion to either posiphen D-tartrate Form B having the above structure or other forms of posiphen (e.g., posiphen D-tartrate Form A).

[0094] The synthesis of posiphen may begin from Compound 8 having the structure:the process comprising the steps of a) preparing a free base of Compound 8, wherein Compound 8 has the structure:and cleaving an ether of the free base of Compound 8 to form Compound 9:wherein R’ is an alkyl group, A is an acid, and wherein Compound 8 is an acid salt of acidA; and b) converting Compound 9 to Compound 10:

[0095] In step a), Compound 8 can comprise an acid salt derivative of (+)-eserethole. For example, Compound 8 can be (+)-eserethole L-malate where R’ is ethyl and A is L-malic acid such that Compound 8 is an L-malate salt. Because the first step in the process comprises cleavage of the ether of Compound 8, any suitable ether may be present. For example, R’ in Compound 8,in addition to ethyl as found in (+)-eserethole L-malate, can include any linear and branched alkyls such methyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl, tert-butyl, secbutyl, and neo-pentyl.

[0096] Compound 8 can also be a salt of any acid, preferably an organic acid. Examples include, but are not limited to formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, P-hydroxybutyric, salicylic, galactaric and galacturonic acids. Preferably, the acid is L-malic acid, which has been observed to improve the chiral purity as described further herein.

[0097] Preferably, in some embodiments, Compound 8 is (+)-eserethole L-malate, and is also referred to as Compound 8A:

[0098] Compound 8A, an L-malate acid salt, is first converted into a corresponding free base via reaction with a base. Any suitable base may be used as long as it is compatible with the solvent used. Examples of bases include, but are not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, cesium hydroxide (i.e. metal hydroxide bases), sodium carbonate, potassium carbonate, lithium carbonate (i.e. metal carbonate bases), potassium bicarbonate, sodium bicarbonate (i.e. metal bicarbonate bases), ammonia, triethylamine (i.e. amine bases), sodium acetate, potassium acetate (i.e. metal carboxylate bases), sodium methoxide, sodium ethoxide, sodium tert-butoxide (i.e. metal alkoxide bases). In some embodiments, the base is potassium carbonate.

[0099] Cleavage of the ether of the free base of Compound 8 can be accomplished by any suitable reagent and may include, but is not limited to strong acids such as HBr and HI and Lewis acids such as BBn.

[0100] An exemplary transformation of Compound 8 into Compound 9 is shown in the following reaction scheme:

[0101] In step b), Compound 9 is converted to Compound 10, posiphen, via the formation of an intermediate carbamate at the hydroxyl group of Compound 9. Any method or reagent used to form the intermediate carbamate may be used in this step. For example, reagents may include phenylisocyanate or 1, 1’ -carbonyldiimidazole (CDI) in combination with aniline. Although reaction with CDI includes formation of an intermediate carbamate bearing an imidazole, reacting Compound 9 with CDI provides advantages such as being able to utilize milder reaction conditions and formation of an intermediate compound that is highly reactive to aniline, which lead to improved yields over other isocyanate precursors. Further, isocyanates are potential human carcinogens and using CDI circumvents using an isocyanate to obtain a similar compound.

[0102] An exemplary reaction scheme to form Compound 10, posiphen, via the reaction of Compound 9 with CDI to form an intermediate Compound 10-INT1 :that is subsequently reacted with aniline to produce Compound 10.

[0103] In some embodiments, the conversion of Compound 10-INT1 to Compound 10 via reacting with aniline may occur in the presence of an acid and any suitable solvent to speed up the rate of reaction. Any acid may be used to speed up the rate of reaction of the conversion of Compound 10-INT1 to Compound 10. Examples of acids may include but are not limited to hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, phosphoric acids, perchloric, tetrafluoroboronic, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p- toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, P-hydroxybutyric, salicylic, galactaric and galacturonic acids. In some embodiments, the acid is hydrochloric acid in ethyl acetate.

[0104] In some embodiments, the conversion of Compound 9 to Compound 10 via intermediate Compound 10-INT1 occurs according to the following reaction scheme:

[0105] In some embodiments, Compound 10-INT1 may be separately isolated and characterized and may also be collected and stored for future use. In some embodiments, following conversion of Compound 9 to Compound 10-INT1 via reaction with CDI, the reaction contents are directly used for the synthesis of Compound 10, posiphen, without any further purification.

[0106] Posiphen having the structure of Compound 10, may be used to obtain Form B or any other form (e.g., Form A). Thus, in some embodiments, conversion of Compound 10 to posiphen D-tartrate Form B comprises a step c) of converting Compound 10 to posiphen D-tartrate Form B. In some embodiments, the posiphen D-tartrate Form B produced by the process has a purity of greater than 99.5% as determined by HPLC. In some embodiments, the posiphen D-tartrate Form B produced by the process has a purity of greater than 99.6%, greater than 99.7%, greater than 99.8%, or greater than 99.9% as determined by HPLC.

[0107] More in particular, in step c), Compound 10, or posiphen, undergoes conversion to Form B via the formation of the tartate dihydrate salt in a reaction with D-tartaric acid. Posiphen can be mixed with D-tartaric acid in water and any other applicable solvent to yield the tartrate dihydrate of Form B. In some embodiments, the solvent may comprise a co-solvent mixture of water, ethanol, and methyl tert-butyl ether. In some embodiments, the formation of Form B may be promoted via the addition of a seed of Form B and may lead to increased yield via the promotion of the desired Form B. The seed to promote formation of Form B may be added in any amount and may be, for example, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about 1% (w / w).

[0108] The posiphen D-tartrate Form B produced by the present process has high purity and can be substantially pure and free of impurities as determined by HPLC using methods and parameters herein described. In some embodiments, the posiphen D-tartrate Form B produced by the process has a purity of greater than 99.0%, greater than 99.1%, greater than 99.2%, greater than 99.3%, greater than 99.4%, greater than 99.5%, greater than 99.6%, greater than 99.7%,greater than 99.8%, or greater than 99.9% as determined by HPLC. In some embodiments, the posiphen D-tartrate Form B produced by the present process has a purity of 100% as determined by HPLC.

[0109] As characterized and analyzed by HPLC, the posiphen D-tartrate Form B produced by the present process comprises ten or fewer impurity peaks as determined by HPLC, nine or fewer impurity peaks as determined by HPLC, eight or fewer impurity peaks as determined by HPLC, seven or fewer impurity peaks as determined by HPLC, six or fewer impurity peaks as determined by HPLC, five or fewer impurity peaks as determined by HPLC, four or fewer impurity peaks as determined by HPLC, three or fewer impurity peaks as determined by HPLC, or two or fewer impurity peaks as determined by HPLC. In some embodiments, the posiphen D-tartrate Form B produced by the present process comprises only one impurity peak as determined by HPLC. In some embodiments, the posiphen D-tartrate Form B produced by the process comprises zero impurity peaks as determined by HPLC.

[0110] Even if impurities are present, the posiphen D-tartrate Form B produced by the present process, when characterized by HPLC, does not comprise an impurity peak greater than 0.5%, greater than 0.4%, greater than 0.3%, greater than 0.2%, greater than 0.1%, or greater than 0.05%.

[0111] In some embodiments, posiphen, Compound 10, can be converted to posiphen D- tartrate Form A via a step cl) of converting Compound 10 to posiphen D-tartrate Form A.

[0112] More in particular, in step cl), Compound 10, or posiphen, undergoes conversion to Form A via the formation of the tartrate salt in a reaction with D-tartaric acid. Posiphen can be mixed with D-tartaric acid in any applicable solvent to yield the tartrate dihydrate of Form A. In some embodiments, the solvent may comprise ethanol along with a co-solvent mixture of ethanol and an ether. In some embodiments, the ether is MTBE. In some embodiments, the formation of Form A may be promoted via the addition of a seed of Form A. The seed to promote formation of Form A may be added in any amount and may be, for example, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about 1% (w / w).

[0113] The posiphen D-tartrate Form A produced by the present process has high purity and can be substantially pure and free of impurities as determined by HPLC using methods and parameters herein described. In some embodiments, the posiphen D-tartrate Form A produced bythe process has a purity of greater than 99.0%, greater than 99.1%, greater than 99.2%, greater than 99.3%, greater than 99.4%, greater than 99.5%, greater than 99.6%, greater than 99.7%, greater than 99.8%, or greater than 99.9% as determined by HPLC. In some embodiments, the posiphen D-tartrate Form A produced by the present process has a purity of 100% as determined by HPLC.

[0114] As characterized and analyzed by HPLC, the posiphen D-tartrate Form A produced by the present process comprises ten or fewer impurity peaks as determined by HPLC, nine or fewer impurity peaks as determined by HPLC, eight or fewer impurity peaks as determined by HPLC, seven or fewer impurity peaks as determined by HPLC, six or fewer impurity peaks as determined by HPLC, five or fewer impurity peaks as determined by HPLC, four or fewer impurity peaks as determined by HPLC, three or fewer impurity peaks as determined by HPLC, or two or fewer impurity peaks as determined by HPLC. In some embodiments, the posiphen D-tartrate Form A produced by the present process comprises only one impurity peak as determined by HPLC. In some embodiments, the posiphen D-tartrate Form A produced by the process comprises zero impurity peaks as determined by HPLC.

[0115] Even if impurities are present, the posiphen D-tartrate Form A produced by the present process, when characterized by HPLC, does not comprise an impurity peak greater than 0.5%, greater than 0.4%, greater than 0.3%, greater than 0.2%, greater than 0.1%, or greater than 0.05%.

[0116] In another aspect of the present invention, the present invention provides for a process of preparing Compound 8, which is used as a precursor in the synthesis of posiphen and permit access to preparation of various forms and polymorphs of posiphen such as posiphen D-tartrate Form B and / or posiphen D-tartrate Form A.

[0117] Step i) of the process for preparing Compound 8 involves the amination of a starting material, Compound 0, having the following general formula:with methylamine.

[0118] In the above formula of Compound 0, R is an alkyl group and X is a halogen or other suitable organic leaving group. In some embodiments, X is chlorine, bromine, or iodine. R mayinclude any linear and branched alkyls such methyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl, tert-butyl, sec-butyl, and neo-pentyl.

[0119] The amination produces Compound 1 having the following formula:which, in step ii) of the present process, undergoes a substitution reaction with an acylating agent having a leaving group L to form an intermediate Compound 2:

[0120] L can be any suitable leaving group. Preferably L is a halogen such as chlorine, bromine, or iodine. In some embodiments, L is bromine.

[0121] In step iii), intermediate Compound 2, which comprises the leaving group L undergoes cyclization at the carbon atom bearing the leaving group L. The cyclization may occur by any suitable reaction. In some embodiments, the cyclization occurs through a Friedel-Crafts alkylation using any suitable reagent such as, for example, aluminum trichloride, which also cleaves the ether OR of Compound 2. The reaction produces Compound 3, which has the structure:

[0122] Step iv) involves alkylation of the hydroxyl group of Compound 3 via use of an alkylating agent to produce a compound having the formula:

[0123] In the above formula of Compound 4, R’ is an alkyl group, which may be the same or different than the alkyl group R of the starting material of Compound 0. In some embodiments,the alkyl groups R and R’ are the same. In some embodiments, the alkyl groups R and R’ are different. In some embodiments, R is ethyl and R’ is methyl. Any alkylating agent that is able to react with hydroxyl groups in the formation of an ether may be used. In some embodiments the alkylating agent is a sulfate ester. In some embodiments, R’ is ethyl and the alkylating agent is diethyl sulfate.

[0124] Step v) involves allylation of the methylated carbon center of Compound 4. While any suitable allyl compound such as an allyl halide, including allyl chloride, allyl bromide, or allyl iodide may be used, the addition of an allyl group to the methylated carbon center presents the possibility of obtaining a mixture of stereoisomers. Preferably the stereocenter following allylation is an R stereocenter.

[0125] In view of obtaining the preferred R stereocenter, the allylation reaction may optionally include one or more phase transfer catalysts to improve optical purity and obtained the desired stereoisomer. In some embodiments, the phase transfer catalyst is a cinchona alkaloid having the structure:wherein Ar is a monocyclic or polycyclic aryl or heteroaryl group whose carbon atoms may be substituted with a group R3;X is a halogen; each of R2and R3independently represents zero, mono, or up to a maximum allowed substitutions to its associated ring; each of R1, R2, and R3is independently a hydrogen or a substituent comprising deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, arylalkyl, alkoxy, aryloxy, amino, silyl, germyl, boryl, selenyl, alkenyl, cycloalkenyl, heteroalkenyl, alkynyl, aryl, heteroaryl, acyl, carboxylic acid, ether, ester, nitrile, isonitrile, sulfanyl, sulfinyl, sulfonyl, phosphino, or combinations thereof; andany two substituents can be joined or fused together to form a ring.

[0126] In some embodiments, the cinchona alkaloid comprises:. In other embodiments, the cinchona alkaloid is preferably ion forms a compound having the structure:

[0128] In step vi) of the present process, the alkene group of Compound 5 undergoes a transformation to form an aldehyde. Any applicable method used to effect the transformation of an alkene to an aldehyde may be used. In some embodiments, ozonolysis followed by reductive workup (e.g., dimethyl sulfide, zinc dust, or triphenyl phosphine) may be used to form the aldehyde. In some embodiments, the alkene of Compound 5 first undergoes oxidative hydroxylation to form a vicinal diol followed by oxidative cleavage of the vicinal diol to produce an aldehyde compound. Preferably, potassium osmate is used to form the vicinal diol and sodium periodate is used for oxidative cleavage. The transformation of the alkene to an aldehyde results in Compound 6 having the structure:

[0129] The next step involves reacting the aldehyde of Compound 6 with methylamine to form an imine, which subsequently undergoes reduction to form an intermediate Compound 7 having the structure:

[0130] Any method of reducing the imine formed between the reaction between the aldehyde and methylamine may be used to form the intermediate Compound 7. In some embodiments, palladium on activated carbon (Pd / C) under a hydrogen atmosphere may be used to reduce the imine to the intermediate amine compound.

[0131] The ketone of the above intermediate Compound 7 is reduced to the corresponding secondary alcohol whose carbon center undergoes cyclization via substitution with the amine group. The substitution of the secondary alcohol can also result in a mixture of stereoisomers. Any additive or catalyst to improve the optical purity and preference for the desired stereocenter may be utilized. Preferably, the cyclization forms an S stereocenter.

[0132] Compound 8, used as a precursor material in the synthesis of posiphen D-tartrate Form A and Form B is obtained in step viii) and is an acid salt. Step viii) involves reduction of the ketone of intermediate Compound 7 and subsequent cycloaddition, followed by the formation of an acid salt of acid A to obtain Compound 8:

[0133] The acid used in formation of the acid salt of Compound 8 is a chiral resolving agent and facilitates separation of diastereomers. Any acid salt may be used as the chiral resolving agent in formation of Compound 8. Examples include, but are not limited to formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, P-hydroxybutyric, salicylic, galactaric, galacturonic, dibenzoyl-L-tartaric, and (-)-di-p-toluoyl-L-tartaric acids. In some embodiments, the acid is dibenzoyl-L-tartaric acid, (-)-di-p-toluoyl-L-tartaric acid, or L-malic acid. Preferably the acid is L-malic acid. In some embodiments, the optical purity of the precursor obtained via cyclization and reaction with an acid is greater than 85%, greater than 86%, greater than 87%, greater than 88%, greater than 89%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, or 100%.

[0134] Preferably, Compound 8, is (+)-eserethole L-malate, whose process of preparation is herein described in the following Examples.

[0135] In some embodiments, the starting material or Compound 0 is 4-bromoanisole, which is aminated in step i) with methylamine in the presence of Cu O according to the following reaction scheme:

[0136] Step ii) involves acylation of Compound 1A, preferably, with 2-bromopropionyl bromide to form the intermediate Compound 2A according to the following reaction scheme:

[0137] In step iii) the intermediate Compound 2A is cyclized using aluminum trichloride, which also results in the cleavage of the methyl ether of the intermediate Compound 2A to form Compound 3A as shown in the below reaction scheme:Et3N.HCI, AICI31 ,2-dichlorobenzene

[0138] In some embodiments, the intermediate Compound 2A may be isolated, characterized, and stored for future use. In some embodiments, the intermediate Compound 2A may be used directly in the next step without further purification or work up.

[0139] The hydroxyl group of Compound 3 A is alkylated in step iv). Preferably, the alkylating agent is diethyl sulfate and the reaction is performed under basic conditions according to the following reaction scheme to give Compound 4A:

[0140] Any method of combining and contacting the reactants may be used. For example, in some embodiments, Compound 3A along with the remaining reactants may be combined in bulkin a single reactor and stirred until completion of the reaction ahead of purification and characterization.

[0141] In some embodiments, flow chemistry techniques may be used to carry out the alkylation. Flow chemistry involves flowing solutions of the various reactants through one or more microreactors comprising microtubes in a continuous stream having a high area to volume ratio, thereby achieving rapid contact, mixing, and reaction of the reactants to effect the desired transformation. The crude reaction product can be collected in bulk at the end of the series of microreactors for purification, characterization, and use in the next step.

[0142] The tubes of the one or more microcreators used to contact reagents may be of any size and can have any inner diameter. Smaller inner diameters permit increased contact between the contacted reagents. In some embodiments, the inner diameter of the tubes of the one or more mi crocreactors can be about 0.1 mm, about 0.2 mm, about 0.3 mm, about 0.4 mm, about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9 mm about 1 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3 mm, about 3.5 mm, about 4 mm, about 4.5 mm, about 5 mm, about 6 mm, about 7 mm, about 8 mm, about 9 mm, or about 10 mm.

[0143] Parameters such as the number of microreactors can be adjusted as needed. For example, in some embodiments, the alkylation of step iv) can be carried out using flow chemistry techniques in one microreactor. In some embodiments, step iv) is carried out in more than one microreactor connected in series, more than two microreactors connected in series, more than three microreactors connected in series, more than four microreactors connected in series, more than five microreactors connected in series, more than six microreactors connected in series, more than six microreactors connected in series, more than six microreactors connected in series, more than six microreactors connected in series, or more than ten microreactors connected in series.

[0144] In some embodiments, the residence time of the reactants within the one or more microreactors can be varied. The residence time may increase or decrease by virtue of the number of microreactors utilized to carry out the desired transformation. In some embodiments, the alkylation of step iv) occurs over a residence time of about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 90 minutes, or about 120 minutes. In some embodiments, the residence time is about 10 minutes.

[0145] The temperature of the one or more microreactors may be adjusted according to the desired reaction conditions and as long as the temperature does not adversely affect the solvent used (e.g. volatility). Step iv) may be run at elevated or reduced temperatures. The temperatures of each of the one or more microreactors may be the same or different. In some embodiments, the temperature of the one or more microreactors is about 5 °C, about 10 °C, about 15 °C, about 20 °C, about 25 °C, about 30 °C, about 35 °C, about 40 °C, about 45 °C, about 50 °C, about 55 °C, about 60 °C, about 65 °C, about 70 °C, about 75 °C, about 80 °C, about 85 °C, about 90 °C, or about 95 °C.

[0146] In carrying out the alkylation of step iv), the reactants can each be introduced into the one or more microreactors as separate solutions. In some embodiments, one or more of the reactants may be combined in a first solution and introduced to the remaining reactants prepared as a second solution. In some embodiments, step iv) comprises preparing a solution of Compound 3 A, a solution of the alkylating agent, and a solution of the base, wherein each separate solution is simultaneously introduced into the one or more microreactors.

[0147] The yield from performing step iv) utilizing flow chemistry techniques is significantly improved as compared to a batch reaction. Flow chemistry can achieve yields greater than 80%, greater than 81%, greater than 82%, greater than 83%, greater than 84%, greater than 85%, greater than 86%, greater than 87%, greater than 88%, greater than 89%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99% as compared to the batch reaction.

[0148] In step v) Compound 4A undergoes an allylation reaction as shown in the following reaction scheme:

[0149] The allylation reaction of step v) is preferably carried out under strongly basic conditions with allylbromide. The allylation reaction involves introduction of a stereocenter and the reaction conditions can influence the optical purity and resulting enantiomeric excess of theresulting products. Preferably, the stereocenter formed by the allylation in Compound 5A is an R stereocenter.

[0150] In some embodiments, a chiral phase transfer catalyst may be used to promote formation of the desired stereocenter. In some embodiments, the phase transfer catalyst is present in an amount of about 0.01 eq, about 0.02 eq, about 0.03 eq, about 0.04 eq, about 0.05 eq, about 0.06 eq, about 0.07 eq, about 0.08 eq, about 0.09 eq, about 0.1 eq, about 0.12 eq, about 0.14 eq, about 0. 16 eq, about 0.18 eq, or about 0.2 eq. relative to the amount of the compound obtained in step iv). In some embodiments, step v) utilizes about 0.05 eq of the phase transfer catalyst relative to the amount of the compound obtained in step iv).

[0151] The chiral phase transfer catalyst used in the allylation of step v) promotes formation of the desired stereocenter, thereby improving yield of the desired stereoisomeric product. The optical purity achieved using the phase transfer catalyst can be greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, or about 75%.

[0152] Any chiral phase transfer catalyst that promotes formation of the desired stereocenter may be used. In some embodiments, the chiral phase transfer catalyst comprises a cinchona alkaloid having the structure:wherein Ar is a monocyclic or polycyclic aryl or heteroaryl group whose carbon atoms may be substituted with a group R3;X is a halogen; each of R2and R3independently represents zero, mono, or up to a maximum allowed substitutions to its associated ring; each of R1, R2, and R3is independently a hydrogen or a substituent comprising deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, arylalkyl, alkoxy, aryloxy, amino, silyl, germyl, boryl, selenyl, alkenyl, cycloalkenyl, heteroalkenyl, alkynyl, aryl,heteroaryl, acyl, carboxylic acid, ether, ester, nitrile, isonitrile, sulfanyl, sulfinyl, sulfonyl, phosphino, or combinations thereof; and any two substituents can be joined or fused together to form a ring.

[0153] In some embodiments, the cinchona alkaloid comprises:

[0154] In some embodiments, the cinchona alkaloid is preferably

[0155] In some embodiments, the starting materials of step v) may be combined into a single reactor. In some embodiments, the conversion of Compound 4A to Compound 5A may utilize more than one reactor. For example, in some embodiments, the starting material may be pumped in into a first reactor separately and after a particular reaction time, the reaction solution can bepumped into a second, subsequent reactor, and so forth for a series of reactors that may be in fluid connection with each other, such as via peristaltic pumps. The conversion increases from the first reactor to the final due to the increasing of reaction time and all the starting material would be converted when the reaction solution flows out of the last reactor. In some embodiments, the starting material can be continuously pumped into the reactor while the reaction solution continuously flows out of the final reactor for collection.

[0156] In step vi), the alkene of Compound 5A undergoes conversion to an aldehyde according to the following reaction scheme:

[0157] As detailed in the above reaction scheme, the alkene first reacts with potassium osmate and undergoes oxidative hydroxylation, forming a vicinal diol. Although not isolated and characterized, the vicinal diol is converted to the aldehyde via oxidative cleavage using sodium periodate.

[0158] In step vii), the aldehyde of Compound 6A undergoes conversion to an amine via formation of an imine and subsequent reduction of then imine based on the following reaction scheme:

[0159] First, the aldehyde reacts with methylamine to form the imine. The imine, which may or may not be characterized and isolated, is subsequently reduced in the presence of palladium on activated carbon under a hydrogen atmosphere to the intermediate Compound 7A. The intermediate Compound 7A may be isolated, characterized, and stored for further use, or may be used directly in the next step.

[0160] In the final step viii), the ketone of the intermediate Compound 7A is reduced to the corresponding secondary alcohol and cyclized with the amine before formation of an acid salt inthe presence of the respective acid, thereby forming Compound 8. As shown below, the intermediate Compound 7A is reduced, cyclized, and the corresponding L-malate salt (Compound 8A, (+)-eserethole L-malate) formed via reaction of the cyclized product with L-malic acid, the intermediate Compound 7A is reacted with L-malic acid to form, as shown in the following reaction scheme:

[0161] In step viii), the reduction of the ketone and subsequent cyclization is preferably accomplished via Red Al, otherwise known as sodium bis(2-methoxyethoxy)aluminium hydride, which has the structure:

[0162] Similar to the allylation reaction of Compound 4A in step v), the cyclization reaction following the reduction of the ketone can produce a mixture of stereoisomers. Preferably, an S stereocenter is formed. The resulting cyclized product can be reacted with an acid as a chiral resolving agent to form the corresponding acid salt and facilitate separation of diastereomers. In some embodiments, the acid is preferably L-malic acid.

[0163] The form of pharmaceutical compound can have an effect on physical properties such as the dissolution rate in aqueous fluid. The rate of dissolution of an API in a patient's stomach fluid may have therapeutic consequences since the dissolution rate impacts the rate at which an orally administered active ingredient may reach the patient's bloodstream.

[0164] Another such physical property is thermodynamic stability. The thermodynamic stability of an active ingredient may have consequences on the manufacturing process and storage stability of the API and / or the formulation.

[0165] A crystalline form of a compound generally possesses distinct crystallographic and spectroscopic properties when compared to other crystalline forms having the same chemical composition. Crystallographic and spectroscopic properties of the particular form are typicallymeasured by one or more techniques such as powder x-ray diffraction (PXRD), single crystal x- ray crystallography, solid state NMR spectroscopy, infrared spectroscopy (IR), or Raman spectroscopy, among other techniques. A particular solid form of a compound may often exhibit distinct thermal behavior as well. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC).

[0166] Certain polymorphic forms may exhibit enhanced thermodynamic stability or may be more readily manufactured in high purity in large quantities, and thus are more suitable for inclusion in pharmaceutical formulations. Certain polymorphs may display other advantageous physical properties such as lack of hygroscopic tendencies, improved solubility, and enhanced rates of dissolution due to different lattice energies. As such, finding the right conditions to obtain a particular solid form of the desired API (e.g., a particular crystalline polymorphic form or an amorphous form), with pharmaceutically acceptable properties, is critical to drug development, but can take significant time, resources, and effort.

[0167] In further embodiments, the invention relates to pharmaceutical compositions and formulations comprising the novel solid forms of posiphen D-tartrate, and methods of treating and / or preventing various conditions by administering the solid forms.

[0168] As used herein, the term “polymorph” refers to different crystalline forms of the same compound and other solid state molecular forms, including pseudopolymorphs. The terms “pseudopolymorph” and “pseudomorph” as used herein are interchangeable and are meant to include hydrates (i.e., water present in the crystalline structure) and solvates (i.e., solvents other than water) of the compound, of both a fixed or stoichiometric and variable nature. Different crystalline forms, such as polymorphs, have different crystal structures due to a different packing of the molecules in the lattice. This results in a different crystal symmetry and / or unit cell parameters which directly influences the physical properties of the form, including X-ray characteristics (both single-crystal and XRPD) of crystals or powders. A different polymorph, for example, will in general diffract at a different set of angles and will give different values for the intensities. Therefore, when available, X-ray techniques can be used to identify different polymorphs, or a solid form that comprises more than one polymorph, generally in a reproducible and reliable way, S. Bym et al., “Pharmaceutical Solids: A Strategic Approach to Regulatory Considerations,” Pharmaceutical Research, Vol. 12, No. 7, p. 945-954, 1995; J. K. Haleblian andW. McCrone, “Pharmaceutical Applications of Polymorphism,” Journal of Pharmaceutical Sciences, Vol. 58, No. 8, p. 911-929, 1969.

[0169] As used herein, the term “posiphen” refers to (+)-posiphen and may be used interchangeably.

[0170] As used herein, the term “posiphen D-tartrate” refers to (+)-posiphen D-tartate, in particular, the polymorphs of Form A and Form B. Specific designation to the polymorph of Form A or Form B is made where appropriate.

[0171] As used herein, the terms “XRPD” or “PXRD”, used interchangeably, refer to x-ray powder diffraction. Unless otherwise noted, XRPD analyses were performed on a Rigaku Smart Lab X-ray diffraction system.

[0172] The Rigaku Smart-Lab X-ray diffraction system was configured for reflection Bragg- Brentano geometry using a line source X-ray beam. The x-ray source was a Cu Long Fine Focus tube operated at 40 kV and 44 ma. That source provides an incident beam profile at the specimen that changes from a narrow line at high angles to a broad rectangle at low angles. Beam conditioning slits are used on the line X-ray source to ensure that the maximum beam size is less than 10 mm both along the line and normal to the line. The Bragg-Brentano geometry is a parafocusing geometry controlled by passive divergence and receiving slits with the specimen itself acting as the focusing component in the optics. The inherent resolution of Bragg-Brentano geometry is governed in part by the diffractometer radius and the width of the receiving slit used. Typically, the Rigaku Smart-Lab is operated to give peak widths of 0.1 ° 29 or less. The axial divergence of the X-ray beam is controlled by 5.0° Soller slits in both the incident and diffracted beam paths. Each powder specimen was prepared in a low background Si holder using light manual pressure to keep the sample surface flat and level with the reference surface of the sample holder. The single crystal Si low background holders have a small circular recess (7 mm diameter and about 1 min depth) that holds between 5 and 10 mg of powdered material. The standard measurement range was from 2 to 40° 29 using a continuous scan of 3 °29 per minute with an effective step size of 0.02 °29.

[0173] As used herein, the term “'H-NM ” refers to proton nuclear magnetic resonance spectroscopy. SolutionNMR data disclosed herein were acquired on a Bruker Avance NEO 400 spectrometer (400 MHz 'H) spectrometer. Proton chemical shifts are reported in ppm, referenced to the NMR solvent. Unless otherwise indicated, NMR data were collected at 25° C.

[0174] As used herein with respect to the various analytical techniques described herein and data generated therefrom, the terms “substantially the same as” or “substantially similar to” is meant to convey that a particular set of analytical data is, within acceptable scientific limits, sufficiently similar to that disclosed herein such that one of skill in the art would appreciate that the crystal form of the compound is the same as that of the present invention. One of skill in the art would appreciate that certain analytical techniques, such as, for example, XRPD, 'l I-NMR, LC / MS, IR, DSC, TGA, and Raman, will not produce exactly the same results every time due to, for example, instrumental variation, sample preparation, scientific error, etc. By way of example only, XRPD results (e.g., peak locations, intensities, and / or presence) may vary slightly from sample to sample, despite the fact that the samples are, within accepted scientific principles, the same crystalline form, and this may be due to, for example, preferred orientation or varying solvent or water content. It is well within the ability of those skilled in the art, looking at the data as a whole, to appreciate whether such differences indicate the same or a different form, and thus determine whether analytical data being compared to those disclosed herein are or are not substantially the same or similar to the solid form it is being compared with.

[0175] In this regard, and as is commonly practiced within the scientific community, it is not intended that the exemplary analytical data of the novel polymorphic forms of posiphen D-tartrate disclosed herein be met literally in order to determine whether comparative data represent the same form as those disclosed and claimed herein, such as, for example, whether each and every peak of an exemplary XRPD pattern of the novel polymorphic forms of posiphen D-tartrate disclosed herein is present in the comparative data, in the same location, and / or of the same intensity. Rather, as discussed above, it is intended that those of skill in the art, using accepted scientific principles, will make a determination based on the data as a whole regarding whether comparative analytical data represent the same or a different form than the novel polymorphic forms of posiphen D- tartrate disclosed herein.

[0176] As used herein, the term “pharmaceutical composition” refers to a mixture of at least one compound of the invention with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration.

[0177] “Pharmaceutically acceptable” refers to those properties and / or substances that are acceptable to the patient from a pharmacological / toxicological point of view and to the manufacturing pharmaceutical chemist from a physical / chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.

[0178] “Pharmaceutically acceptable carrier” refers to a medium that does not interfere with the effectiveness of the biological activity of the active ingredient(s) and is not toxic to the host to which it is administered.

[0179] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid fdler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0180] As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions.

[0181] As used herein, the “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, Pa.), which is incorporated herein by reference.

[0182] As used herein, the term “salt” embraces addition salts of free acids or free bases that are compounds useful within the invention. Suitable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, phosphoric acids, perchloric and tetrafluorob or onic acids. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p- toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, P-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable base addition salts of compounds useful within the invention include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, lithium, calcium, magnesium, potassium, sodium and zinc salts. Acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glutamine) and procaine. All of these salts may be prepared by conventional means from the corresponding free base compound by reacting, for example, the appropriate acid or base with the corresponding free base.

[0183] An “individual”, “patient” or “subject”, as that term is used herein, includes a member of any animal species including, but are not limited to, birds, humans and other primates, and other mammals including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, and dogs. Preferably, the subject is a human.

[0184] A “subject in need thereof’, as that term is used herein, indicates that the subject is suffering from a particular disease or disorder and has received a diagnosis or an indication of aparticular disease or disorder from a medical practitioner or that the subject is at risk of developing the disease or disorder.

[0185] The term “treat” or “treating”, as used herein, means reducing the frequency with which symptoms are experienced by a subject or administering an agent or compound to reduce the frequency and / or severity with which symptoms are experienced. As used herein, “alleviate” is used interchangeably with the term “treat.” Treating a disease, disorder or condition may or may not include complete eradication or elimination of the symptom. The term “therapeutic” as used herein means a treatment and / or prophylaxis

[0186] As used herein, “(3aR)-l, 3a, 8-trimethyl-l, 2, 3, 3a, 8, 8a-hexahydropyrrolo (2, 3-b) indol-5-yl phenyl-carbamate tartrate” refers to “posiphen D-tartrate Form A” or “Form A”, and are used interchangeably.

[0187] As used herein, “(3aR)-l, 3a, 8-trimethyl-l, 2, 3, 3a, 8, 8a-hexahydropyrrolo (2, 3-b) indol-5-yl phenyl-carbamate tartrate dihydrate” refers to “posiphen D-tartrate Form B” or “Form B”, and are used interchangeably.

[0188] As used herein, “Vol.” means the number of liters of a liquid ingredient per kilogram of the limiting reagent of a reaction.

[0189] Any method may be used to analyze and characterize the purity of posiphen D-tartrate. For example, analytical methods for analyzing the purity of the posiphen D-tartrate Form B include, but are not limited to high-performance liquid chromatography (HPLC), chiral HPLC, gas chromatography, and quantitative nuclear magnetic resonance.

[0190] HPLC can be used to separate the components of a mixture into its separate components, including any detectable impurities. Briefly, a sample dissolved in a mobile phase is introduced into a column packed with particles of a stationary phase wherein the compound and its components each interact with the stationary phase based on the relative affinity of the components for the stationary phase to separate the mixture into its separate components. The components are separated based on the time taken to elute from the column wherein the elution time for each component differs based on the relative affinity for and interactions with the stationary phase. Normal phase HPLC utilizes a nonpolar mobile phase and a polar stationary phase whereas reverse phase HPLC utilizes a polar mobile phase and a nonpolar stationary phase. In a mixture involving stereoisomers, chiral HPLC can also be used to determine the chirality and enantiomeric excess of the mixture. Chiral HPLC involves the use of a chiral stationary phase thatcontains a single enantiomer wherein the stereoisomers contained in the mixture to be separated each interact differently with the chiral stationary phase to accomplish the separation.

[0191] Following synthesis of pharmaceutical products such as active pharmaceutical ingredients, there may be residual solvents left over from the manufacturing process. The presence of residual solvents may have an effect on the properties of the pharmaceutical product such as the potential toxicity of the product, solubility, crystallinity, and bioavailability. Gas chromatography, in particular headspace gas chromatography, can be used to analyze and quantify residual solvents in pharmaceutical products. Headspace sampling involves analysis of the gas layer of a dissolved sample in a vial versus direct injection of the dissolved sample itself. The components to be analyzed by headspace gas chromatography are required to be highly volatile. The injected headspace sample passes through a column containing a stationary phase while being carried by a nonreactive or inert gas wherein the various components of the mixture interact differently with the stationary phase of the column based on their affinity and elute at different rates based on these interactions.

[0192] Quantitative nuclear magnetic resonance (Q-NMR) is used to determine the purity of small molecules and can be used to obtain the concentration, purity, and mass fraction of the analyte of interest. In Q-NMR, the peak areas of the analyte are compared to the peak areas of a known amount of an internal calibrant. The measured peak area of a particular signal is proportional to the number of nuclei (e.g., protons) present. The purity of the analyte can be determined by comparing the peak areas of the analyte with those of the internal calibrant. The internal calibrant should have at least one peak that does not overlap with the analyte. On occasion, the calculated purity (e.g., mass fraction of analyte) may exceed the theoretical maximum of 100% Potential reasons for >100% purity values may include, but are not limited to differences in residual water content between the internal calibrant and the analyte, or the use of an internal calibrant that is significantly less pure than the target analyte.

[0193] In one embodiment, the present invention provides a method of inhibiting production of amyloid precursor protein in a cell, comprising contacting the cell with posiphen D-tartrate Form A, posiphen D-tartrate Form B, and any combination thereof. As used herein, “inhibiting” means decreasing the amount or concentration of amyloid precursor protein. “Inhibition” also refers to halting or reducing the production of amyloid protein precursor, wherein the concentration of amyloid protein precursor is reduced. Thus, the inhibition of production ofamyloid precursor protein can be measured, for example, by comparing the amount of amyloid precursor protein produced by cells after contacting the cells with the posiphen D-tartrate Form A, posiphen D-tartrate Form B, and any combination thereof, with the amount of amyloid precursor protein produced by control cells that have not been contacted with the posiphen D-tartrate Form A, posiphen D-tartrate Form B, and any combination thereof. In one embodiment, the cell that is contacted with the compound is in vivo, ex vivo, or in vitro. The cell of this invention can be a mammalian cell, desirably a human cell.

[0194] In a desirable embodiment, the compounds inhibit production of amyloid precursor protein, A 1-4O, and / or A0i-42 in a cell or a mammal by at least 30, 50, 60, 70, 80, 90, 95, or 100% compared to a buffer control, as measured using standard assays such as those described herein. In another desirable embodiment, the compound inhibits production of amyloid precursor protein, A 1-4O, and / or A01-42 in a cell or a mammal by at least 2, 5, 10, 20, or 50-fold compared to a buffer control, as measured using standard assays such as those described herein.

[0195] As used herein, “contacting” means exposure of at least one cell to a compound of the present invention. The cell of this invention can be, but is not limited to, a neural cell or supporting cell (e.g., glial or astrocyte). The term “neural cell” is defined as any cell that can be located in the central or peripheral nervous system or is a precursor or derivative thereof, including, for example, but not limited to, neuronal cells, glial cells, neural stem cells, neuronal stem cells and neuroblasts. The cell can be contacted in vitro with the compound, for example, by adding the compound to the culture medium (by continuous infusion, by bolus delivery, or by changing the medium to a medium that contains the compound), or the cell can be contacted with the compound in vivo (e.g., by local delivery, systemic delivery, intravenous injection, bolus delivery, or continuous infusion). In vitro contact may be preferred, for example, for measuring the effect of the compound on a population of cells. In vivo contact would be employed for inhibiting production of amyloid precursor protein in a subject in need of such inhibition, (e.g., a subject) with a neurodegenerative disease or disorder, for example, Alzheimer's disease.

[0196] The subject of this invention can be any mammal that produces amyloid precursor protein, such as a primate and more desirably, a human. The subject of this invention can also be domesticated animals, such as cats, dogs, etc., livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, etc.).

[0197] The duration of contact with a cell or population of cells is determined by the time the compound is present at physiologically effective levels or at presumed physiologically effective levels in the medium or extracellular fluid bathing the cell or cells. Desirably, the duration of contact is 1-48 hours and, more desirably, for 24 hours, but such time would vary based on the half-life of the compound.

[0198] In another embodiment, the present invention also provides a method of inhibiting production of amyloid precursor protein in a subject, comprising administering to the subject an effective amount of the posiphen D-tartrate Form A, posiphen D-tartrate Form B, and any combination thereof in a pharmaceutically acceptable carrier, whereby the compound inhibits production of amyloid precursor protein in the subject.

[0199] In a desirable embodiment, the compounds of the invention inhibit production of amyloid precursor protein, A01-4O, and / or A0i-42 in the subject or in a sample from the subject by at least 30, 50, 60, 70, 80, 90, 95, or 100% compared to a buffer control, as measured using standard assays such as those described herein. In another desirable embodiment, the compound inhibits production of amyloid precursor protein, A01-4O, and / or A0i-42 in the subject or in a sample from the subject by at least 2, 5, 10, 20, or 50-fold compared to a buffer control, as measured using standard assays such as those described herein.

[0200] The compounds of the present invention can be administered in vivo to a subject in need thereof by commonly employed methods for administering compounds in such a way to bring the compound in contact with cells. The compounds of the present invention can be administered orally, parenterally, transdermally, extracorporeally, topically or the like, although oral or parenteral administration is typically desired. Parenteral administration of the compounds of the present invention, if used, is generally characterized by injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution of suspension in liquid prior to injection, or as emulsions. As used herein, “parenteral administration” includes intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, intra-articular and intratracheal routes. Additionally, the compound can be administered via a slow release or sustained release system such that a constant dosage is maintained. The compounds can also be administered using polymer-based delivery systems, including, for example, microencapsulation, which techniques are well known in the art.

[0201] The dosage of the compound varies depending on the weight, age, sex and condition of the subject as well as the method and route of administration. As an example, the dosage of the compound is from about 0.1 mg / kg to about 100 mg / kg of body weight. The lower limit for the dosage can be about 0.1, 0.5, 1, 2, 5, 10, 15, 20, 25, 30, or 40 mg / kg and the upper limit can be about 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, or 100 mg / kg. Any lower limit can be used with any upper limit. More desirably, the compound is administered in vivo in an amount of about 1 to about 20 mg / kg. Thus, an administration regimen could include long-term, daily treatment. By “long-term” is meant at least two weeks and, desirably, several weeks, months, or years of duration. Necessary modifications in this dosage range may be determined by one of ordinary skill in the art using only routine experimentation given the teachings herein. See Remington's Pharmaceutical Sciences (Martin, E. W., ed., latest edition), Mack Publishing Co., Easton, Pa. The dosage can also be adjusted by the individual physician in the event of any complication.

[0202] The compounds can be administered conventionally as compositions containing the active compound as a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required diluent (i.e., carrier or vehicle). Depending on the intended mode of administration, the compound can be in pharmaceutical compositions in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, gels, or the like, desirably in unit dosage form suitable for single administration of a precise dosage. The compositions will include, as noted above, an effective amount of the selected compound in combination with a pharmaceutically acceptable carrier and, in addition, may include other medicinal compounds, pharmaceutical compounds, carriers, adjuvants, diluents, etc. By “pharmaceutically acceptable” is meant a material that is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with the selected compound without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.

[0203] Administration of a compound useful within the invention may be achieved in a number of different ways, using methods known in the art. The therapeutic and prophylactic methods of the invention thus encompass the use of pharmaceutical compositions comprising the compounds useful within the invention to practice the methods of the invention. The pharmaceuticalcompositions useful for practicing the invention may be administered to deliver a dose of 1 ng / kg / day to 100 mg / kg / day.

[0204] The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w / w) active ingredient.

[0205] Although the description of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions that are suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions of the invention is contemplated include, but are not limited to, humans and other primates, mammals including commercially relevant mammals such as non-human primates, cattle, pigs, horses, sheep, cats, and dogs.

[0206] Typically, dosages which may be administered in a method of the invention to an animal, preferably a human, range in amount from 0.5 pg to about 50 mg per kilogram of body weight of the animal. While the precise dosage administered will vary depending upon any number of factors, including but not limited to, the type of animal and type of disease state being treated, the age of the animal and the route of administration, the dosage of the compound will preferably vary from about 1 pg to about 10 mg per kilogram of body weight of the animal. More preferably, the dosage will vary from about 3 pg to about 1 mg per kilogram of body weight of the animal.

[0207] Pharmaceutical compositions that are useful in the methods of the invention may be prepared, packaged, or sold in formulations suitable for oral, parenteral, topical, buccal, or another route of administration. Other contemplated formulations include projected nanoparticles, liposomal preparations, resealed erythrocytes containing the active ingredient, and immunologically based formulations.

[0208] The formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, suchpreparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit.

[0209] A pharmaceutical composition of the invention may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses. As used herein, a “unit dose” is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

[0210] In one embodiment, the compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions of the invention comprise a therapeutically effective amount of a compound or conjugate of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers that are useful, include, but are not limited to, glycerol, water, saline, ethanol and other pharmaceutically acceptable salt solutions such as phosphates and salts of organic acids. Examples of these and other pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey).

[0211] The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.

[0212] Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, vaginal, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode or administration,known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and / or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents.

[0213] As used herein, “additional ingredients” include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials. Other “additional ingredients” that may be included in the pharmaceutical compositions of the invention are known in the art and described, for example in Genaro, ed. (1985, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.), which is incorporated herein by reference.

[0214] The composition of the invention may comprise a preservative from about 0.005% to 2.0% by total weight of the composition. The preservative is used to prevent spoilage in the case of exposure to contaminants in the environment. Examples of preservatives useful in accordance with the invention include but are not limited to those selected from the group consisting of benzyl alcohol, sorbic acid, parabens, imidurea and combinations thereof. A particularly preferred preservative is a combination of about 0.5% to 2.0% benzyl alcohol and 0.05% to 0.5% sorbic acid.

[0215] The composition preferably includes an anti-oxidant and a chelating agent that inhibits the degradation of the compound. Preferred antioxidants for some compounds are BHT, BHA, alpha-tocopherol and ascorbic acid in the preferred range of about 0.01% to 0.3% and more preferably BHT in the range of 0.03% to 0.1% by weight by total weight of the composition. Preferably, the chelating agent is present in an amount of from 0.01% to 0.5% by weight by total weight of the composition. Particularly preferred chelating agents include edetate salts (e g. di sodium edetate) and citric acid in the weight range of about 0.01% to 0.20% and more preferably in the range of 0.02% to 0.10% by weight by total weight of the composition. The chelating agent is useful for chelating metal ions in the composition that may be detrimental to the shelflife of theformulation. While BHT and disodium edetate are the particularly preferred antioxidant and chelating agent respectively for some compounds, other suitable and equivalent antioxidants and chelating agents may be substituted therefore as would be known to those skilled in the art.

[0216] Liquid suspensions may be prepared using conventional methods to achieve suspension of the active ingredient in an aqueous or oily vehicle. Aqueous vehicles include, for example, water, and isotonic saline. Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin. Liquid suspensions may further comprise one or more additional ingredients including, but not limited to, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents. Oily suspensions may further comprise a thickening agent. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose. Known dispersing or wetting agents include, but are not limited to, naturally occurring phosphatides such as lecithin, condensation products of an alkylene oxide with a fatty acid, with a long chain aliphatic alcohol, with a partial ester derived from a fatty acid and a hexitol, or with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively). Known emulsifying agents include, but are not limited to, lecithin, and acacia. Known preservatives include, but are not limited to, methyl, ethyl, or n- propyl-para-hydroxybenzoates, ascorbic acid, and sorbic acid. Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin. Known thickening agents for oily suspensions include, for example, beeswax, hard paraffin, and cetyl alcohol.

[0217] Liquid solutions of the active ingredient in aqueous or oily solvents may be prepared in substantially the same manner as liquid suspensions, the primary difference being that the active ingredient is dissolved, rather than suspended in the solvent. As used herein, an “oily” liquid is one which comprises a carbon-containing liquid molecule and which exhibits a less polar character than water. Liquid solutions of the pharmaceutical composition of the invention may comprise each of the components described with regard to liquid suspensions, it being understood that suspending agents will not necessarily aid dissolution of the active ingredient in the solvent.Aqueous solvents include, for example, water, and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.

[0218] Powdered and granular formulations of a pharmaceutical preparation of the invention may be prepared using known methods. Such formulations may be administered directly to a subject or used, for example, to form tablets, to fill capsules, or to prepare an aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto. Each of these formulations may further comprise one or more of dispersing or wetting agent, a suspending agent, and a preservative. Additional excipients, such as fillers and sweetening, flavoring, or coloring agents, may also be included in these formulations.

[0219] For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying compounds, pH buffering compounds and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc. Thus, the compositions are administered in a manner compatible with the dosage formulation and in a therapeutically effective amount. As discussed above, precise amounts of active ingredient required to be administered depend on the judgment of the practitioner and are peculiar to each individual.

[0220] A pharmaceutical composition of the invention may also be prepared, packaged, or sold in the form of oil-in-water emulsion or a water-in-oil emulsion. The oily phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin, or a combination of these. Such compositions may further comprise one or more emulsifying agents such as naturally occurring gums such as gum acacia or gum tragacanth, naturally occurring phosphatides such as soybean or lecithin phosphatide, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partialesters with ethylene oxide such as polyoxyethylene sorbitan monooleate. These emulsions may also contain additional ingredients including, for example, sweetening or flavoring agents.

[0221] Methods for impregnating or coating a material with a chemical composition are known in the art, and include, but are not limited to methods of depositing or binding a chemical composition onto a surface, methods of incorporating a chemical composition into the structure of a material during the synthesis of the material (i.e., such as with a physiologically degradable material), and methods of absorbing an aqueous or oily solution or suspension into an absorbent material, with or without subsequent drying.

[0222] Controlled or sustained release formulations of a composition of the invention may be made using conventional technology, in addition to the disclosure set forth elsewhere herein. In some cases, the dosage forms to be used can be provided as slow or controlled release of one or more active ingredients therein using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profde in varying proportions. Suitable controlled release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the compositions of the invention.

[0223] Controlled release of an active ingredient can be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds. The term “controlled release component” in the context of the present invention is defined herein as a compound or compounds, including, but not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes, nanoparticles, or microspheres or a combination thereof that facilitates the controlled release of the active ingredient.Administration / Dosing

[0224] The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either prior to or after a diagnosis of disease. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

[0225] Administration of the compositions of the present invention to a subject, preferably a mammal, more preferably a human, may be carried out using known procedures, at dosages and for periods of time effective to prevent or treat disease. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the activity of the particular compound employed; the time of administration; the rate of excretion of the compound; the duration of the treatment; other drugs, compounds or materials used in combination with the compound; the state of the disease or disorder, age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well-known in the medical arts. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound of the invention is from about 1 and 5,000 mg / kg of body weight / per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

[0226] The compound may be administered to an animal as frequently as several times daily, or it may be administered less frequently, such as once a day, once a week, once every two weeks, once a month, or even less frequently, such as once every several months or even once a year or less. The frequency of the dose will be readily apparent to the skilled artisan and will depend upon any number of factors, such as, but not limited to, the type and severity of the disease being treated, the type and age of the animal, etc. The formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit.

[0227] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention 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 subject, composition, and mode of administration, without being toxic to the subject.

[0228] A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition 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.

[0229] In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such a therapeutic compound for the treatment of a disease in a subject.

[0230] In one embodiment, the compositions of the invention are administered to the subject in dosages that range from one to five times per day or more. In another embodiment, the compositions of the invention are administered to the subject in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks. It will be readily apparent to one skilled in the art that the frequency of administration of the various combination compositions of the invention will vary from subject to subject depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, the invention should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any subject will be determined by the attending physical taking all other factors about the subject into account.

[0231] In one embodiment, the present invention is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a composition of the invention, alone or in combination with a second pharmaceutical agent; and instructions for using the composition to treat, prevent, or reduce one or more symptoms of a disease in a subject.

[0232] Routes of administration of any of the compositions of the invention include oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal, and (trans)rectal), intravesical,intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

[0233] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.Oral Administration

[0234] For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. Other formulations suitable for oral administration include, but are not limited to, a powdered or granular formulation, an aqueous or oily suspension, an aqueous or oily solution, a paste, a gel, toothpaste, a mouthwash, a coating, an oral rinse, or an emulsion. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.

[0235] Tablets may be non-coated or they may be coated using known methods to achieve delayed disintegration in the gastrointestinal tract of a subject, thereby providing sustained release and absorption of the active ingredient. By way of example, a material such as glyceryl monostearate or glyceryl distearate may be used to coat tablets. Further by way of example, tablets may be coated using methods described in U.S. Pat. Nos. 4,256,108; 4,160,452; and 4,265,874 to form osmotically controlled release tablets. Tablets may further comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination of these in order to provide for pharmaceutically elegant and palatable preparation.

[0236] Hard capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. Such hard capsules comprise the active ingredient, andmay further comprise additional ingredients including, for example, an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin.

[0237] Soft gelatin capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. Such soft capsules comprise the active ingredient, which may be mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0238] For oral administration, the compositions of the invention may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents; fillers; lubricants; disintegrates; or wetting agents. If desired, the tablets may be coated using suitable methods and coating materials such as OPADRY® film coating systems available from Colorcon, West Point, Pa. (e.g., OPADRY® OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OPADRY® White, 32K18400).

[0239] Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl para-hydroxy benzoates or sorbic acid). Liquid formulations of a pharmaceutical composition of the invention which are suitable for oral administration may be prepared, packaged, and sold either in liquid form or in the form of a dry product intended for reconstitution with water or another suitable vehicle prior to use.

[0240] A tablet comprising the active ingredient may, for example, be made by compressing or molding the active ingredient, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing, in a suitable device, the active ingredient in a free-flowing form such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, a surface active agent, and a dispersing agent. Molded tablets may be made by molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least sufficient liquid to moisten the mixture. Pharmaceutically acceptable excipients used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, binding agents, and lubricating agents. Known dispersing agents include, but are not limited to, potato starch and sodium starch glycollate. Known surface-active agentsinclude, but are not limited to, sodium lauryl sulphate. Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate. Known granulating and disintegrating agents include, but are not limited to, corn starch and alginic acid. Known binding agents include, but are not limited to, gelatin, acacia, pre-gelatinized maize starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. Known lubricating agents include, but are not limited to, magnesium stearate, stearic acid, silica, and talc.

[0241] Granulating techniques are well known in the pharmaceutical art for modifying starting powders or other particulate materials of an active ingredient. The powders are typically mixed with a binder material into larger permanent free-flowing agglomerates or granules referred to as a “granulation.” For example, solvent-using “wet” granulation processes are generally characterized in that the powders are combined with a binder material and moistened with water or an organic solvent under conditions resulting in the formation of a wet granulated mass from which the solvent must then be evaporated.

[0242] Melt granulation generally consists in the use of materials that are solid or semi-solid at room temperature (i.e. having a relatively low softening or melting point range) to promote granulation of powdered or other materials, essentially in the absence of added water or other liquid solvents. The low melting solids, when heated to a temperature in the melting point range, liquefy to act as a binder or granulating medium. The liquefied solid spreads itself over the surface of powdered materials with which it is contacted, and on cooling, forms a solid granulated mass in which the initial materials are bound together. The resulting melt granulation may then be provided to a tablet press or be encapsulated for preparing the oral dosage form. Melt granulation improves the dissolution rate and bioavailability of an active (i.e. drug) by forming a solid dispersion or solid solution.

[0243] U.S. Pat. No. 5,169,645 relates to directly compressible wax-containing granules having improved flow properties. The granules are obtained when waxes are admixed in the melt with certain flow improving additives, followed by cooling and granulation of the admixture. In certain embodiments, only the wax itself melts in the melt combination of the wax(es) and additives(s), and in other cases both the wax(es) and the additives(s) will melt.

[0244] The present invention also includes a multi-layer tablet comprising a layer providing for the delayed release of one or more compounds of the invention, and a further layer providingfor the immediate release of a medication for treatment of a disease. Using a wax / pH-sensitive polymer mix, a gastric insoluble composition may be obtained in which the active ingredient is entrapped, ensuring its delayed release.Parenteral Administration

[0245] As used herein, “parenteral administration” of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue. Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, intraocular, intravitreal, subcutaneous, intraperitoneal, intramuscular, intrasternal injection, intratumoral, and kidney dialytic infusion techniques.

[0246] Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multi-dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in dry (i.e. powder or granular) form for reconstitution with a suitable vehicle (e.g. sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.

[0247] The pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations may be prepared using a non-toxic parenterally acceptable diluent or solvent, such as water or 1,3-butanediol, for example. Otheracceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di -glycerides. Other parentally administrable formulations that are useful include those which comprise the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer systems. Compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt.Topical Administration

[0248] A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for topical administration. There are several advantages to delivering compounds, including drugs or other therapeutic agents, into the skin (dermal drug delivery) or into the body through the skin (transdermal drug delivery). Transdermal compound delivery offers an attractive alternative to injections and oral medications. Dermal compound delivery offers an efficient way to deliver a compound to the skin of a mammal, and preferably a human, and provides a method of treatment of the skin, or otherwise provides a method of affecting the skin, without the need to break or damage the outer layer of the skin. In the present invention, dermal delivery, by way of a dermally acting compound of the invention, provides these advantages for treatment of a skin-related condition, disorder or disease.

[0249] A number of compounds, including some drugs, will penetrate the skin effectively simply because the molecules are relatively small and potent at small doses of 0.1 mg to 15 mg / day (Kanikkannan et al., 2000, Curr. Med. Chem. 7:593-608). Many other compounds and drugs can be delivered only when an additional enhancement system is provided to “force” them to pass through the skin. Among several methods of transdermal drug delivery are electroporation, sonophoresis, iontophoresis, permeation enhancers (cyclodextrins), and liposomes. While the aforementioned methods are also included in the present invention for dermal delivery of the compounds of the invention, liposomes represent a preferred dermal delivery method.

[0250] The composition of the invention may consist of the active ingredient alone, in a form suitable for administration to a subject, or the composition may comprise at least one active ingredient and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these. The active ingredient may be present in the composition in the form of a physiologically acceptable ester or salt, such as in combination with aphysiologically acceptable cation or anion, as is well known in the art. Compositions of the invention will also be understood to encompass pharmaceutical compositions useful for treatment of other conditions, disorders and diseases associated with the skin.

[0251] In one aspect, a dermal delivery vehicle of the invention is a composition comprising at least one first compound that can facilitate dermal delivery of at least one second compound associated with, or in close physical proximity to, the composition comprising the first compound. As will be understood by the skilled artisan, when armed with the disclosure set forth herein, such delivery vehicles include, but should not be limited to, liposomes, nanosomes, phospholipid-based non-liposome compositions (e.g., selected cochleates), among others.

[0252] Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid preparations such as liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes, and solutions or suspensions. Topically administrable formulations may, for example, comprise from about 0.001% to about 90% (w / w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[0253] In one aspect of the invention, a dermal delivery system includes a liposome delivery system, and that the present invention should not be construed to be limited to any particular liposome delivery system. Based on the disclosure set forth herein, the skilled artisan will understand how to identify a liposome delivery system as being useful in the present invention.

[0254] The present invention also encompasses the improvement of dermal and transdermal drug delivery through the use of penetration enhancers (also called sorption promoters or accelerants), which penetrate into skin to reversibly decrease the barrier resistance. Many compounds are known in the art for penetration enhancing activity, including sulfoxides (such as dimethylsulfoxide, DMSO), azones (e.g. laurocapram), pyrrolidones (for example, 2-pyrrolidone, 2P), alcohols and alkanols (ethanol, or decanol), glycols (for example propylene glycol, PG, a common excipient in topically applied dosage forms), surfactants (also common in dosage forms) and terpenes. Other enhancers include oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethyl sulfoxide, polar lipids, or N-methyl-2-pyrrolidone.

[0255] In alternative embodiments, the topically active pharmaceutical or cosmetic composition may be optionally combined with other ingredients such as moisturizers, cosmeticadjuvants, antioxidants, chelating agents, surfactants, foaming agents, conditioners, humectants, wetting agents, emulsifying agents, fragrances, viscosifiers, buffering agents, preservatives, sunscreens and the like. In another embodiment, a permeation or penetration enhancer is included in the composition and is effective in improving the percutaneous penetration of the active ingredient into and through the stratum corneum with respect to a composition lacking the permeation enhancer. Various permeation enhancers, including oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethyl sulfoxide, polar lipids, or N- methyl-2-pyrrolidone, are known to those of skill in the art.

[0256] In another aspect, the composition may further comprise a hydrotropic agent, which functions to increase disorder in the structure of the stratum corneum, and thus allows increased transport across the stratum corneum. Various hydrotropic agents such as isopropyl alcohol, propylene glycol, or sodium xylene sulfonate, are known to those of skill in the art. The compositions of this invention may also contain active amounts of retinoids (i.e., compounds that bind to any members of the family of retinoid receptors), including, for example, tretinoin, retinol, esters of tretinoin and / or retinol and the like.

[0257] The composition of the invention may comprise a preservative from about 0.005% to 2.0% by total weight of the composition. The preservative is used to prevent spoilage in the case of an aqueous gel because of repeated patient use when it is exposed to contaminants in the environment from, for example, exposure to air or the patient's skin, including contact with the fingers used for applying a composition of the invention such as a therapeutic gel or cream. Examples of preservatives useful in accordance with the invention include but are not limited to those selected from the group consisting of benzyl alcohol, sorbic acid, parabens, imidurea and combinations thereof. A particularly preferred preservative is a combination of about 0.5% to 2.0% benzyl alcohol and 0.05% to 0.5% sorbic acid.

[0258] The composition preferably includes an antioxidant and a chelating agent which inhibit the degradation of the compound for use in the invention in the aqueous gel formulation. Preferred antioxidants for some compounds are BHT, BHA, alpha-tocopherol and ascorbic acid in the preferred range of about 0.01% to 5% and BHT in the range of 0.01% to 1% by weight by total weight of the composition. Preferably, the chelating agent is present in an amount of from 0.01% to 0.5% by weight by total weight of the composition. Particularly preferred chelating agents include edetate salts (e.g. disodium edetate) and citric acid in the weight range of about 0.01% to0.20% and more preferably in the range of 0.02% to 0.10% by weight by total weight of the composition. The chelating agent is useful for chelating metal ions in the composition which may be detrimental to the shelf life of the formulation. While BHT and disodium edetate are the particularly preferred antioxidant and chelating agent respectively for some compounds, other suitable and equivalent antioxidants and chelating agents may be substituted therefore as would be known to those skilled in the art.

[0259] Additional components may include, but should not be limited to those including water, oil (e.g., olive oil / PEG7), biovera oil, wax (e.g., jojoba wax), squalene, myristate (e.g., isopropyl myristate), triglycerides (e.g., caprylic triglyceride), Solulan 98, cocoa butter, shea butter, alcohol (e.g., behenyl alcohol), stearate (e.g., glycerol-monostearate), chelating agents (e.g., EDTA), propylene glycol, SEPIGEL (Seppic, Inc., Fairfield, N.J.), silicone and silicone derivatives (e.g., dimethicone, cyclomethicone), vitamins (e.g., vitamin E), among others.Buccal Administration

[0260] A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for buccal administration. Such formulations may, for example, be in the form of tablets or lozenges made using conventional methods, and may, for example, 0.1 to 20% (w / w) active ingredient, the balance comprising an orally dissolvable or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations suitable for buccal administration may comprise a powder or an aerosolized or atomized solution or suspension comprising the active ingredient. Such powdered, aerosolized, or aerosolized formulations, when dispersed, preferably have an average particle or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.Rectal Administration

[0261] A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for rectal administration. Such a composition may be in the form of, for example, a suppository, a retention enema preparation, and a solution for rectal or colonic irrigation.

[0262] Suppository formulations may be made by combining the active ingredient with a nonirritating pharmaceutically acceptable excipient which is solid at ordinary room temperature (i.e., about 20° C.) and which is liquid at the rectal temperature of the subject (i.e., about 37° C. in ahealthy human). Suitable pharmaceutically acceptable excipients include, but are not limited to, cocoa butter, polyethylene glycols, and various glycerides. Suppository formulations may further comprise various additional ingredients including, but not limited to, antioxidants, and preservatives.

[0263] Retention enema preparations or solutions for rectal or colonic irrigation may be made by combining the active ingredient with a pharmaceutically acceptable liquid carrier. As is well known in the art, enema preparations may be administered using, and may be packaged within, a delivery device adapted to the rectal anatomy of the subject. Enema preparations may further comprise various additional ingredients including, but not limited to, antioxidants, and preservatives.Additional Administration Forms

[0264] Additional dosage forms of this invention include dosage forms as described in U.S. Pat. Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837 and 5,007,790. Additional dosage forms of this invention also include dosage forms as described in U.S. Patent Applications Nos. 20030147952, 20030104062, 20030104053, 20030044466, 20030039688, and 20020051820. Additional dosage forms of this invention also include dosage forms as described in PCT Applications Nos. WO 03 / 35041, WO 03 / 35040, WO 03 / 35029, WO 03 / 35177, WO 03 / 35039, WO 02 / 96404, WO 02 / 32416, WO 01 / 97783, WO 01 / 56544, WO 01 / 32217, WO 98 / 55107, WO 98 / 11879, WO 97 / 47285, WO 93 / 18755, and WO 90 / 11757.

[0265] In another embodiment, the present invention provides a method of treating a disorder associated with abnormal production of amyloid precursor protein, such as, for example, dementia in a subject, comprising administering to the subject an effective amount of the posiphen D-tartrate Form A, posiphen D-tartrate Form B, and any combination thereof in a pharmaceutically acceptable carrier, whereby the compound treats the disorder in the subject. As used herein, the term “dementia” describes a neurodegenerative disorder that results from an organic brain disease in which a subject experiences usually irreversible deterioration of intellectual faculties with accompanying emotional disturbances. An example of dementia includes, but is not limited to, Alzheimer's disease. An example of another disorder that can be treated by the methods of this invention includes, but is not limited to, cerebral amyloidosis. In a desirable embodiment, a compound used for the treatment of dementia improves a symptom associated with dementia or Alzheimer's, stabilizes a symptom, or delays the worsening of a symptom. In other desirableembodiments, the compound increases the lifespan of a subject compared to the average life-span of corresponding subjects not administered the compound. In yet other desirable embodiments, the compound is used to prevent or delay the onset of dementia or Alzheimer's disease.

[0266] In another embodiment, the present invention also provides a method of inhibiting production of the amyloid precursor protein in Down syndrome comprising administering an effective amount of (3aR)-l, 3a, 8-trimethyl-l, 2, 3, 3a, 8, 8a-hexahydropyrrolo (2, 3-b) indol-5- yl phenyl-carbamate tartrate dihydrate (Form B) to a subject in need thereof. While not intending to be bound by one theory of the invention, the following may help to explain the relationship between the amyloid precursor protein in Down syndrome and that of Alzheimer's disease. In persons with Alzheimer's disease, amyloid fibrils (aggregates of A protein subunits) are deposited in the brain. A similar process occurs at an earlier age in people with Down Syndrome. Rumble et al. “Amyloid Ap protein and its precursor in Down's syndrome and Alzheimer's disease,” A. Engl. J. Med., 320(22): 1446-1452 (Jun. 1, 1989). Thus, the formation of the amyloid fibrils in Down Syndrome can be inhibited in a similar manner as it does in Alzheimer's disease. Further, the cerebrovascular amyloid protein from a case of adult Down syndrome has been isolated and purified. Amino acid sequence analysis showed it to be homologous to that of the beta protein of Alzheimer's disease. Glenner G & Wong C W “Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein,” Biochem Biophys Res Commun., 122(3): 1131- 5 (Aug. 16, 1984).

[0267] In general, an “effective amount” of a compound is that amount needed to achieve the desired result or results. Thus, for example, administering to a subject (e g., a human) with Alzheimer's disease an effective amount of a compound of the present invention can result in slowing, stopping, or even possibly reversing the deterioration of the subject's intellectual faculties and other accompanying neurological signs and symptoms. Therefore, the inhibition of the production of amyloid precursor protein, by the methods of the present invention, treats the subject with Alzheimer's disease. The effective amount of the compound needed to treat dementia is from about 0.5 mg to about 200 mg. The lower limit for the effective amount of the compound can be about 0.5, 1, 2, 5, 10, 20, 30, 40, 50, 100, or 150 mg, and the upper limit can be about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg. Any lower limit can be used with any upper limit. In one embodiment, when the subject is a human, the effective amount of compound to treat dementia is from about 0.5 to about 100 mg. In another embodiment, posiphenD-tartrate Form A can be used in these amounts to treat dementia. In a desired embodiment, posiphen D-tartrate Form B can be used in these amounts to treat dementia in a subject.

[0268] Any form of (3aR)-l, 3a, 8-trimethyl-l, 2, 3, 3a, 8, 8a-hexahydropyrrolo (2, 3-b) indol- 5-yl phenyl-carbamate tartrate can be delivered using formulations and doses from, for example, U.S. Pat. No. 7,786,162 (oral formulations and doses), U.S. Pat. No. 8,258,172 (transdermal formulations and doses), U.S. Pat. No. 10,383,851 (formulations and oral dosage in gelatin capsule form), U.S. Pat. No. 11,400,075 (formulations and doses), US 2018 / 0228771 (intravenous and intraocular administration).

[0269] In a desirable embodiment of any of the aspects of the invention, the compound inhibits cholinesterase activity, such as acetylcholinesterase or butyryl cholinesterase activity, by less than 80, 70, 60, 50, 40, 30, 20, 10, or 5% (in order of increasing preference) relative to a buffer only control. In other desirable embodiments, inhibition of cholinesterase activity, such as acetylcholinesterase or butyrylcholinesterase activity, by the compound is at least 2-, 5-, 10-, 20-, 50-, or 100-fold less than the inhibition of cholinesterase activity by the corresponding amount of posiphen D-tartrate Form A. In other desirable embodiments, inhibition of cholinesterase activity, such as acetylcholinesterase or butyryl cholinesterase activity, by posiphen D-tartrate Form A is at least 2-, 5-, 10-, 20-, 50-, or 100-fold less than the inhibition of cholinesterase activity by the corresponding amount of posiphen D-tartrate Form B. In yet other desirable embodiments, the compound is substantially free of cholinesterase inhibitory activity. Inhibition of cholinesterase activity can be measured using any standard assay. For example, the assay and the in vivo mouse model described in U.S. Pat. No. 4,791,107, which is incorporated by reference in its entirety, or the in vivo mouse model described herein can be used.

[0270] In other desirable embodiments of any of the aspects of the invention, the compound results in a less than 20-, 10-, 5-, or 2-fold increase in the amount of released lactate dehydrogenase (a marker of cell viability and integrity) relative to the amount of released lactate dehydrogenase in the absence of the compound or in the presence of a buffer control. In still other desirable embodiments, the amount of compound that is administered to a subject per kg body weight of the subject does not cause tremors or death when administered in the in vivo mouse model described herein. In yet other desirable embodiments, less than 80, 70, 60, 50, 40, 30, 20, 10, or 5% of the neuronal cells contacted with the compound are killed by the compound. In another desirableembodiment, the dose of the compound is equal to or greater than 1 mg / kg of body weight, 5 mg / kg, or 10 mg / kg.

[0271] In other desirable embodiments of any of the aspects of the invention, the compound inhibits production of amyloid precursor protein, A0i-4O, and / or APi-42by at least 30, 50, 60, 70, 80, 90, 95, or 100% compared to a buffer control. In another embodiment, the compound inhibits production of amyloid precursor protein, A i-4O, and / or Afli-42 by at least 30, 50, 60, 70, 80, 90, 95, or 100% compared to a buffer control, and inhibits cholinesterase activity by less than 80, 70, 60, 50, 40, 30, 20, 10, or 5% relative to a buffer only control. In other desirable embodiments, the compound inhibits intracellular and / or extracellular APP or Ap production. In yet other desirable embodiments, the compound inhibits production of amyloid precursor protein in a cell or mammal by at least 2-, 5-, 10-, 20-, or 50-fold more than it inhibits cholinesterase activity in the cell or mammal. In still other desirable embodiments, the amount of compound required to inhibit production of amyloid precursor protein in a cell or mammal by 50% (ICso value) is at least 2-, 5- , 10-, 20-, 50-, or 100-fold less than the amount of compound required to inhibit cholinesterase activity by 50% (ICso value) in the cell or mammal, as measured using standard assays.

[0272] Although the present invention and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined in the appended claims.

[0273] The present invention will be further illustrated in the following Examples which are given for illustration purposes only and are not intended to limit the invention in any way.Examples

[0274] FIG. 1 shows the overall reaction scheme to obtain posiphen D-tartrate Form B starting from 4-bromoanisole. The processes outlined in the reaction scheme of FIG. 1 are described herein in Examples 1-3: the synthesis of posiphen (Compound 10) from eserethole L-malate (Compound 8A); the synthesis of posiphen D-tartate Form B from posiphen (Compound 10); and the synthesis of eserethole L-malate malate (Compound 8A) from 4-bromoanisole.Example 1 - Synthesis of Posiphen

[0275] Preparation of posiphen, which can be used to access various forms and polymorphs of posiphen (e.g., posiphen D-tartrate Forms A and B) may begin from a precursor material, (+)- eserethole L-malate (Compound 8A), whose preparation is discussed in Example 3.

[0276] The overall reaction scheme for the synthesis of posiphen (Compound 10) starting from Compound 8A is shown below:Synthesis of (+)-Eseroline from Eserethole L-Malate

[0277] The first step starting from eserethole L-malate (Compound 8A) involves conversion of the (+)-eserethole L-malate to (+)-eseroline (Compound 9) via formation of a free base, in particular, an eserethole base, followed by the cleavage of an ether of the esetherole base as shown in the reaction scheme below:

[0278] An exemplary process is described below.

[0279] A reactor was charged with soft water soft water (5.0 vol.) and anhydrous potassium carbonate (2.5 eq). The mixture was stirred at 25±5 °C to obtain a clear solution. Eserethole L- malate (1.0 eq.) was subsequently charged into the reactor at 25±5 °C and stirred for 2 h at 25±5 °C after which dichloromethane (DCM) (6.0 vol.) was charged into the reactor and the resulting mixture stirred for at least 0.5 hours at 25±5 °C.

[0280] After mixing, the resulting aqueous and organic layers were separated and the organic layer collected. The aqueous layer was extracted with DCM (4.0 vol.). The organic layers were combined and concentrated at not more than (NMT) 40 °C under vacuum to 4.0-4.5 vol.

[0281] The water content of the resulting material was determined via Karl Fischer titration (KF), the criteria being < 0.10%. If the limit is not met, DCM (4.0 vol.) is charged into the reactor and the resulting solution concentrated to 4.0-4.5 vol. and resampled.

[0282] Upon meeting the limit, the resulting material was cooled and maintained at 5±5 °C while BBrs (3.0 eq.) was added dropwise into the reactor. The mixture was stirred for 1 h at 5±5 °C after which the solution was sampled by HPLC for the presence of eserethole base. The criteria limit is the area% of eserethole base <1%.

[0283] If the limit is not met, additional BBrs is added, and the resulting mixture stirred for 1 hour at 5±5 °C, after which the solution is resampled for presence of eserethole base under the same criteria.

[0284] The reaction mixture was concentrated at NMT 40 °C in vacuum down to 1.5-2.0 vol. DCM (5.0 vol.) was charged into the residue at NMT 30 °C and the reaction mixture was concentrated at NMT 40 °C in vacuum down to 1.5-2.0 vol. Additional DCM (5.0 vol.) was charged into the residue at NMT 30 °C and the resulting solution was charged into a biphasic mixture of 20% KHCO3 (aq.) (18 vol.) and DCM (5.0 vol.) at 5±5 °C in a dropwise manner. The reaction mixture was warmed to 25±5 °C and stirred for at least 0.5 hours at 25±5 °C until the aqueous phase reached a pH of at least 8. KHCO3 may be added to raise the pH.

[0285] Na2SO3 (0.05 eq.) was charged into the reactor at 25±5 °C and the mixture was stirred for at least 0.5 hours at 25±5 °C after which the organic layer was separated and collected. The aqueous layer was extracted with DCM (5.0 vol.x2), combined with the collected organic layer, and washed a solution of 20% NaCl (aq.) 3.0 vol. at 25±5 °C. The organic layers were then concentrated at NMT 40 °C (jacket temperature) under vacuum down to 3.0-3.5 vol.

[0286] Toluene (4.0 vol.) was added to the residue at NMT 30 °C and further concentrated at NMT 45 °C (jacket temperature) under vacuum down to 3.0-3.5 vol. The residue was sampled via gas chromatography for the presence of DCM with the criteria limit being the area% of DCM < 3%. If the limit is not met, additional toluene (4.0 vol.) can be charged into the reactor and concentrated to 3.0-3.5 vol. until the limit is met as determined by resampling the residue.

[0287] The reaction mixture was stirred for at least 1 hour at 30±5 °C prior to addition of n- heptane (3.0 vol.) into the residue over the course of at least 1 hour at 30±5 °C. The n-heptane solution was stirred for at least 1 hour at 30±5 °C prior to additional n-heptane (5.0 vol.) being charged into the residual over the course of at least 2 hours at 3O±5 °C and the reaction mixture was stirred further for at least 2 hours at 30±5 °C. The reaction mixture was cooled to -5±5 °C and stirred at this lower temperature for at least 2 hours.

[0288] The reaction solution was fdtered and the recovered cake washed with n-heptane (2.0 vol.) and dried for at least 2 hours under vacuum at 40±5 °C. The recovered cake was sampled for loss-on-drying (LoD), the criteria being < 3%. The sample was dried further until the limit is met.

[0289] The dry cake was sampled via HPLC for the (+)-eseroline product, the being the area% of the (+)-eseroline product > 95%.

[0290] If the limit is not met, the (+)-eseroline product can be recrystallized and further purified according to the following procedure until the limit is met.

[0291] DCM (5.0 vol.) was charged into the reactor along with the dry cake and the contents stirred for 0.5 h at 25±5 °C. Toluene was then charged into the reactor and the reaction solution concentrated at NMT 50 °C (jacket temperature) under vacuum to 3.0-3.5 vol. The residue was sampled via gas chromatography for the presence of DCM with the criteria limit being the area% of DCM < 3%. If the limit is not met, additional toluene (4.0 vol.) can be charged into the reactor and concentrated to 3.0-3.5 vol. until the limit is met as determined by resampling the residue.

[0292] Once the limit is met, the residue is stirred for 1 h at 30±5 °C after which n-heptane (5.0 vol.) is charged into the reactor at 30±5 °C and stirred for 2 h at 30±5 °C. After stirring for 2 h at 30±5 °C, the reaction mixture is cooled to -5±5 °C and stirred for another 2 h at this lower temperature.

[0293] The reaction mixture was then filtered and the recovered cake washed with n-heptane (2.0 vol.) and dried for at least 2 hours under vacuum at 40±5 °C.

[0294] The recovered cake was resampled for LoD, the criteria being < 3%. The sample was dried further until the limit is met.

[0295] The dry cake obtained from the recrystallization process was resampled via HPLC for the (+)-eseroline product, the being the area% of the (+)-eseroline product > 95%. The product was collected once the limit is met.

[0296] Results from an exemplary reaction batch are shown below:Table 1 . Characterization of Reaction Batch to Obtain (+)-EserolineTable 2. Results from Exemplary (+)-Eseroline SynthesisSynthesis of (+)-Posiphen

[0297] The next step involves conversion of the (+)-eseroline product obtained above to (+)- posiphen (Compound 10) as shown in the reaction scheme below:

[0298] An exemplary process is described below.

[0299] A reactor was charged with N, N-dimethylacetamide (DMAc) (7 vol.) and bubbled below solvent level with N2 for a minimum of 30 minutes with agitation.

[0300] The reaction mixture was sampled for KF, the limit being KF<0.1%. If the limit is not met, the DMAc is discarded from the reactor and the above process repeated until the limit is met.

[0301] Upon meeting the limit, the reactor temperature was adjusted to 25±5 °C, charged with eseroline (1.0 eq.) and 1, 1’ -carbonyldiimidazole (CDI) (1.05 eq.), and stirred for at least for 30 min at 25±5 °C. The reaction conversion to the intermediate imidazole carbamate was analyzed via HPLC, the limit being the area% of the eseroline starting material < 2%. If the limit is not met,additional CDI (remaining starting material %x 1.05 eq.) can be charged into the reactor and stirred for 0.5 h at 25±5 °C, and the conversion reanalyzed via HPLC as described above.

[0302] Upon meeting the limit, a solution of HCl / EtOAc (4 M) (3.7 eq.) was charged into the reactor at 25±5 °C and stirred for at least 30 min prior to aniline (1.2 eq.) being charged into the reactor at 25±5 °C. The reaction mixture was stirred for at least for 10 h at 25±5 °C.

[0303] The conversion to (+)-posiphen was analyzed and determined via HPLC, the limit being the area% of the peak corresponding to the imidazole carbamate intermediate < 2%. If the limit is not met, the reaction mixture is stirred for another 3 h and the conversion reanalyzed by HPLC. If the limit is still not met after the additional stirring time, additional aniline (remaining intermediate%x l.05 eq.) is charged into the reactor and stirred for an additional 3 h prior to resampling.

[0304] Upon meeting the limit, the reaction mixture was concentrated at NMT 40 °C under vacuum until approximately 8.5-9.5 vol. remained. The remaining reaction mixture was charged into 20% KHCO3 (aq.) (30 vol.) at 25±5 °C, filtered, and the cake washed with H2O (4 vol.).

[0305] The cake was slurried in H2O (10 vol.), refiltered, and rewashed with additional H2O (4 vol.). The wet cake was sampled for (+)-posiphen by HPLC, the criteria limit being the area% of (+)-posiphen > 97%.

[0306] Upon meeting the limit, the product is dried as described herein below. If the limit following slurrying and washing with water is not met, the product can be recrystallized according to the following procedure.

[0307] DM Ac (7.0 vol.) is charged into the reactor along with the wet cake into the reactor and the mixture is stirred for 0.5 h at 25±5 °C. Soft water (14.0 vol.) is then charged into the reactor and the mixture stirred for 2 h at 25±5 °C.

[0308] The cake is then filtered and washed with additional soft water (4.0 vol.). The resulting cake is slurried with H2O (10.0 vol.), filtered, and washed with additional soft water (4.0 vol.). The cake is reanalyzed for posiphen (> 97%). If the limit is met, the product is dried as described herein below and the product collected.

[0309] If the limit is still not met, a reactor is charged with EtOAc (0.8 vol.), methyl tert-butyl ether (MTBE) (3.2 vol.) and the wet cake, and warmed to at 40±5 °C for 1 h after which the product was cooled to 0±5 °C and stirred for an 2 h, refiltered, washed with MTBE (2.0 vol.), and reanalyzed for posiphen (> 97%). The recrystallization process can be repeated until the criterialimit for (+)-posiphen as analyzed by HPLC is met. The product is dried after the limit is met as described herein below.

[0310] The cake was dried under vacuum at 50 °C for 2 h and sampled for KF, the criteria being KF < 1%. The cake was dried under vacuum until the limit is met. The sample was collected.

[0311] Results from an exemplary reaction batch are shown below:Table 3. Characterization of Reaction Batch to Obtain (+)-PosiphenTable 4. Results from Exemplary (+)-Posiphen SynthesisExample 2 - Synthesis of Posiphen D-Tartrate Form B

[0312] The posiphen (Compound 10) obtained in Example 1 can be used to produce and access different forms and polymorphs of posiphen, including posiphen D-tartrate Form B. The conversion of posiphen to the tartrate dihydrate Form B (posiphen D-tartrate Form B) is illustrated in the reaction scheme below:Posiphen D-tartrate Form B

[0313] An exemplary process is described.

[0314] H2O (1.6 vol.) and D-tartaric acid (1.1 eq.) were charged into a drum and stirred for at least 0.5 h to obtain a clear solution.

[0315] EtOH (5.0 vol.) and (+)-posiphen (Compound 10) (1.0 eq.), were charged into a reactor and warmed to 5O±5 °C. The D-tartaric acid solution was charged into the reactor and stirred at 0±5 °C for at least 0.5 h to obtain a clear solution.

[0316] The solution was transferred to another reactor and cooled to 28±2 °C and seeds of posiphen D-tartrate Form B (0.5% w / w) were charged into the reactor. The mixture was stirred for at least 1 h at 28±5 °C after which MTBE (20 vol.) was added into the reactor at 28±5 °C and the mixture stirred for at least 1 hour at 28±5 °C.

[0317] The reaction mixture was cooled to 0±5 °C and stirred for 4 h at 0±5 °C. The reaction mixture was filtered, the cake washed with 4 vol. of a mixture of EtOH / Water / MTBE: 0.75 / 0.25 / 3, and dried at 40 °C under vacuum for at least 4 h.

[0318] The cake was sampled for KF, the criteria being KF < 8%. The cake was dried until the limit is met.

[0319] The recovered solid from the cake is posiphen D-tartrate Form B and characterized to verify conversion to posiphen D-tartrate Form B.

[0320] The crude Form B was sampled for residual solvent impurities by GC, the criteria limit being DCM < 480 ppm, toluene < 710ppm, n-heptane < 4000ppm, EtOAc < 4000ppm, DMAc < 870ppm, EtOH < 4000ppm, MTBE < 4000ppm

[0321] The material was also analyzed via XRPD for the characteristic peaks of Form B as previously described.

[0322] The purity of the obtained Form B was also analyzed by HPLC, the criteria being the area% of posiphen D-tartrate Form B > 97.0% and those of individual impurities < 0.5%.

[0323] Having satisfied the above test criteria, the finished product posiphen D-tartate Form B was collected.

[0324] If the criteria for XRPD, HPLC, and residual DMAc are met and the limits for other solvent residues are not met, the recovered solid is dried at 40 °C under vacuum until the limits are met.

[0325] If any of the criteria for XRPD, HPLC, and DMAc residues are not met, the recovered solid is recrystallized as follows.

[0326] H2O (1.5 vol.), EtOH (4.5 vol.), and the dry cake were charged into a reactor and warmed to 50±5 °C. The mixture was stirred for at least 0.5 h to obtain a clear solution and cooled to 28±2 °C. Seeds of posiphen D-tartrate Form B (0.5% w / w) were charged into the reactor and the mixture stirred for at least 1 h at 28±5 °C. MTBE (18 vol.) was then charged into the reactor at 28±5 °C and the mixture stirred for at least 1 h at 28±5 °C. The reaction mixture was cooled to 0±5 °C and stirred for 4 h at 0±5 °C.

[0327] The reaction mixture was filtered, the cake washed with 4 vol. of a mixture of EtOH / Water / MTBE: 0.75 / 0.25 / 3 and dried 40 °C under vacuum for at least 4 h. The cake as sampled for KF, the criteria being <8 % and dried until the limit is met.

[0328] Upon reaching an acceptable moisture level, the recovered solid posiphen D-tartrate Form B was recharacterized using the same criteria previously described.

[0329] Results from an exemplary reaction batch are shown below:Table 5. Characterization of Reaction Batch to Obtain Posiphen D-tartrate Form B^Quantitation limitTable 6. Results from Exemplary Synthesis of Posiphen D-tartrate Form BExample 3 - Synthesis of (+)-Eser ethole L-malate

[0330] The present invention also provides improved methods for the preparation of (+)- eserethole L-malate (Compound 8A) that may be used in the synthesis of posiphen as described in Example 1 to access different forms and polymorphs of posiphen such as D-tartrate Form A or posiphen D-tartrate Form B. Compound 8A may be produced from any appropriate starting material and an exemplary process for preparation of (+)-eserethole L-malate starting from 4- bromoanisole according to the present invention is described herein.Synthesis of Compound 1A from 4-Bromoanisole

[0331] Although any suitable starting material may be used, the present example utilizes 4- bromoanisole as the starting material. The reaction proceeds according to the following reaction scheme:4-Bromoanisole 1A

[0332] An exemplary process is described herein.

[0333] A reactor was purged with N2 three times and charged with 27% CH3NH2 (aq.) (16.0 L, 6.0 vol.), 4-bromoanisole (4.0 kg, 1 .0 eq.), and CU2O (306.1 g, 10% eq ). The reactor was then purged an additional three times with N2 and heated to 100±5 °C and stirred for at least 10 h at 100±5 °C. The reaction mixture was cooled to 20±5 °C and the conversion of the 4-bromoanisole was monitored and analyzed by HPLC, the criteria being the area% of 4-bromoanisole < 1%.

[0334] Upon complete conversion of the starting material, MTBE (20.0 L, 5.0 vol.) was charged into the reaction mixture and stirred. The organic and aqueous layers were separated. The organic layer was washed with 1 N NaOH (aq.) (20.0 L, 5.0 vol.).

[0335] The process starting from 4-bromoanisole was repeated five additional times. The parameters of each batch are shown in Table 7 below.

[0336] The organic phases of entries 2-6 were combined with that of entry 1 and distilled under vacuum until distillate was observed to no longer distill out. The end product was concentrated for not less than (NLT) 3 h at NMT 40 °C under vacuum.

[0337] 20.2 kg of the desired product as a brown oil was obtained and stored into a drum at25±5 °C.Table 7. Reaction Parameters and Conditions for Synthesis of Compound 1 ASynthesis of Compound 3A

[0338] The overall reaction scheme for the conversion of Compound 1A via intermediateCompound 2A is shown below:

[0339] DCM (265.9 kg, 10.0 vol.), Compound 1A (20.1 kg, 1.0 eq.), and triethylamine (TEA) (17.7 kg, 1.05 eq.) were charged into a reactor, which was cooled to 5±5 °C.

[0340] 2-Bromopropionyl bromide (33.3 kg, 1.05 eq.) was charged into the reactor at 5±5 °C and the reaction mixture was stirred for at least 1 h at 5±5 °C. The conversion of Compound 1A was analyzed by HPLC, the criteria limit being the area% of Compound 1A < 1.

[0341] Water (100.0 kg, 5.0 vol.) was then added into the reactor at 5±5 °C, warmed to 20±5 °C, and stirred for 30 min at20±5 °C. The organic phase was separated and collected. The aqueous phase was further extracted with DCM (54.9 kg, 2.0 vol.). The organic phases were combined, washed with water (100.0 kg, 5.0 vol.) twice, and concentrated under vacuum until 3.0-4.0 vol. remained.

[0342] 1,2- Dichlorobenzene (105.8 kg, 4.0 vol.) was charged into the reactor containing the residue and concentrated to obtain a solution of intermediate Compound 2A in 1,2- dichlorobenzene, which was used at next step directly.

[0343] The reactor was charged with n-heptane (192.6 kg, 16.0 vol ), EtsN HCl (50.20 kg, 2.5 eq.), and AICI3 (121.0 kg, 6.25 eq.) and heated to 80±5 °C. The reaction mixture was stirred for at least 4 h at 80±5 °C after which the reaction mixture was cooled to 30±5 °C and concentrated under vacuum at NMT 50 °C until completion to obtain an ionic liquid directly used in the next steps to complete the synthesis of Compound 3A.

[0344] 1,2 -Dichlorobenzene (99.6 kg, 4.0 vol.) and the solution containing Compound 2A were charged into the reactor containing the ionic liquid and heated to 155±5 °C. The reaction mixture was stirred for at least 10 h at 155±5 °C. The reaction mixture was cooled to 60±5 °C and analyzed for conversion of Compound 2A, the criteria being the area% of Compound 2A < 2%.

[0345] Upon verifying completion of the reaction, the reaction mixture was further cooled to 20±5 °C and 7% NaHCCh (aq.) (56.00 kg of NaHCO i in 752.3 kg of water, 40 vol.) was charged into the reactor and stirred for at least 1 h at 20±5 °C.

[0346] The reaction mixture was filtered and the cake washed with water (80.0 kg, 4.0 vol.). The cake was charged into 3% NaHCCh (aq.) (12.00 kg of NaHCCh in 387.0 kg of water, 20 vol.) and stirred for 1 h at 20±5 °C.

[0347] The mixture was filtered and washed with water (79.5 kg, 4.0 vol.). The recovered cake was charged into DCM (268.0 kg, 10.0 vol ), stirred for 3 h at 20±5 °C, filtered, and washed with additional DCM (107.0 kg, 4.0 vol.).

[0348] The cake was dried for 16 h at 50 °C under vacuum.

[0349] The water and moisture content of the cake was analyzed by KF, the criteria being < 1%.

[0350] 21.52 kg of Compound 3 A was obtained as brown solid.Table 8. Reaction Parameters and Conditions for Synthesis of Compound 2ATable 9. Reaction Parameters and Conditions for Synthesis of Compound 3ASynthesis of Compound 4A

[0351] The overall reaction scheme for the conversion of Compound 3A to Compound 4A is shown below:

[0352] The process for synthesizing Compound 4A utilized flow chemistry techniques and an exemplary procedure according to entry 4 as described in Table 11 is herein described.

[0353] DMSO (45.0 L, 10.0 vol.) and Compound 3A (4.5 kg, 1.0 eq.) were charged into a reactor and stirred to obtain a clear solution, which was filtered to remove particulates, and then bubbled below solvent level with N2 for a minimum of 30 min with agitation.

[0354] K2CO3 (35.0 kg, 10.0 eq.) was dissolved into H2O (67.5 kg, 15 vol.) to obtain a clear solution, and bubbled below solvent level with N2 for a minimum of 30 min with agitation.

[0355] Diethyl sulfate (11.75 kg, 3.0 eq.) was charged into a flask and bubbled below solvent level with N2 for a minimum of 30 min with agitation.

[0356] The above three solutions were flowed into a micro tube reactor at the same time for a residence time of 10 min at 40 °C to complete the reaction.

[0357] The reaction mixture was collected and sampled for conversion of Compound 3A by HPLC, the criteria limit being the area% of Compound 3A < 2.

[0358] The collected reaction mixture was flowed into a co-solution of MTBE (54.0 L, 12.0 vol.) and water (90.0 kg, 20.0 vol.) at 5±5 °C and mixed.

[0359] The organic phase was separated from the aqueous layer and collected. The organic phase was washed with 10% NaCl solution (22.5 L, 5.0 vol ), charged into 27% CH3NH2 (aq.) (9.0 L, 2.0 vol.), and stirred for 1.5 h at 25±5 °C. A 20% NaCl solution (22.5 L,5.0 vol.) was charged into the mixture and mixed.

[0360] The organic phase was separated from the aqueous layer and collected. The organic phase was washed with 10% NaCl solution (22.5 L, 5.0 vol.) and concentrated atNMT 40 °C under vacuum until 2.0-2.5 vol. remained.

[0361] The reactor was charged with n-heptane (2.25 L, 0.5 vol.), heated to 45±5 °C, and stirred to obtain a clear solution. After stirring, the reaction mixture was cooled to 38-40 °C.

[0362] Seeds of Compound 4A (22.5 g, 0.5% w / w) were charged into the reactor at 38-40 °C and stirred for 1 h at 35-40 °C. The reaction mixture was cooled to cooled to 0-5 °C and n-heptane (13.5 L, 3.0 vol.) was charged into the reactor at 0-5 °C. The mixture was stirred for 2 h at 0-5 °C, fdtered, and the cake washed with additional n-heptane (9.0 L, 2.0 vol.).

[0363] The cake was dried at 40 °C under vacuum for 2 h and sampled for loss-on-drying (LoD), the criteria being LoD < 3%.

[0364] 4.0 kg of Compound 4A was obtained as brown solid.Table 10. Reaction Parameters and Conditions for Synthesis of Compound 4ASynthesis of Compound 5A

[0365] The overall reaction scheme for the conversion of Compound 4A to Compound 5A is provided below:

[0366] An exemplary procedure is herein described.

[0367] Toluene (72.0 L, 10.0 vol.) was charged into a reactor A along with 50% KOH (aq.) (118.0 kg, 50.0 vol.). The solution was bubbled below solvent level with N2 for 30 min with agitation.

[0368] Toluene (72.0 L, 10.0 vol.) along with Compound 4A (7.2 kg, 1.0 eq.), 3-bromoprop- 1-ene (allyl bromide) (4.46 kg, 1.05 eq.), a phase transfer catalyst (PTC-3) (936.0 g, 0.05 eq.) were charged into a second reactor B and bubbled below solvent level with N2 for 30 min with agitation.

[0369] The mixture from reactor B was charged into reactor A at 25±5 °C over a duration of 20 min and stirred for stirred for 30 min at 25±5 °C. The conversion of Compound 4A was determined by HPLC, the criteria limit being the area% of Compound 4A < 1%.

[0370] The organic phase was separated from the aqueous phase, washed with 1 N HC1 (aq.) (36.0 L, 5.0 vol.), 10% NaCl (aq.) (36.0 L, 5.0 vol.).

[0371] The process described utilized the parameters of entry 3 as shown in Table 12. The process was repeated for the batches of entries 1, 2, and 4.

[0372] The organic phase of entries 1-4 were combined and half the volume of the organic phase was charged into a reactor. The organic phase in the reactor was concentrated until 2.0-2.5 vol. remained. The reactor was charged with n-heptane (40.1 L, 4.5 vol.) and concentrated until 4.0-4.5 vol. remained.

[0373] The remaining reaction mixture was warmed to 40-45 °C, stirred for 1 h at 40-45 °C, cooled to -10 - 5 °C, and stirred for an additional 2-3 h at -10 - 5 °C.

[0374] The reaction mixture was fdtered, the cake washed with n-heptane (9.0 L, 1.0 vol.), and dried at 40±5 °C under vacuum for 12 h. The cake was sampled for loss-on-drying (LoD), the criteria being LoD < 3%.

[0375] 9.05 kg of Compound 5A was obtained as brown solid.

[0376] The process was repeated for the other half of the reaction mixture, which yielded 9.65 kg of Compound 5A as brown solid.Table 11. Reaction Parameters and Conditions for Synthesis of Compound 5A

[0377] In the above Table 11 , the reported yields are the result of combining the organic phases of all four batches to obtain a homogeneous solution, and the combined organic phase divided into two equal parts. One part yielded 9.05 kg of Compound 5A and the other part yielded 9.65 kg of Compound 5A.Synthesis of Compound 6A[00378J The overall reaction scheme for the conversion of Compound 5A to Compound 6A is provided below:

[0379] Toluene (139.8 kg, 10.0 vol.), Compound 5A (16.0 kg, 1.0 eq.), K2OsO42H2O (0.360 kg, 0.015 eq.), and pyridine (9.96 kg, 2.0 eq.) were charged into a reactor, which was warmed to 40±5 °C. An aqueous solution of NaIC (238.0 kg, 1.3 eq. of NalO i in 13.0 vol. of water) was charged into the reactor and the mixture stirred for 1 h at 40±5 °C. The conversion of Compound 5A was monitored by HPLC, the limit being the area% of Compound 5A < 2%.

[0380] The organic phase was separated from the aqueous phase and collected. The aqueous phase was extracted with toluene (71.1 kg, 5.0 vol.) and the organic layer from the toluene extract was combined with the collected organic phase. The combined organic phases were washed twice with Na2S20.3 (aq.) and washed twice with brine.

[0381] The organic phase was filtered and concentrated under vacuum until 2.5-3.0 vol. remained.

[0382] The reactor containing the organic phase was charged with n-heptane (33.0 kg, 3.0 vol.) at 40±5 °C and stirred for at least 2 h at 40±5 °C after which additional n-heptane (55.7 kg, 5.0 vol.) was charged into the reactor at 40±5 °C and stirred for an additional 2 h at 40±5 °C. Themixture was cooled to a temperature of about -10 to about -5 °C and additional n-heptane (41.7 kg, 4.0 vol.) was charged into the reactor a temperature of about -10 to about -5 °C. The mixture was stirred for 4 h at a temperature of about -10 to about -5 °C, filtered, the cake washed with n- heptane (24.1 kg, 1.0 vol.), and dried under vacuum at 40±5 °C for at least 4 h.

[0383] The cake was sampled for loss-on-drying (LoD), the criteria being LoD < 3%.

[0384] 11.82 kg of Compound 6A were obtained as a solid.Table 12. Reaction Parameters and Conditions for Synthesis of Compound 6ASynthesis of (+)-Eserethole L-Malate (Compound 8A)

[0385] The overall reaction scheme for the conversion of Compound 6A to Compound 8A via intermediate Compound 7A is provided below:((+)-Eserethole L-Malate)

[0386] MeOH (43.9 kg, 5.0 vol.), Compound 6A (11.10 kg, 1.0 eq.), 27% CH3NH2 (aq.) (99.3 kg, 10.0 vol.), and 10% Pd / C (as calculated by wet weight based on the water content being about 50%, which corresponds to 5% w / w based calculation by dry weight) were charged into the reactor, which was purged with N2 three times and H2 three times. The reactor was then filled with H2 gas until the pressure reached 7 atm and the reaction mixture was stirred for 30 h at 25±5 °C.

[0387] The conversion of Compound 6A to Compound 7A was monitored by HPLC, the limit being Compound 6A < 3%.

[0388] Pd / C was removed by filtering the reaction mixture through a celite cake. DCM (75.2 kg, 5.0 vol.) was charged into the reaction mixture and the organic phase collected.

[0389] The aqueous phase was extracted twice with DCM (75.8 kg, 5.0 vol.) and (74.0 kg, 5.0 vol.), the organic layers combined and washed with 10%NaCl (aq.) (65.5 kg, 5.0 vol.). The organic phase was concentrated at NMT 50 °C under vacuum until 3.0-3.5 vol. remained.

[0390] Toluene (47.9 kg, 5.0 vol.) was charged into the reactor containing the organic phase residue and the organic phase was further concentrated at NMT 60 °C under vacuum until 3.0-3.5 vol. remained.

[0391] Toluene (69.9 kg, 7.0 vol.) was charged into the reactor and the mixture sampled for water content via KF, the criteria limit being < 0.05%. Upon satisfaction of the KF criteria, the solution was warmed to 80±5 °C, charged with 35% w / w Red Al (sodium bis(2- methoxyethoxy)aluminium hydride) (30.70 kg, 1.2 eq.), and stirred for 1 h at 80±5 °C.

[0392] The conversion of Compound 7A, which undergoes reduction and cycloaddition, was monitored by HPLC, the limit being Compound 7A < 1%. Upon meeting the limit, the reaction solution was cooled to 25±5 °C and charged with 20% NaOH (aq.) (134.5 kg, 10 vol.) at 25±5 °C. Following extraction, the organic phase was collected, washed with additional 20% NaOH (aq.) (135.0 kg, 10.0 vol.), and concentrated under vacuum at NMT 60 °C until 2.5-3.0 vol. remained.

[0393] The L-malate salt was formed following the reduction and cycloaddition of Compound 7A. EtOH (86.5 kg, 10.0 vol.) was charged into the reactor containing the residue and the residue of the organic phase further concentrated under vacuum at NMT 50 °C until 5.0-5.5 vol. remained. The solution containing the product was filtered and transferred to another reactor. The reactor was rinsed with EtOH (18.0 kg, 2.0 vol.) and filtered and transferred to the reactor containing the product.

[0394] EtOH (86.9 kg, 10.0 vol.) and L-malic acid (7.16 kg, 1.2 eq.) were charged into a separate reactor, which was heated to 45±5 °C and the reaction mixture stirred to obtain a clear solution. The solution above was charged into the reactor containing L-malic acid solution at 45±5 °C, stirred for 1 h at 45±5 °C, and cooled to 37±2 °C.

[0395] Seeds of Compound 8A (0.055 kg, 0.5% w / w) were charged into the reactor at 37±2 °C, which was then stirred 2 h at 37±5 °C, cooled to 0±5 °C, and stirred for an additional 2 h at 0±5 °C.

[0396] The reaction mixture was then filtered and the recovered cake washed with EtOH (17.7 kg, 2.0 vol.) and dried at 45±5 °C for 2 h under vacuum.

[0397] Sampled for loss-on-drying (LoD) (the limit is LoD<l%, the result: 0.49%, pass).

[0398] 11.3 kg of Compound 8 A were obtained.Table 13. Reaction Parameters and Conditions for Synthesis of Compound 7ATable 14. Reaction Parameters and Conditions for Synthesis of Compound 8AExample 4 - Synthesis of Posiphen D-tartrate Form A

[0399] An exemplary process for the synthesis of Form A is described below.

[0400] (+)-posiphen (Compound 10) (900 g) produced according to Example 1 was charged into a reactor and dissolved in ethanol (3.2 L). The reaction solution was warmed to about 37 °C.

[0401] D -tartaric acid (401 g) was added to a solution of ethanol (3.2 L) and water (0.27 L), heated to about 49 °C, and stirred for at least 0.5 h to obtain a clear solution. The D-tartaric acid solution was charged into the reactor containing Compound 10 and stirred at about 49 °C for at least 0.5 h.

[0402] The reaction solution was cooled to about 9 °C and stirred for 1.5 h. The batch was filtered and the filter cake was washed with a mixture of MTBE / ethanol (1.5: 1, v / v, 4.1 L) and dried under vacuum for at about 50 °C for 48 h to obtain posiphen D-tartrate Form A (1154 g,88.7% yield). As analyzed by HPLC and chiral HPLC, the product had 99.8% chemical purity and 99.9% optical purity.

[0403] The material was also analyzed via XRPD for the characteristic peaks of Form A as previously described.Example 5 - Powder X-ray diffraction of Posiphen D-tartrate Forms A and B

[0404] Powder X-ray diffraction (PXRD) was used to characterize the obtained posiphen D- tartrate Forms A and B according to the present methods, which were found to be crystalline.

[0405] Posiphen D-tartrate Form A is characterized by an X-ray powder diffraction pattern having characteristic peaks at 4.2, 8.5, 11.6, 11.8, 12.0, 12.8, 13.5, 14.4, 14.6, 14.9, 15.0, 15.2,15.4, 16.2, 16.5, 17.0, 17.3, 17.9, 18.3, 18.6, 19.4, 19.6, 20.0, 20.4, 20.8, 21.0, 21.3, 21.8, 23.1,23.6, 23.8, 24.2, 24.4, 24.8, 25.0, 25.2, 25.6, 25.8, 26.9, 27.9, 28.0, 28.4, 29.0, 29.5, 30.0, 30.4,30.7, 31.3, 31.6, 32.3, 32.6, 33.0, 34.6, 35.0, 35.7, 36.8, 37.7, 38.6, in 20.

[0406] An exemplary listing of representative XRPD peaks and relative intensities of an embodiment of posiphen D-tartrate Form A is shown in the below Table 15.Table 15. XRPD Peaks, Relative Intensities, and d-spacing Values of Posiphen D-tartrate Form A

[0407] Posiphen D-tartrate Form B is characterized by an X-ray powder diffraction pattern having characteristic peaks at 5.16, 8.56, 10.3, 11.24, 13.14, 13.48, 14.66, 15.24, 15.44, 15.76, 16.18, 16.54, 17.48, 17.94, 18.08, 19.72, 20.62, 20.76, 21.22, 21.5, 22.2, 22.54, 23.46, 24.4, 24.72, 26.4, 26.86, 27.14, 27.48, 27.7, 28.52, 28.74, 29.14, 29.96, 30.68, 31.14, 32.3, 33.26, 35.44, 37.24, and 37.74 in 26.

[0408] An exemplary listing of representative XRPD peaks of an embodiment of posiphen D- tartrate Form B can be found in Table 16.Table 16. XRPD Peaks, Relative Intensities, and d-spacing Values of Posiphen D-tartrate Form BExample 6 - Purity analysis of posiphen D-tartrate Form B

[0409] The posiphen D-tartrate Form B synthesized according to Example 2 as herein described was analyzed for purity.

[0410] HPLC Analysis

[0411] A solution of posiphen D-tartrate Form B as prepared according to the process herein described was analyzed using high performance liquid chromatography (HPLC) system, gradient mobile phase programming, and a C-18 column. An ultraviolet HPLC detector was used to measure the peak responses at a wavelength of 280 nm. The composition of Mobile Phase A was 0.01 M ammonium acetate, 10% methanol / 90% water, and 0.5% acetic acid. The composition of Mobile Phase B was 0.01 M ammonium acetate, 100% methanol; 0.5% acetic acid. The reference standard was a 0.5 mg / mL solution of posiphen D-tartrate Form B in methanol, diluted to a final concentration of 0.005 mg / mL in methanol, or 1% of the sample final theoretical concentration of 0.5 mg / mL of posiphen D-tartrate Form B prepared similarly. A high-performance liquid chromatography system capable of programmed gradient operation was used, with an HPLC UV / VIS detector and the ability to monitor 280 nm. Column: 3.9x 150 mm Waters Symmetry C- 18 column, 5 pm, (or equivalent) capable of at least 20,000 plates / column for fluorescein. Flow Rate: 0.6 mL / min. The gradient program was as follows as shown in Table 17:Table 17. Gradient Program for HPLC

[0412] Using peak areas, the percent concentration of impurities equal to or greater than 0.025% were calculated, as shown in the calculation section below. Although the limit of quantitation for this method is 0.025%, impurities are generally reported at concentrations >0.05%.

[0413] The relative retention time was calculated by dividing the retention time of the impurity peak by the retention time of the peak corresponding to the product of interest.

[0414] Chiral HPLC to assess enantiomer content was performed utilizing the above method with a chiral stationary phase.

[0415] Gas Chromatography

[0416] Headspace gas chromatography was used to determine the concentration of residual solvents in the obtained posiphen D-tartrate Form B. Briefly, a gas chromatograph (Agilent technologies 6890N) equipped with a flame ionization detector, a headspace sampler (Agilent technologies G1888) was used to load the sample. An analytical balance (XS 205 from Mettler Toledo) and autopipette (100 - 1000 pL from Eppendorf) were used.

[0417] The conditions used in the headspace injector and gas chromatograph are shown in the following Table 18:Table 18. Gas Chromatography Conditions

[0418] DMSO was utilized as the standard and sample diluent. A stock solution of posiphen D-tartrate Form B and its known residual solvents (ethanol, methyl tertiary butyl ether, N,N- dimethylacetamide, ethyl acetate, dichloromethane, n-heptane, and toluene) was pre-prepared such that the final concentrations of residual solvents were as follows: 5000 ppm ethanol, 5000 ppm methyl tert-butyl ether, 1090 ppm N,N-dimethylacetamide, 5000 ppm ethyl acetate, 600 ppm dichloromethane, 5000 ppm n-heptane, and 890 ppm toluene.

[0419] The standard vial was prepared with 1 mb of the standard solution and the sample vials were prepared with approximately 120 mg of sample with 1 mL DMSO as diluent.

[0420] Quantitative NMR (Q-NMR)

[0421] A known amount between 4-12 mg of posiphen D-tartrate Form B was weighed on a balance and dissolved in 600 pL of DMSO-d6 in a 5 mm NMR tube. A known amount of dimethylsulfone of a known purity was added as an internal calibrant. The sample was analyzed on a Bruker Avance NEO 400 spectrometer (400 MHz1H) spectrometer.

[0422] The results from HPLC, chiral HPLC, Q-NMR, in addition to Karl Fischer and acidbase titrations to determine water and acid content, respectively, are shown in the following Table 19.Table 19. Purity Analysis Results

[0423] The 0.4% difference between the determined Q-NMR purity (100.4%) and the theoretical maximum of 100% is well within the accuracy of typical laboratory settings (NMR and balance validation). Other potential reasons for >100% purity values are differences in residual water content between the internal calibrant and the analyte, or the use of an internal calibrant that is significantly less pure than the target analyte.

[0424] Based on the above data, the present methods can be used to synthesize and isolate substantially pure posiphen D-tartrate Form B, or posiphen D-tartrate Form B that has little or no detectable impurities as shown in the above data, by the analyses reported herein (e.g., Q-NMR and / headspace gas chromatography and / or HPLC and / or chiral HPLC).Example 7 - Chiral Resolution of ( -Esereihole

[0425] The conversion of Compound 6A forms a mixture of stereoisomers in which only (+)- eserethole is the desired enantiomer for the subsequent synthesis of (+)-posiphen. Chiral resolution of these stereoisomers may be accomplished via diastereomeric salt formation with chiral acids.

[0426] The chiral resolution by diastereomeric salt formation was conducted with four chiral acids. About 20 mg of racemic (±)-eserethole was added into EtOH (0.2 mL) at RT then acid (1.2 eq.) was added and stirred at RT. The detailed information and results are summarized in Table 20:Table 20. Preparation of Desired Enantiomer with Chiral Acids

[0427] Chiral purity was determined with a Waters E2695 series instrument and an Agilent HPLC 1260 series instrument according to the following protocol:Table 21. HPLC Method for Chiral Purity Test

[0428] The results in Table 20 revealed that desired enantiomer was enriched in the solid phase with L-Malic acid, Dibenzoyl-L-tartaric acid, and (-)-Di-p-toluoyl-L-tartaric acid, and the chiral purity were 98.64%, 91.85% and 89.69%, respectively, with malate showing the highest chiral purity. Accordingly, such acids may be utilized as chiral resolving agents for the desired (+)- eserethole enantiomer.Additional Description of Embodiments

[0429] Additional embodiments of the invention are further described by the following numbered paragraphs:

[0430] 1. A process for preparing (+)-posiphen (Compound 10) comprising the steps of: a) preparing a free base of Compound 8, wherein Compound 8 has the structure:and cleaving an ether of the free base to form Compound 9:wherein R’ is an alkyl group, A is an acid, and wherein Compound 8 is an acid salt of acid A; and b) converting Compound 9 to Compound 10:

[0431] 2 A process for producing (3aR)-l, 3a, 8-trimethyl-l, 2, 3, 3a, 8, 8a- hexahydropyrrolo (2, 3-b) indol-5-yl phenyl-carbamate tartrate dihydrate (posiphen D-tartrate Form B), which has the formula:comprising a step c) of converting Compound 10 as produced by the process of paragraph 1 to posiphen D-tartrate Form B; wherein the posiphen D-tartrate Form B has a purity of greater than 99.5% as determined by HPLC.

[0432] 3. (3aR)-l, 3a, 8-trimethyl-l, 2, 3, 3a, 8, 8a-hexahydropyrrolo (2, 3-b) indol-5-yl phenyl-carbamate tartrate dihydrate (posiphen D-tartrate Form B) having been prepared by the process of paragraph 2, characterized by an X-ray powder diffraction pattern having characteristic peaks at 5.16, 8.56, 10.3, 11.24, 13.14, 13.48, 14.66, 15.24, 15.44, 15.76, 16.18, 16.54, 17.48, 17.94, 18.08, 19.72, 20.62, 20.76, 21.22, 21.5, 22.2, 22.54, 23.46, 24.4, 24.72, 26.4, 26.86, 27.14, 27.48, 27.7, 28.52, 28.74, 29.14, 29.96, 30.68, 31.14, 32.3, 33.26, 35.44, 37.24, and 37.74 in 20.

[0433] 4. (3aR)-l, 3a, 8-trimethyl-l, 2, 3, 3a, 8, 8a-hexahydropyrrolo (2, 3-b) indol-5-yl phenyl-carbamate tartrate dihydrate (posiphen D-tartrate Form B) having been prepared by the process of paragraph 2, characterized by an X-ray powder diffraction pattern having the following characteristic peaks, relative intensities, and d-spacing values:

[0434] 5. The process any one of paragraphs 2-4, wherein the posiphen D-tartrate Form B produced by the process has a purity of greater than 99.6%, or having a purity of greater than 99.7%, or having a purity of greater than 99.8%, or having a purity of greater than 99.9% as determined by HPLC.

[0435] 6. The process any one of paragraphs 2-5, wherein the posiphen D-tartrate Form B produced by the process comprises two or fewer impurity peaks as determined by HPLC and / or no impurity peak greater than 0.2% as determined by HPLC.

[0436] 7. Posiphen D-tartrate Form B produced by the process of any of paragraphs 2-6, wherein the posiphen D-tartrate Form B is substantially pure or has little or no detectable impurities as shown in the data herein, by the analyses reported herein (e.g., Q-NMR and / headspace gas chromatography and / or HPLC and / or chiral HPLC), or posiphen D-tartrate Form B having a purity of greater than 99.5%, or having a purity of greater than 99.6%, or having a purity of greater than 99.7%, or having a purity of greater than 99.8%, advantageously as determined by one or more analyses reported herein (e.g., Q-NMR and / headspace gas chromatography and / or HPLC and / or chiral HPLC).

[0437] 8. The process of paragraph 1, wherein step a) comprises forming the free base ofCompound 8 and reacting the free base of Compound 8 with BBn according to the following reaction scheme:to form Compound 9.

[0438] 9. The process of paragraphs 1 or 8, wherein R’ is an ethyl group, A is L-malic acid, and wherein Compound 8 is (+)-eserethole L-malate.

[0439] 10. The process according to any one of paragraphs 1, 8, or 9, wherein step b) comprises reacting Compound 9 with 1 , I ’-carbonyldiimidazole (CDI) to form an intermediate Compound 10-INT1 having the formula:and reacting Compound 10-INT1 with aniline to produce Compound 10 according to the following reaction scheme:

[0440] 11 The process according to any one of paragraphs 2-7, wherein step c) comprises reacting Compound 10 with D-tartaric acid to form posiphen D-tartrate Form B.

[0441] 12. The process according to any one of paragraphs 2-7, wherein step c) proceeds according to the following reaction scheme:O OH and comprises the steps: c-i) reacting a solution of Compound 10 in ethanol with an aqueous solution of D-tartaric acid; and c-ii) adding a seed of posiphen D-tartrate Form B to form posiphen D-tartrate Form B.

[0442] 13. A process for producing Compound 8 for the process of paragraph 1, comprising the steps of: i) aminating a Compound 0 having the general formula:wherein R is an alkyl and X is a halogen; with methylamine to form Compound 1, which has the structure:ii) reacting Compound 1 with an acylating agent having a leaving group L to form an intermediate Compound 2 having the structure:iii) cyclizing the intermediate Compound 2 to form Compound 3, which has the structure:iv) alkylating the hydroxyl group of Compound 3 with an alkylating agent to obtain Compound 4, which has the structure:wherein R’ is an alkyl and may be the same or different as the alkyl of Compound 0 of step i); v) performing an allylation reaction Compound 4 with an allyl compound to obtain Compound 5, which has the structure:vi) hydroxylating Compound 5 to form a vicinal diol and oxidatively cleaving said vicinal diol to obtain Compound 6 having the structure:vii) reacting Compound 6 with methylamine to form an imine and reducing said imine to obtain an intermediate Compound 7 having the structure:; and viii) obtaining Compound 8 by reducing the ketone of intermediate Compound 7, performing a cycloaddition reaction, and forming the acid salt A:5 wherein Compound 8 has an optical purity greater than 99% as determined by chiral chromatography.

[0443] 14. The process according to paragraph 13, wherein alkylating step iv) comprises the step of simultaneously flowing a solution of Compound 3 dissolved in a solvent, a solution of the alkylating agent dissolved in a solvent, and an aqueous solution of a base through one or more microreactors; wherein the solution of Compound 3, the solution of the alkylating agent, and the solution of the base simultaneously contact each other; and wherein each microreactor is arranged in series and in fluid connection with each other.

[0444] 15. The process according to paragraph 13 or 14, wherein the alkylating agent is diethyl sulfate.

[0445] 16. The process according to any one of paragraphs 13-15, wherein step v) of performing the allylation reaction comprises reacting Compound 4 with the allyl compound and a chiral phase transfer catalyst.

[0446] 17. The process according to any one of paragraphs 13-16, wherein the chiral phase transfer catalyst comprises a cinchona alkaloid having the structure:wherein Ar is a monocyclic or polycyclic aryl or heteroaryl group whose carbon atoms may be substituted with a group R3;X is a halogen;each of R2and R3independently represents zero, mono, or up to a maximum allowed substitutions to its associated ring; each of R1, R2, and R3is independently a hydrogen or a substituent comprising deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, arylalkyl, alkoxy, aryloxy, amino, silyl, germyl, boryl, selenyl, alkenyl, cycloalkenyl, heteroalkenyl, alkynyl, aryl, heteroaryl, acyl, carboxylic acid, ether, ester, nitrile, isonitrile, sulfanyl, sulfinyl, sulfonyl, phosphino, or combinations thereof; and any two substituents can be joined or fused together to form a ring.

[0447] 18. The process according to any one of paragraphs 13-17, wherein the cinchona alkaloid comprises:

[0448] 19. The process according to any one of paragraphs 13-18, wherein the cinchonaalkaloid is

[0449] 20. The process according to any one of paragraphs 13-19, wherein Compound 5 as obtained in step v) has an optical purity greater than 70%, or an optical purity greater than 71%, or an optical purity greater than 72%, or an optical purity greater than 73%, or an optical purity greater than 74%, or an optical purity of about 75% as determined by chiral chromatography.

[0450] 21. The process according to any one of paragraphs 13-20, wherein R and R’ are different from each other.

[0451] 22. The process according to any one of paragraphs 13-21, wherein Compound 0 is 4- bromoanisole, and step i) comprises aminating the 4-bromoanisole with methylamine in the presence of Q O according to the following reaction scheme to obtain Compound 1 A:

[0452] 23. The process according to any one of paragraphs 13-22, wherein step ii) comprises reacting Compound 1A with 2-bromopropionyl bromide to obtain intermediate Compound 2 A according to the following reaction scheme:

[0453] 24. The process according to any one of paragraphs 13-23, wherein the intermediateCompound 2A is not isolated and / or purified and used directly in cyclizing step iii).

[0454] 25. The process according to any one of paragraphs 13-24, wherein step iv) comprises alkylating the hydroxyl group of Compound 3A with the alkylating agent, wherein the alkylating agent is diethyl sulfate, to obtain Compound 4A according to the following reaction scheme:

[0455] 26. The process according to any one of paragraphs 13-25, wherein step v) comprises performing the allylation reaction on Compound 4A to obtain Compound 5A according to the following reaction scheme:

[0456] 27. The process according to any one of paragraphs 13-26, wherein step v) occurs in the presence of a chiral phase transfer catalyst.

[0457] 28. The process according to paragraph 13-27, wherein the chiral phase transfer catalyst comprises a cinchona alkaloid having the structure:wherein Ar is a monocyclic or polycyclic aryl or heteroaryl group whose carbon atoms may be substituted with a group R3;X is a halogen; each of R2and R3independently represents zero, mono, or up to a maximum allowed substitutions to its associated ring; each of R1, R2, and R3is independently a hydrogen or a substituent comprising deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, arylalkyl, alkoxy, aryloxy, amino, silyl, germyl, boryl, selenyl, alkenyl, cycloalkenyl, heteroalkenyl, alkynyl, aryl, heteroaryl, acyl, carboxylic acid, ether, ester, nitrile, isonitrile, sulfanyl, sulfinyl, sulfonyl, phosphino, or combinations thereof; andany two substituents can be joined or fused together to form a ring.

[0458] 29. The process according to any one of paragraphs 13-28, wherein the cinchona alkaloid comprises:

[0459] 30. The process according to any one of paragraphs 13-29, wherein the cinchonaalkaloid is

[0460] 31. The process according to any one of paragraphs 13-30, wherein step vi) comprises hydroxylating Compound 5A to form the vicinal diol and oxidatively cleaving said vicinal diol to obtain Compound 6A according to the following reaction scheme:

[0461] 32. The process according to any one of paragraphs 13-31, wherein step vii) comprises reacting Compound 6A with methylamine to form an imine and reducing the imine to form intermediate Compound 7A according to the following reaction scheme:

[0462] 33. The process of according to any one of paragraphs 13-32, wherein step viii) comprises reducing intermediate Compound 7A, cyclizing, and forming a salt of L-malic acid to obtain Compound 8A according to the following reaction scheme:wherein Compound 8A is (+)-eserethole L-malate.

[0463] 34. A process for preparing (3aR)-l, 3a, 8-trimethyl-l, 2, 3, 3a, 8, 8a-hexahydropyrrolo(2, 3-b) indol-5-yl phenyl-carbamate tartrate (posiphen D-tartrate Form A), which has the formula:comprising a step cl) of converting Compound 10 as produced by the process of any one of paragraphs 1 or 8-10 to posiphen D-tartrate Form A;wherein the posiphen D-tartrate Form A produced by the process has a purity of greater than 99.5% as determined by HPLC.

[0464] 35. The process according to paragraph 34, wherein step cl) comprises reactingCompound 10 with D-tartaric acid to form posiphen D-tartrate Form A.

[0465] 36. The process according to any one of paragraphs 34-35, wherein the posiphen D- tartrate Form A produced by the process is characterized by an X-ray powder diffraction pattern having characteristic peaks at 4.2, 8.5, 11.6, 11.8, 12.0, 12.8, 13.5, 14.4, 14.6, 14.9, 15.0, 15.2,15.4, 16.2, 16.5, 17.0, 17.3, 17.9, 18.3, 18.6, 19.4, 19.6, 20.0, 20.4, 20.8, 21.0, 21.3, 21.8, 23.1,23.6, 23.8, 24.2, 24.4, 24.8, 25.0, 25.2, 25.6, 25.8, 26.9, 27.9, 28.0, 28.4, 29.0, 29.5, 30.0, 30.4,30.7, 31.3, 31.6, 32.3, 32.6, 33.0, 34.6, 35.0, 35.7, 36.8, 37.7, and 38.6 in 29.

[0466] 37. The process according to any one of paragraphs 34-36, wherein the posiphen D- tartrate Form A produced by the process is characterized by an X-ray powder diffraction pattern having the following characteristic peaks, relative intensities, and d-spacing values:

[0467] 38. A pharmaceutical formulation comprising the (3aR)-l, 3a, 8-trimethyl-l, 2, 3, 3a,8, 8a-hexahydropyrrolo (2, 3-b) indol-5-yl phenyl-carbamate tartrate dihydrate (posiphen D- tartrate Form B) having been prepared by the process of any one of paragraphs 2-7 and a pharmaceutically acceptable carrier.

[0468] 39. A method of treating a neurological disorder in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition comprising (3aR)-l, 3a, 8-trimethyl-l, 2, 3, 3a, 8, 8a-hexahydropyrrolo (2, 3-b) indol-5-yl phenylcarbamate tartrate dihydrate (posiphen D-tartrate Form B) as prepared by the process of any one of paragraphs 2-7, and a pharmaceutically acceptable carrier; wherein the neurological disorder comprises: a chronic neurodegeneration, comprising Alzheimer’s disease, frontotemporal dementia, chronic traumatic encephalopathy, tauopathies, Parkinson’s and alpha-synucleopathies, prion disease, transmissible spongiform encephalopathies (TSE), Down Syndrome, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, or other dementias and neurodegenerative disorders which present as misfolding, aggregation and accumulation of proteins in the brain, resulting in axonal transport impairment, inflammation, and eventual cell death; or an acute neurodegeneration, wherein the acute neurodegeneration comprises traumatic brain injury, stroke, acute brain injury induced by brain ischemia, acute brain injury induced by insufficient oxygen supply to the brain, acute brain injury induced by anoxia or hypoxia, micro infarcts, acute brain injury induced by concussion, post-operative cognitive decline resulting from anesthesia or surgery-induced inflammation, acute brain injury induced by drowning, acute brain injury associated with whip lash, acute brain injury associated with bicycle crashes, acute brain injury associated with automobile accidents, shaken baby syndrome, acute brain injury induced by falling, acute brain injury associated with physical impact of the head, or acute angle-closure glaucoma; or a neuropsychiatric indication, wherein the neuropsychiatric indication comprises depression, schizophrenia, dementia, Alzheimer’s disease, anxiety, or substance abuse disorder; or a mental illness comprising autism, attention deficit-hyperactivity disorder, bipolar disorder, depression and major depressive disorder, behavioral problems, posttraumatic stress disorder or schizophrenia.

[0469] 40. The method of paragraph 39, wherein the dosage of posiphen D-tartrate Form B is from about 0.1 mg / kg to about 100 mg / kg of body weight; or wherein the dosage of posiphen D- tartrate Form B is from about 1 mg / kg to about 20 mg / kg of body weight.

[0470] 41. The method of any one of paragraphs 39 or 40, wherein the pharmaceutical composition is administered daily to the subject; or wherein the pharmaceutical composition is administered once daily to the subject.

[0471] 42. The method of any one of paragraphs 39-41, wherein the subject is human.

[0472] 43. The method of any one of paragraphs 39-42, wherein the administrating is oral administration.

[0473] 44. Use of (3aR)-l, 3a, 8-trimethyl-l, 2, 3, 3a, 8, 8a-hexahydropyrrolo (2, 3-b) indol-5-yl phenyl-carbamate tartrate dihydrate (posiphen D-tartrate Form B), as prepared by the process of any one of paragraphs 2-7 or use of a pharmaceutical formulation of paragraph 38, for performing a method of any one of paragraphs 39-43.

[0474] 45. A pharmaceutical composition comprising the posiphen D-tartrate Form B as prepared by the process of any one of paragraphs 2-7, and a pharmaceutically acceptable carrier, or the pharmaceutical formulation of paragraph 38 for use in performing the method of any one of paragraphs 39-43.* * *

[0475] Having thus described in detail preferred embodiments of the present invention, it is to be understood that the invention defined by the above paragraphs is not to be limited to particular details set forth in the above description as many apparent variations thereof are possible without departing from the spirit or scope of the present invention.

Claims

WHAT IS CLAIMED IS:

1. A process for preparing (+)-posiphen (Compound 10) comprising the steps of: a) preparing a free base 8B of Compound 8, wherein Compound 8 has the structure:and cleaving an ether of the free base to form Compound 9:wherein R’ is an alkyl group, A is an acid, and wherein Compound 8 is an acid salt of acidA; and b) converting Compound 9 to Compound 10:

2. A process for producing (3aR)-l, 3a, 8-trimethyl-l, 2, 3, 3a, 8, 8a-hexahydropyrrolo (2, 3- b) indol-5-yl phenyl-carbamate tartrate dihydrate (posiphen D-tartrate Form B) having the formulacomprising a step c) of converting Compound 10 as produced by the process of claim 1 to posiphen D-tartrate Form B; wherein the posiphen D-tartrate Form B has a purity of greater than 99.5% as determined by HPLC.

3. The process of claim 2, wherein the posiphen D-tartrate Form B is characterized by an X- ray powder diffraction pattern having characteristic peaks at 5.16, 8.56, 10.3, 11.24, 13.14, 13.48, 14.66, 15.24, 15.44, 15.76, 16.18, 16.54, 17.48, 17.94, 18.08, 19.72, 20.62, 20.76, 21.22, 21.5, 22.2, 22.54, 23.46, 24.4, 24.72, 26.4, 26.86, 27.14, 27.48, 27.7, 28.52, 28.74, 29.14, 29.96, 30.68, 31.14, 32.3, 33.26, 35.44, 37.24, and 37.74 in 20.

4. The process of claim 2, wherein the posiphen D-tartrate Form B is characterized by an X- ray powder diffraction pattern having the following characteristic peaks, relative intensities, and d-spacing values:

5. The process of claim 2, wherein the posiphen D-tartrate Form B produced by the process has a purity of greater than 99.6%, or having a purity of greater than 99.7%, or having a purity of greater than 99.8%, or having a purity of greater than 99.9% as determined by HPLC.

6. The process of claim 2, wherein the posiphen D-tartrate Form B produced by the process comprises two or fewer impurity peaks as determined by HPLC and / or no impurity peak greater than 0.2% as determined by HPLC.

7. The process of claim 1, wherein step a) comprises reacting the free base of Compound 8 with BBr.3 according to the following reaction scheme:to form Compound 9.

8. The process of claim 7, wherein R’ is an ethyl group, A is L-malic acid, and wherein Compound 8 is (+)-eserethole L-malate.

9. The process of claim 1, wherein step b) comprises reacting Compound 9 with 1, 1’- carbonyldiimidazole (CDI) to form an intermediate Compound 10-INTI having the formula:and reacting Compound 10-INT1 with aniline to produce Compound 10 according to the following reaction scheme:

10. The process of claim 2, wherein step c) comprises reacting Compound 10 with D-tartaric acid to form posiphen D-tartrate Form B.

11. The process of claim 10, wherein step c) proceeds according to the following reaction scheme:and comprises the steps: c-i) reacting a solution of Compound 10 in ethanol with an aqueous solution of D-tartaric acid; and c-ii) adding a seed of posiphen D-tartrate Form B to the solution of Compound 10 and D- tartaric acid to form posiphen D-tartrate Form B.

12. A process for producing Compound 8 for the process of claim 1, comprising the steps of: i) aminating a Compound 0 having the general formula:wherein R is an alkyl and X is a halogen; with methylamine to form Compound 1, which has the structure:ii) reacting Compound 1 with an acylating agent having a leaving group L to form an intermediate Compound 2 having the structure:iii) cyclizing the intermediate Compound 2 to form Compound 3, which has the structure:iv) alkylating the hydroxyl group of Compound 3 with an alkylating agent to obtainCompound 4, which has the structure:wherein R’ is an alkyl and may be the same or different as the alkyl of Compound 0 of step i); v) performing an allylation reaction Compound 4 with an allyl compound to obtain Compound 5, which has the structure:vi) hydroxylating Compound 5 to form a vicinal diol and oxidatively cleaving said vicinal diol to obtain Compound 6 having the structure:vii) reacting Compound 6 with methylamine to form an imine and reducing said imine to obtain an intermediate Compound 7 having the structure:; and viii) obtaining Compound 8 by reducing the ketone of intermediate Compound 7, performing a cycloaddition reaction, and forming the acid salt Awherein Compound 8 has an optical purity greater than 99% as determined by chiral chromatography.

13. The process of claim 12, wherein alkylating step iv) comprises the step of simultaneously flowing a solution of Compound 3 dissolved in a solvent, a solution of the alkylating agent dissolved in a solvent, and an aqueous solution of a base through one or more microreactors; wherein the solution of Compound 3, the solution of the alkylating agent, and the solution of the base simultaneously contact each other; and wherein each microreactor is arranged in series and in fluid connection with each other.

14. The process of claim 13, wherein the alkylating agent is diethyl sulfate.

15. The process of claim 12, wherein step v) of performing the allylation reaction comprises reacting Compound 4 with the allyl compound and a chiral phase transfer catalyst.

16. The process of claim 15, wherein the chiral phase transfer catalyst comprises a cinchona alkaloid having the structure:wherein Ar is a monocyclic or polycyclic aryl or heteroaryl group whose carbon atoms may be substituted with a group R3;X is a halogen;each of R2and R3independently represents zero, mono, or up to a maximum allowed substitutions to its associated ring; each of R1, R2, and R3is independently a hydrogen or a substituent comprising deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, arylalkyl, alkoxy, aryloxy, amino, silyl, germyl, boryl, selenyl, alkenyl, cycloalkenyl, heteroalkenyl, alkynyl, aryl, heteroaryl, acyl, carboxylic acid, ether, ester, nitrile, isonitrile, sulfanyl, sulfinyl, sulfonyl, phosphino, or combinations thereof; and any two substituents can be joined or fused together to form a ring.

17. The process of claim 16, wherein the cinchona alkaloid comprises:

18. The process of claim 17, wherein the cinchona alkaloid is19. The process of claim 16, wherein Compound 5 as obtained in step v) has an optical purity greater than 70%, or an optical purity greater than 71%, or an optical purity greater than 72%, or an optical purity greater than 73%, or an optical purity greater than 74%, or an optical purity of about 75% as determined by chiral chromatography.

20. The process of claim 12, wherein in step i), R is methyl and X is bromine.

21. The process of claim 12, wherein R and R’ are different from each other.

22. The process of claim 12, wherein Compound 0 is 4-bromoanisole, and step i) comprises aminating the 4-bromoanisole with methylamine in the presence of Cu O according to the following reaction scheme to obtain Compound 1A:

23. The process of claim 22, wherein step ii) comprises reacting Compound 1A with 2- bromopropionyl bromide to obtain intermediate Compound 2A according to the following reaction scheme:

24. The process of claim 23, wherein step iii) comprises cyclizing the intermediateCompound 2A to obtain Compound 3 A according to the following reaction scheme:

25. The process of claim 23, wherein the intermediate Compound 2A is not isolated and / or purified and used directly in cyclizing step iii).

26. The process of claim 24, wherein step iv) comprises alkylating the hydroxyl group ofCompound 3A with the alkylating agent, wherein the alkylating agent is diethyl sulfate, to obtainCompound 4A according to the following reaction scheme:

27. The process of claim 26, wherein step v) comprises performing the allylation reaction onCompound 4A to obtain Compound 5 A according to the following reaction scheme:

28. The process of claim 27, wherein step v) occurs in the presence of a chiral phase transfer catalyst.

29. The process of claim 28, wherein the chiral phase transfer catalyst comprises a cinchona alkaloid having the structure:wherein Ar is a monocyclic or polycyclic aryl or heteroaryl group whose carbon atoms may be substituted with a group R3;X is a halogen; each of R2and R3independently represents zero, mono, or up to a maximum allowed substitutions to its associated ring; each of R1, R2, and R3is independently a hydrogen or a substituent comprising deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, arylalkyl, alkoxy, aryloxy, amino, silyl, germyl, boryl, selenyl, alkenyl, cycloalkenyl, heteroalkenyl, alkynyl, aryl, heteroaryl, acyl, carboxylic acid, ether, ester, nitrile, isonitrile, sulfanyl, sulfinyl, sulfonyl, phosphino, or combinations thereof; and any two substituents can be joined or fused together to form a ring.

30. The process of claim 29, wherein the cinchona alkaloid comprises:The process of claim 30, wherein the cinchona alkaloid is32. The process of claim 27, wherein step vi) comprises hydroxylating Compound 5A to form the vicinal diol and oxidatively cleaving said vicinal diol to obtain Compound 6A according to the following reaction scheme:

33. The process of claim 32, wherein step vii) comprises reacting Compound 6A with methylamine to form an imine and reducing the imine to form intermediate Compound 7A.

34. The process of claim 33, wherein step vii) occurs according to the following reaction scheme:

35. The process of claim 33, wherein step viii) comprises reducing intermediate Compound 7A, performing cycloaddition, and forming a salt with L-malic acid to obtain Compound 8A according to the following reaction scheme:, wherein Compound 8A is (+)-eserethole L-malate.

36. A process for preparing (3aR)-l, 3a, 8-trimethyl-l, 2, 3, 3a, 8, 8a-hexahydropyrrolo (2, 3- b) indol-5-yl phenyl-carbamate tartrate (posiphen D-tartrate Form A), which has the formula:the process comprising a step cl) of converting Compound 10 as produced by the process of claim 1 to posiphen D-tartrate Form A; wherein the posiphen D-tartrate Form A produced by the process has a purity of greater than 99.5% as determined by HPLC.

37. The process of claim 36, wherein step cl) comprises reacting Compound 10 with D- tartaric acid to form posiphen D-tartrate Form A.

38. The process of claim 36, wherein the posiphen D-tartrate Form A is characterized by anX-ray powder diffraction pattern having characteristic peaks at 4.2, 8.5, 1 1 .6, 11 .8, 12.0, 12.8,13.5, 14.4, 14.6, 14.9, 15.0, 15.2, 15.4, 16.2, 16.5, 17.0, 17.3, 17.9, 18.3, 18.6, 19.4, 19.6, 20.0,20.4, 20.8, 21.0, 21.3, 21.8, 23.1, 23.6, 23.8, 24.2, 24.4, 24.8, 25.0, 25.2, 25.6, 25.8, 26.9, 27.9,28.0, 28.4, 29.0, 29.5, 30.0, 30.4, 30.7, 31.3, 31.6, 32.3, 32.6, 33.0, 34.6, 35.0, 35.7, 36.8, 37.7, and 38.6 in 29.

39. The process of claim 36, wherein the posiphen D-tartrate Form A is characterized by an X- ray powder diffraction pattern having the following characteristic peaks, relative intensities, and d-spacing values:

40. A pharmaceutical formulation comprising the (3aR)-l, 3a, 8-trimethyl-l, 2, 3, 3a, 8, 8a- hexahydropyrrolo (2, 3-b) indol-5-yl phenyl-carbamate tartrate dihydrate (posiphen D-tartrate Form B) having been prepared by the process of claim 2 and a pharmaceutically acceptable carrier.

41. A method of treating a neurological disorder in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition comprising (3aR)-l, 3a, 8-trimethyl-l, 2, 3, 3a, 8, 8a-hexahydropyrrolo (2, 3-b) indol-5-yl phenyl-carbamatetartrate dihydrate (posiphen D-tartrate Form B) produced by the process of claim 2 and a pharmaceutically acceptable carrier; wherein the neurological disorder is selected from: a chronic neurodegeneration, wherein the chronic neurodegeneration is selected from Alzheimer’s disease, frontotemporal dementia, chronic traumatic encephalopathy, tauopathies, Parkinson’s and alpha-synucleopathies, prion disease, transmissible spongiform encephalopathies (TSE), Down Syndrome, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, other dementias and neurodegenerative disorders which present as misfolding, aggregation and accumulation of proteins in the brain, resulting in axonal transport impairment, inflammation, and eventual cell death; an acute neurodegeneration, wherein the acute neurodegeneration is selected from traumatic brain injury, stroke, acute brain injury induced by brain ischemia, acute brain injury induced by insufficient oxygen supply to the brain, acute brain injury induced by anoxia or hypoxia, micro infarcts, acute brain injury induced by concussion, post-operative cognitive decline resulting from anesthesia or surgery-induced inflammation, acute brain injury induced by drowning, acute brain injury associated with whip lash, acute brain injury associated with bicycle crashes, acute brain injury associated with automobile accidents, shaken baby syndrome, acute brain injury induced by falling, acute brain injury associated with physical impact of the head, and acute angle-closure glaucoma; a neuropsychiatric indication, wherein the neuropsychiatric indication is selected from depression, schizophrenia, dementia, Alzheimer’s disease, anxiety, and substance abuse disorder; or a mental illness, wherein the mental illness is selected from autism, attention deficithyperactivity disorder, bipolar disorder, depression and major depressive disorder, behavioral problems, posttraumatic stress disorder and schizophrenia.The method of claim 7, wherein the neurological disorder is a chronic neurodegeneration.

42. The method of claim 41, wherein the chronic neurodegeneration is selected from Alzheimer’s disease, frontotemporal dementia, chronic traumatic encephalopathy, tauopathies, Parkinson’s and alpha-synucleopathies, prion disease, transmissible spongiform encephalopathies (TSE), Down Syndrome, Huntington's disease, amyotrophic lateral sclerosis,multiple sclerosis, other dementias and neurodegenerative disorders which present as misfolding, aggregation and accumulation of proteins in the brain, resulting in axonal transport impairment, inflammation, and eventual cell death.

43. The method of claim 42, wherein the neurological disorder is an acute neurodegeneration.

44. The method of claim 43, wherein the acute neurodegeneration is selected from traumatic brain injury, stroke, acute brain injury induced by brain ischemia, acute brain injury induced by insufficient oxygen supply to the brain, acute brain injury induced by anoxia or hypoxia, micro infarcts, acute brain injury induced by concussion, post-operative cognitive decline resulting from anesthesia or surgery-induced inflammation, acute brain injury induced by drowning, acute brain injury associated with whip lash, acute brain injury associated with bicycle crashes, acute brain injury associated with automobile accidents, shaken baby syndrome, acute brain injury induced by falling, acute brain injury associated with physical impact of the head, and acute angle-closure glaucoma.

45. The method of claim 41, wherein the neurological disorder is a neuropsychiatric indication.

46. The method of claim 45, wherein the neuropsychiatric indication is selected from depression, schizophrenia, dementia, Alzheimer’s disease, anxiety, and substance abuse disorder.

47. The method of claim 41, wherein the neurological disorder is a mental illness.

48. The method of claim 47, wherein the mental illness is selected from autism, attention deficit-hyperactivity disorder, bipolar disorder, depression and major depressive disorder, behavioral problems, posttraumatic stress disorder and schizophrenia.

49. The method of claim 41, wherein the dosage of posiphen D-tartrate Form B is from about 0.1 mg / kg to about 100 mg / kg of body weight.

50. The method of claim 49, wherein the dosage of posiphen D-tartrate Form B is from about 1 mg / kg to about 20 mg / kg of body weight.

51. The method of claim 41, wherein the pharmaceutical composition is administered daily to the subject.

52. The method of claim 51, wherein the pharmaceutical composition is administered once daily to the subject.

53. The method of claim 41, wherein the subject is human.

54. The method of claim 41, wherein the administrating is oral administration.

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