WO2012142067A2

WO2012142067A2 - Formulations, salts, and solid forms of substituted cyclohexylmethanamines, processes for preparation, and uses thereof

Info

Publication number: WO2012142067A2
Application number: PCT/US2012/032977
Authority: WO
Inventors: John Dankwardt; Susan S. D'souza; Steve FABIAN; Michael FILIOS; Sharon M. Laughlin; Michael Joseph SIZENSKY; John Snoonian; Charles VANDENBOSSCHE; Harold Scott Wilkinson
Original assignee: Sunovion Pharmaceuticals Inc.
Priority date: 2011-04-13
Filing date: 2012-04-11
Publication date: 2012-10-18
Also published as: WO2012142067A3

Abstract

Provided herein are pharmaceutical compositions and single unit dosage forms comprising a substituted cyclohexylmethanamine, or a pharmaceutically acceptable salt or solid form thereof. Also provided are methods of making the substituted cyclohexylmethanamine, or a pharmaceutically acceptable salt or solid form thereof, methods of making a pharmaceutical composition comprising the substituted cyclohexylmethanamine, or a pharmaceutically acceptable salt or solid form thereof, and method of their use for treating, managing, or preventing various disorders, such as a CNS disease.

Description

FORMULATIONS, SALTS, AND SOLID FORMS OF SUBSTITUTED CYCLOHEXYLMETHANAMINES, PROCESSES FOR PREPARATION,

AND USES THEREOF 1. CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. provisional patent application no. 61 475,098, filed April 13, 201 1, the content of which is hereby incorporated by reference in its entirety.

2. FIELD

Provided herein are salts or solid forms of substituted cyclohexylmethanamines;

pharmaceutical compositions comprising a substituted cyclohexylmethanamine, or a salt or solid form thereof; methods of preparing a substituted cyclohexylmethanamine, or a salt or solid form thereof; methods of preparing a pharmaceutical composition comprising a substituted

cyclohexylmethanamine, or a salt or solid form thereof; and methods of their use for the treatment of diseases or disorders.

3. BACKGROUND

Whether crystalline or amorphous, solid forms of a pharmaceutical compound may include single-component and multiple-component solids. Single-component solids consist essentially of the pharmaceutical compound in the absence of other compounds. Variety among single-component crystalline materials may potentially arise, e.g., from the phenomenon of polymorphism, wherein multiple three-dimensional arrangements exist for a particular pharmaceutical compound.

Solid forms such as salts and polymorphic forms (e.g., crystal forms) of a compound are known in the pharmaceutical art to affect, for example, solubility, stability, flowability, fractability, and compressibility of the compound as well as the safety and efficacy of drug products derived from the compound.

The importance of studying polymorphs was underscored by the case of ritonavir, an HIV protease inhibitor that was formulated as soft gelatin capsules. About two years after the product was launched, the unanticipated precipitation of a new, less soluble polymorph in the formulation necessitated the withdrawal of the product from the market until a more consistent formulation could be developed (see S. R. Chemburkar et al., Org. Process Res. Dev., (2000) 4:413- 17). Thus, the preparation of solid forms is of great importance in the development of a safe, effective, stable, and marketable pharmaceutical compound.

Certain substituted cyclohexylmethanamine compounds are described, e.g., in U.S. Patent Application No. 1 1/649,927, filed January 5, 2007 and U.S. Patent Application No. 12/688,474, filed January 15, 2010, both of which are incorporated by reference in their entireties. The substituted cyclohexylmethanamine compounds inhibit monoamine reuptake, and are useful for the treatment, prevention, or management of various diseases or disorders, for example, a disease of the central nervous system (CNS), including, but not limited to, depression, anxiety, schizophrenia, pain, fibromyalgia, neurodegenerative disease, and sleep disorder. A need exists for new formulations or

SDI- 1 16984v3 1 FORMULATIONS, SALTS, AND SOLID FORMS OF SUBSTITUTED CYCLOHEXYLMETHAN AMINES, PROCESSES FOR PREPARATION,

AND USES THEREOF 1. CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. provisional patent application no. 61/475,098, filed April 13, 2011, the content of which is hereby incorporated by reference in its entirety.

2. FIELD

Provided herein are salts or solid forms of substituted cyclohexylmethanamines;

3. BACKGROUND

Solid forms such as salts and polymorphic forms (e.g. , crystal forms) of a compound are known in the pharmaceutical art to affect, for example, solubility, stability, flowability, fractability, and compressibility of the compound as well as the safety and efficacy of drug products derived from the compound.

The importance of studying polymorphs was underscored by the case of ritonavir, an HIV protease inhibitor that was formulated as soft gelatin capsules. About two years after the product was launched, the unanticipated precipitation of a new, less soluble polymorph in the formulation necessitated the withdrawal of the product from the market until a more consistent formulation could be developed (see S. R. Chemburkar et al, Org. Process Res. Dev., (2000) 4:413^417). Thus, the preparation of solid forms is of great importance in the development of a safe, effective, stable, and marketable pharmaceutical compound.

Certain substituted cyclohexylmethanamine compounds are described, e.g., in U.S. Patent Application No. 11/649,927, filed January 5, 2007 and U.S. Patent Application No. 12/688,474, filed January 15, 2010, both of which are incorporated by reference in their entireties. The substituted cyclohexylmethanamine compounds inhibit monoamine reuptake, and are useful for the treatment, prevention, or management of various diseases or disorders, for example, a disease of the central nervous system (CNS), including, but not limited to, depression, anxiety, schizophrenia, pain, fibromyalgia, neurodegenerative disease, and sleep disorder. A need exists for new formulations or

SDI-116984v2 dosage forms of substituted cyclohexylmethanamines having advantageous physical and

pharmaceutical properties. Moreover, salts and solid forms of substituted cyclohexylmethanamines can further the development of formulations or dosage forms of the compounds for the treatment, prevention, or management of diseases and disorders.

Citation of any references in this section of the application is not to be construed as an admission that such references are prior art to the present application.

4. SUMMARY

In one embodiment, provided herein is a salt of a substituted cyclohexyl-methanamine described herein. In certain embodiments, provided herein is a pharmaceutically acceptable salt of a substituted cyclohexylmethanamine. In one embodiment, the substituted cyclohexylmethanamines described herein include, but are not limited to:

czs'-4-(aminomethyl)-4-(3,4-dichlorophenyl)- l-methylcyclohexanol;

czs'-4-(3,4-dichlorophenyl)- l -methyl-4-((methylamino)methyl)cyclohexanol;

c^-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)- l-methylcyclohexanol;

?ra«i'-4-(aminomethyl)-4-(3,4-dichlorophenyl)- l-methylcyclohexanol;

?ra«,y-4-(3,4-dichlorophenyl)- 1 -methyl-4-((methylamino)methyl)cyclohexanol; and

ira«i'-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)- l-methylcyclohexanol;

which have the following chemical structures:

In certain embodiments, a salt of a substituted cyclohexylmethanamine provided herein is a pharmaceutically acceptable salt, as described herein elsewhere. In certain embodiments, the salt provided herein is a solid, which is substantially free of water (i.e., substantially anhydrous). In certain embodiments, the salt provided herein is a solid, which is substantially free of solvent (i.e., substantially unsolvated). In certain embodiments, the salt provided herein is a solid, which exists in a solvated form (e.g., a hydrated form, including, e.g., a stoichiometric or non-stoichiometric hydrate).

In one embodiment, provided herein is a solid form (e.g., a crystal form, an amorphous form, or a mixture of two or more thereof) of a substituted cyclohexyl-methanamine provided herein. In another embodiment, provided herein is a crystal form or a solid form of a salt of a substituted cyclohexylmethanamine provided herein. In one embodiment, the crystal form or solid form

SDI-116984v2 2 described herein may be unsolvated or solvated (e.g., hydrated).

In one embodiment, provided herein is a pharmaceutical composition comprising a substituted cyclohexylmethanamine provided herein, or a salt, crystal form, or solid form thereof. In certain embodiments, provided herein is a pharmaceutical composition comprising a pharmaceutically acceptable salt of a substituted cyclohexylmethanamine provided herein. In one embodiment, the pharmaceutical composition provided herein further comprises one or more pharmaceutically acceptable excipient(s) or carrier(s). In one embodiment, the pharmaceutical composition provided herein is a single unit dosage form.

In one embodiment, provided herein is a stable pharmaceutical composition comprising a substituted cyclohexylmethanamine provided herein, or a pharmaceutically acceptable salt, crystal form, or solid form thereof. In certain embodiments, provided herein is a stable pharmaceutical composition comprising a pharmaceutically acceptable salt of a substituted cyclohexylmethanamine provided herein. In one embodiment, the stable pharmaceutical composition provided herein is suitable for oral dosing. In one embodiment, the stable pharmaceutical composition provided herein is in an immediate-release dosage form. In one embodiment, the stable pharmaceutical composition provided herein is in a controlled-release dosage form.

In one embodiment, provided herein is a method of preparing a substituted

cyclohexylmethanamine provided herein, including, e.g., a method of stereoselective synthesis of one or more stereoisomer(s) of the substituted cyclohexylmethanamine.

In one embodiment, provided herein is a method of preparing a salt of a substituted cyclohexylmethanamine provided herein. In certain embodiments, provided herein is a method of preparing a pharmaceutically acceptable salt of a substituted cyclohexylmethanamine provided herein.

In one embodiment, provided herein is a method of preparing a crystal form or a solid form of a substituted cyclohexylmethanamine provided herein. In one embodiment, provided herein is a method of preparing a crystal form or a solid form of a salt of a substituted cyclohexylmethanamine provided herein. In certain embodiments, provided herein is a method of preparing a crystal form or a solid form of a pharmaceutically acceptable salt of a substituted cyclohexylmethanamine provided herein.

Also provided herein are methods of treating, preventing, or managing a disease or disorder, which comprises administering to a subject (e.g., a human) in need thereof a pharmaceutical composition provided herein. In one embodiment, provided herein is a method of treating, preventing, or managing a neurological disease, comprising administering to a subject in need thereof a pharmaceutical composition provided herein. In one embodiment, provided herein is a method of treating, preventing, or managing a CNS disease, comprising administering to a subject in need thereof a pharmaceutical composition provided herein. In one embodiment, the CNS diseases include, but are not limited to, depression (e.g., major depressive disorder, unipolar depression, bipolar depression, seasonal affective disorder, treatment-resistant depression, and dysthymia),

SDI-116984v2 3 cognitive deficit, fibromyalgia, pain (e.g., neuropathic pain), sleep disorder (e.g., sleep apnea), attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), restless leg syndrome, schizophrenia, anxiety, obsessive compulsive disorder, posttraumatic stress disorder, seasonal affective disorder (SAD), premenstrual dysphoria, and neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's disease). Other diseases or disorders that may be treated, prevented, or managed by the methods provided herein are described in detail herein elsewhere. In some embodiments, the pharmaceutical composition provided herein is administered in combination with one or more additional therapeutic agents as described herein elsewhere. In one embodiment, also provided herein are kits comprising pharmaceutical compositions or dosage forms provided herein. 5. DETAILED DESCRIPTION

Provided herein are salts or solid forms (e.g. , a crystal form, an amorphous form, or a mixture of two or more thereof) of certain substituted cyclohexylmethanamines. Also provided herein are pharmaceutical dosage forms, formulations, or pharmaceutical compositions comprising a substituted cyclohexylmethanamine, or a pharmaceutically acceptable salt or solid form thereof. In some embodiments, the dosage forms are suitable for oral administration to a patient. In other

embodiments, the dosage forms provided herein exhibit advantageous physical and/or

pharmacological properties. Such properties include, but are not limited to, ease of assay, content uniformity, flow properties for manufacture, dissolution and bioavailability, and stability. In certain embodiments, the dosage forms provided herein have a shelf life of at least about 12 months, at least about 24 months, or at least about 36 months without refrigeration.

5.1. DEFINITIONS

As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in connection with doses, amounts, or weight percents of ingredients of a composition or a dosage form, mean a dose, amount, or weight percent that is recognized by those of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. Specifically, the terms "about" and "approximately," when used in this context, contemplate a dose, amount, or weight percent within 30 %, 25%, 20%, 15%, 10%, 5%, 3%, or 1% of the specified dose, amount, or weight percent.

As used herein, and unless otherwise specified, the term "pharmaceutically acceptable" herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, and unless otherwise specified, the term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. In one embodiment, a pharmaceutically acceptable salt is an acid addition salt prepared from a pharmaceutically acceptable non-toxic acids, including inorganic acids and organic

SDI-116984v2 4 acids. These salts may be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound provided herein in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification. Suitable pharmaceutically acceptable salts include acid addition salts of inorganic and organic acids, including, but not limited to, acetic, acetoxybenzoic, adipic, alginic, aminosalicylic, anthranilic, ascorbic, aspartic, benzenesulfonic, benzoic, camphorsulfonic, carbonic,

chlortheophyllinic, cinnamic, citric, dihydrogenphosphoric, edetic, edisylic, estolic, ethanedisulfonic, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluceptic, glucoheptonic, gluconic, glucuronic, glutamic, glutaric, glycidic, glycolic, hippuric, hydrobromic, hydrochloric, hydroiodic,

hydroxymaleic, hydroxynaphthoic, isethionic, isobutyric, isonicotinic, isothionic, lactic, lactobionic, lauric, laurylsulphonic, maleic, malic (e.g., L-malic), malonic, mandelic (e.g., S-mandelic), methanesulfonic, methylsulfuric, monohydrogencarbonic, monohydrogenphosphoric,

monohydrogensulfuric, monohydrogentartaric, mucic, naphthoic, napsylic, nitric, octadecanoic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phosphoric, phthalic, polygalacturonic, propionic, pyroglutamic, saccharic, salicylic, stearic, suberic, succinic, sulfamic, sulfanilic, sulfosalicylic, sulfuric, tannic, tartaric (e.g., L-tartaric acid and D-tartaric acid), p-toluenesulfonic, trifluoroacetic, and valeric acid salts. Compounds that include an amine moiety can form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Certain specific compounds described herein may contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

As used herein, and unless otherwise specified, the term "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, which may be liquid or solid. Exemplary excipients include vehicles, diluents, additives, liquid and solid fillers, carrier, solvents, solvent encapsulating materials. Each excipient must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable excipients include: (1) sugars, such as, lactose, glucose, and sucrose; (2) starches, such as, corn starch and potato starch; (3) cellulose, and its derivatives, such as, sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppository waxes; (9) oils, such as, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as, propylene glycol; (11) polyols, such as, glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as, ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as, magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen- free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates, and/or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations.

As used herein, and unless otherwise specified, the term "solvate" means a compound

SDI-116984v2 5 provided herein, or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.

As used herein, and unless otherwise specified, the term "crystalline," when used to describe a substance, component, or product, means that the substance, component, or product is substantially crystalline as determined, for example, by X-ray diffraction. See, e.g., Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21^st ed. (2005).

As used herein, and unless otherwise specified, the term "crystalline form," "crystal form," and related terms herein refer to the various crystalline material comprising a given substance, including single-component crystal forms and multiple-component crystal forms, and including, but not limited to, polymorphs, solvates, hydrates, co-crystals and other molecular complexes, as well as salts, solvates of salts, hydrates of salts, other molecular complexes of salts, and polymorphs thereof. In certain embodiments, a crystal form of a substance may be substantially free of amorphous forms and/or other crystal forms. In other embodiments, a crystal form of a substance may contain about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45% or about 50% of one or more amorphous form(s) and/or other crystal form(s) on a weight and/or molar basis.

Different crystal forms may have different physical properties such as, for example, melting temperatures, heats of fusion, solubilities, dissolution rates, and/or vibrational spectra, as a result of the arrangement or conformation of the molecules or ions in the crystal lattice. The differences in physical properties exhibited by crystal forms affect pharmaceutical parameters, such as storage stability, compressibility and density (factors affecting formulation and product manufacturing), and dissolution rate (a factor affecting bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one crystal form than when comprised of another crystal form) or mechanical changes (e.g., tablets crumble on storage as one crystal form converts into another) or both (e.g., tablets of one crystal form are more susceptible to breakdown at high humidity). As a result of

solubility/dissolution differences, in the extreme case, some crystal form transitions may result in lack of potency or, at the other extreme, toxicity. In addition, the physical properties of the crystal form may be important in processing; for example, one crystal form might be more likely to form solvates or might be difficult to filter and wash free of impurities (e.g. , particle shape and size distribution might be different between crystal forms).

Crystal forms of a substance can be obtained by a number of methods, as known in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, recrystallization in confined spaces, such as, e.g., in nanopores or capillaries, recrystallization on surfaces or templates, such as, e.g. , on polymers, recrystallization in the presence of additives, such as, e.g. , co-crystal counter-molecules, desolvation, dehydration, rapid evaporation,

SDI-116984v2 6 rapid cooling, slow cooling, vapor diffusion, sublimation, grinding, solvent-drop grinding, microwave-induced precipitation, sonication-induced precipitation, laser- induced precipitation, and/or precipitation from a supercritical fluid.

Techniques for characterizing crystal forms and amorphous forms include, but are not limited to, thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X-ray diffractometry, vibrational spectroscopy, e.g., infrared (IR) and Raman spectroscopy, solid-state nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies.

As used herein, and unless otherwise specified, the term "peak," when used in connection with the spectra or data presented in graphical form (e.g., XRPD, IR, Raman, and NMR spectra), refers to a peak or other special feature that one skilled in the art would recognize as not attributable to background noise. The term "significant peak" refers to peaks at least the median size (e.g. , height) of other peaks in the spectrum or data, or at least 1.5, 2, or 2.5 times the median size of other peaks in the spectrum or data.

As used herein, and unless otherwise specified, the terms "polymorph," "polymorphic form," and related terms herein refer to a solid crystal form of a compound or complex, consisting of the same molecule, molecules and/or ions as another crystal form of the compound or complex. Different polymorphs of the same compound can exhibit different physical, chemical, and/or spectroscopic properties.

As used herein, and unless otherwise specified, the terms "solid form" and related terms herein refer to a physical form comprising a compound provided herein or a salt or solvate thereof, which is not in a liquid or a gaseous state. Solid forms may be crystalline, amorphous, partially crystalline and/or partially amorphous.

As used herein, and unless otherwise specified, the term "amorphous," "amorphous form," and related terms herein mean that the substance, component or product in question is not substantially crystalline as determined by X-ray diffraction. In certain embodiments, an amorphous form of a substance may be substantially free of other amorphous forms and/or crystal forms. In other embodiments, an amorphous form of a substance may contain about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45% or about 50% of one or more other amorphous forms and/or crystal forms on a weight and/or molar basis. Amorphous forms of a substance can be obtained by a number of methods, as known in the art. Such methods include, but are not limited to, heating, melt cooling, rapid melt cooling, solvent evaporation, rapid solvent evaporation, desolvation, sublimation, grinding, cryo- grinding, spray drying, and freeze drying.

As used herein and unless otherwise specified, a composition that is "substantially free" of a

SDI-116984v2 7 compound means that the composition contains less than about 20 percent by weight, less than about 10 percent by weight, less than about 5 percent by weight, less than about 3 percent by weight, or less than about 1 percent by weight of the compound.

As used herein, and unless otherwise specified, the term "stereomerically pure" means a composition or substance that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound. For example, a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of other stereoisomers (e.g., diastereoisomers or enantiomers, or syn or anti isomers, or cis or trans isomers) of the compound. A typical stereomerically pure compound comprises greater than about 80 percent by weight of one stereoisomer of the compound and less than about 20 percent by weight of other stereoisomers of the compound, greater than about 90 percent by weight of one stereoisomer of the compound and less than about 10 percent by weight of the other stereoisomers of the compound, greater than about 95 percent by weight of one stereoisomer of the compound and less than about 5 percent by weight of the other stereoisomers of the compound, or greater than about 97 percent by weight of one stereoisomer of the compound and less than about 3 percent by weight of the other stereoisomers of the compound.

As used herein, and unless otherwise specified, the term "enantiomerically pure" means a stereomerically pure composition of a compound having one or more chiral center(s).

As used herein, and unless otherwise specified, the terms "enantiomeric excess" and "diastereomeric excess" are used interchangeably herein. In some embodiments, compounds with a single stereocenter may be referred to as being present in "enantiomeric excess," and those with at least two stereocenters may be referred to as being present in "diastereomeric excess." For example, the term "enantiomeric excess" is well known in the art and is defined as:

cone, of a - cone, of b

ee_a 100

cone, of a + cone, of b

Thus, the term "enantiomeric excess" is related to the term "optical purity" in that both are measures of the same phenomenon. The value of ee will be a number from 0 to 100, zero being racemic and 100 being enantiomerically pure. A compound which in the past might have been called 98% optically pure is now more precisely characterized by 96% ee. A 90% ee reflects the presence of 95% of one enantiomer and 5% of the other(s) in the material in question.

As used herein, and unless otherwise specified, the term "substantially pure" when used to describe a polymorph, a crystal form, or a solid form of a compound or complex described herein means a solid form of the compound or complex that comprises a particular polymorph and is substantially free of other polymorphic and/or amorphous forms of the compound. A representative substantially pure polymorph comprises greater than about 80% by weight of one polymorphic form of the compound and less than about 20% by weight of other polymorphic and/or amorphous forms of

SDI-116984v2 8 the compound; greater than about 90% by weight of one polymorphic form of the compound and less than about 10% by weight of other polymorphic and/or amorphous forms of the compound; greater than about 95% by weight of one polymorphic form of the compound and less than about 5% by weight of other polymorphic and/or amorphous forms of the compound; greater than about 97% by weight of one polymorphic form of the compound and less than about 3% by weight of other polymorphic and/or amorphous forms of the compound; or greater than about 99% by weight of one polymorphic form of the compound and less than about 1% by weight of other polymorphic and/or amorphous forms of the compound.

As used herein, and unless otherwise specified, a crystal form that is "essentially free" of water and/or solvent in the crystal lattice has a quantity of water and/or solvent in the crystal lattice which is, in certain embodiments, approximately near the limit of detection, in other embodiments, approximately at the limit of detection, and in other embodiments, approximately below the limit of detection for solvent and/or water in the crystal lattice when measured using a conventional solid-state analytical technique, e.g., a technique described herein. In certain embodiments, the solid-state analytical technique used to determine the quantity of water and/or solvent in the crystal lattice is thermogravimetric analysis. In other embodiments, the solid-state analytical technique used to determine the quantity of water and/or solvent in the crystal lattice is Karl Fischer analysis. In other embodiments, a crystal form which is "essentially free" of water and/or solvent in the crystal lattice has a quantity of water and/or solvent which is less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.05%, or less than about 0.01% of the total weight of the crystal form.

As used herein, a crystalline or amorphous form that is "pure," i.e., substantially free of other crystalline or amorphous forms, contains less than about 10 percent by weight of one or more other crystalline or amorphous form, less than about 5 percent by weight of one or more other crystalline or amorphous form, less than about 3 percent by weight of one or more other crystalline or amorphous form, or less than about 1 percent by weight of one or more other crystalline or amorphous form.

As used herein, and unless otherwise specified, the term "stable" refers to a compound or composition that does not readily decompose or change in chemical makeup or physical state. A stable composition or formulation provided herein does not significantly decompose under normal manufacturing or storage conditions. In some embodiments, the term "stable," when used in connection with a formulation or a dosage form, means that the active ingredient of the formulation or dosage form remains unchanged in chemical makeup or physical state for a specified amount of time and does not significantly degrade or aggregate or become otherwise modified (e.g., as determined, for example, by HPLC, FTIR, or XRPD). In some embodiments, about 70 percent or greater, about 80 percent or greater, about 90 percent or greater, about 95 percent or greater, about 98 percent or

SDI-116984v2 9 greater, or about 99 percent or greater of the compound remains unchanged after the specified period.

The compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as, for example, tritium (³H), iodine-125 (¹²⁵I) or carbon- 14 (¹⁴C). In other embodiments, the compounds may be enriched with non-radioactive isotopes at certain positions, such as, for example, deuterium (²H), carbon- 13 (¹³C), or nitrogen- 15 (¹⁵N). All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.

As used herein, and unless otherwise specified, the terms "treat," "treating," and "treatment" refer to the eradication or amelioration of a disease or disorder, or of one or more symptom(s) associated with the disease or disorder. In certain embodiments, the terms refer to minimizing the spread or worsening of the disease or disorder resulting from the administration of one or more therapeutic agents to a subject having such a disease or disorder. In some embodiments, the terms refer to the administration of a compound or a composition provided herein, with or without other additional active agent, after the onset of symptoms of a particular disease.

As used herein, and unless otherwise specified, the terms "prevent," "preventing," and "prevention" refer to the prevention of the onset, recurrence, or spread of a disease or disorder, or of one or more symptom(s) thereof. In certain embodiments, the terms refer to the treatment with or administration of a compound or a composition provided herein, with or without other additional active compound, prior to the onset of symptoms of a disease or disorder, for example, to patients at risk of a disease or disorder provided herein. The terms encompass the inhibition or reduction of a symptom of a particular disease. In certain embodiments, patients with familial history of a disease are candidates for preventive regimens. In other embodiments, patients who have a history of recurring symptoms are also potential candidates for the prevention. In this regard, the term

"prevention" may be interchangeably used with the term "prophylactic treatment."

As used herein, and unless otherwise specified, the terms "manage," "managing," and "management" refer to preventing or slowing the progression, spread, or worsening of a disease or disorder, or of one or more symptom(s) thereof. Often, the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disease or disorder. In this regard, the term "managing" encompasses treating a patient who had suffered from the particular disease in an attempt to prevent or minimize the recurrence of the disease.

As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or disorder, or to delay or minimize one or more symptom(s) associated with the disease or disorder. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the disease or disorder. The term "therapeutically effective amount" can encompass

SDI-116984v2 10 an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.

As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease or disorder, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

As used herein, and unless otherwise specified, the term "subject" is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like. In specific embodiments, a subject is a human.

As used herein, and unless otherwise specified, the term "monoamine transporter ligand" refers to a compound, which binds to a monoamine transporter. Ligands include endogenous monoamines, which are the natural ligands for a given monoamine transporter as well as drug molecules and other compounds, such as synthetic molecules known to bind to a particular monoamine transporter. In one example, the ligand includes a radioisotope, such as tritium or is otherwise (e.g., fluore scent ly) labeled. It is within the abilities of a skilled person to select an appropriate ligand for a given monoamine transporter. For example, known ligands for the dopamine transporter include dopamine and WIN35428, known ligands for the serotonin transporter include 5- hydroxytryptamine (serotonin) and citalopram, and ligands for the norepinephrine transporter include norepinephrine and nisoxetine

As used herein, and unless otherwise specified, the term "neurological disorder" refers to any condition of the central or peripheral nervous system of a mammal. The term "neurological disorder" includes, but is not limited to, neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis), neuropsychiatric diseases (e.g., schizophrenia and anxieties, such as general anxiety disorder), and affective disorders (e.g. , depression and attention deficit disorder). Exemplary neurological disorders include, but are not limited to, MLS (cerebellar ataxia), Huntington's disease, Down syndrome, multi-infarct dementia, status epilecticus, contusive injuries (e.g., spinal cord injury and head injury), viral infection induced neurodegeneration, (e.g., AIDS, encephalopathies), epilepsy, benign forgetfulness, closed head injury, sleep disorders, depression, dementias, movement disorders, psychoses, alcoholism, post-traumatic stress disorder and the like. "Neurological disorder" also includes any condition associated with the disorder. For instance, a method of treating a neurodegenerative disorder includes methods of treating loss of memory and/or loss of cognition associated with a neurodegenerative disorder. An exemplary method would also include treating or preventing loss of neuronal function characteristic of neurodegenerative disorder. "Neurological disorder" also includes any disease or condition that is implicated, at least in part, in monoamine (e.g., norepinephrine) signaling pathways (e.g., cardiovascular disease).

SDI-116984v2 1 1 As used herein, and unless otherwise specified, the term "central nervous system disorder" refers to any abnormal condition of the central nervous system of a mammal. In one embodiment, central nervous system disorder includes, but is not limited to, neurodegenerative diseases (e.g. , Alzheimer's disease and Parkinson's disease), neuropsychiatric diseases (e.g., schizophrenia), anxieties, sleep disorders, depression, dementias, movement disorders, psychoses, alcoholism, posttraumatic stress disorder, and the like. Central nervous system disorder also includes any condition associated with the disorder, such as loss of memory and/or impairment of cognition. For instance, a method of treating a neurodegenerative disease would also include treating or preventing loss of neuronal function characteristic of such disease. In one embodiment, central nervous system disorder also includes any disease or condition that is implicated, at least in part, in monoamine (e.g., norepinephrine) signaling pathways (e.g., cardiovascular disease).

As used herein, and unless otherwise specified, the term "affective disorder" includes depression, attention deficit disorder, attention deficit disorder with hyperactivity, bipolar and manic conditions (e.g., bipolar disorder), and the like. The terms "attention deficit disorder" (ADD) and "attention deficit disorder with hyperactivity" (ADDH), or attention deficit/hyper activity disorder (ADHD), are used herein in accordance with the accepted meanings as found in Diagnostic and Statistical Manual of Mental Disorders, 4th Ed., American Psychiatric Association (1997) (DSM IV™).

As used herein, and unless otherwise specified, the term "depression" includes all forms of depression including, but not limited to, major depressive disorder (MDD), bipolar disorder (e.g., bipolar depression), seasonal affective disorder (SAD), treatment-resistant depression, and dysthymia. "Major depressive disorder" is used herein interchangeably with "unipolar depression" and "major depression." "Depression" may also include any condition commonly associated with depression, such as all forms of fatigue (e.g., chronic fatigue syndrome) and cognitive deficits.

As used herein, and unless otherwise specified, the terms "obsessive-compulsive disorder,"

"substance abuse," "pre -menstrual syndrome," "anxiety," "eating disorders" and "migraine" are used herein in a manner consistent with their accepted meanings in the art. See, e.g., DSM-IV™. For example, the term "eating disorder," as used herein, refers to abnormal compulsions to avoid eating or uncontrollable impulses to consume abnormally large amounts of food. These disorders may affect not only the social well-being, but also the physical well-being of sufferers. Examples of eating disorders include, but are not limited to, anorexia nervosa, bulimia, and binge eating.

As used herein, and unless otherwise specified, the term "fibromyalgia" refers to a chronic condition characterized by diffuse or specific muscle, joint, or bone pain, along with fatigue and a range of other symptoms. Previously, fibromyalgia was known by other names such as fibrositis, chronic muscle pain syndrome, psychogenic rheumatism and tension myalgias.

As used herein, and unless otherwise specified, the term "convulsion" refers to a neurological disorder and is used interchangeably with "seizure," although there are many types of seizure, some of

SDI-116984v2 12 which have subtle or mild symptoms instead of convulsions. Seizures of all types may be caused by disorganized and sudden electrical activity in the brain. In some embodiments, convulsions are a rapid and uncontrollable shaking during which the muscles contract and relax repeatedly.

As used herein, and unless otherwise specified, the term "pain" refers to an unpleasant sensory and emotional experience. The term "pain," as used herein, refers to all categories of pain, including pain that is described in terms of stimulus or nerve response, e.g., somatic pain (normal nerve response to a noxious stimulus) and neuropathic pain (abnormal response of a injured or altered sensory pathway, often without clear noxious input); pain that is categorized temporally, e.g., chronic pain and acute pain; pain that is categorized in terms of its severity, e.g., mild, moderate, or severe; and pain that is a symptom or a result of a disease state or syndrome, e.g., inflammatory pain, cancer pain, AIDS pain, arthropathy, migraine, trigeminal neuralgia, cardiac ischaemia, and diabetic peripheral neuropathic pain. See, e.g., Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et al., eds., 12th ed. 1991); Williams et al, J. Med. Chem. 42: 1481-1485 (1999), herein each incorporated by reference in their entirety. "Pain" is also meant to include mixed etiology pain, dual mechanism pain, allodynia, causalgia, central pain, hyperesthesia, hyperpathia, dysesthesia, and hyperalgesia. In addition, the term "pain" includes pain resulting from dysfunction of the nervous system: organic pain states that share clinical features of neuropathic pain and possible common pathophysiology mechanisms, but are not initiated by an identifiable lesion in any part of the nervous system.

As used herein, and unless otherwise specified, the term "somatic pain" refers to a normal nerve response to a noxious stimulus such as injury or illness, e.g., trauma, burn, infection, inflammation, or disease process such as cancer, and includes both cutaneous pain (e.g., skin, muscle or joint derived) and visceral pain (e.g., organ derived).

As used herein, and unless otherwise specified, the term "neuropathic pain" refers to a heterogeneous group of neurological conditions that result from damage to the nervous system. The term also refers to pain resulting from injury to or dysfunctions of peripheral and/or central sensory pathways, and from dysfunctions of the nervous system, where the pain often occurs or persists without an obvious noxious input. This includes pain related to peripheral neuropathies as well as central neuropathic pain. Common types of peripheral neuropathic pain include diabetic neuropathy (also called diabetic peripheral neuropathic pain, or DN, DPN, or DPNP), post- herpetic neuralgia

(PHN), and trigeminal neuralgia (TGN). Central neuropathic pain, involving damage to the brain or spinal cord, can occur following stroke, spinal cord injury, and as a result of multiple sclerosis, and is also encompassed by the term. Other types of pain that are meant to be included in the definition of neuropathic pain include, but are not limited to, pain from neuropathic cancer pain, HIV/AIDS induced pain, phantom limb pain, and complex regional pain syndrome.

As used herein, and unless otherwise specified, the term "neuropathic pain" also encompasses the common clinical features of neuropathic pain including, but not limited to, sensory loss, allodynia

SDI-116984v2 13 (non-noxious stimuli produce pain), hyperalgesia and hyperpathia (delayed perception, summation, and painful aftersensation). Pain is often a combination of nociceptive and neuropathic types, for example, mechanical spinal pain and radiculopathy or myelopathy.

As used herein, and unless otherwise specified, the term "acute pain" refers to the normal, predicted physiological response to a noxious chemical, thermal or mechanical stimulus typically associated with invasive procedures, trauma and disease. It is generally time-limited, and may be viewed as an appropriate response to a stimulus that threatens and/or produces tissue injury. The term also refers to pain which is marked by short duration or sudden onset.

As used herein, and unless otherwise specified, the term "chronic pain" encompasses the pain occurring in a wide range of disorders, for example, trauma, malignancies and chronic inflammatory diseases such as rheumatoid arthritis. Chronic pain may last more than about six months. In addition, the intensity of chronic pain may be disproportionate to the intensity of the noxious stimulus or underlying process. The term also refers to pain associated with a chronic disorder, or pain that persists beyond resolution of an underlying disorder or healing of an injury, and that is often more intense than the underlying process would predict. It may be subject to frequent recurrence.

As used herein, and unless otherwise specified, the term "inflammatory pain" is pain in response to tissue injury and the resulting inflammatory process. Inflammatory pain is adaptive in that it elicits physiologic responses that promote healing. However, inflammation may also affect neuronal function. Inflammatory mediators, including PGE2 induced by the COX2 enzyme, bradykinins, and other substances, bind to receptors on pain-transmitting neurons and alter their function, increasing their excitability and thus increasing pain sensation. Much chronic pain has an inflammatory component. The term also refers to pain which is produced as a symptom or a result of inflammation or an immune system disorder.

As used herein, and unless otherwise specified, the term "visceral pain" refers to pain which is located in an internal organ.

As used herein, and unless otherwise specified, the term "mixed etiology pain" refers to pain that contains both inflammatory and neuropathic components.

As used herein, and unless otherwise specified, the term "dual mechanism pain" refers to pain that is amplified and maintained by both peripheral and central sensitization.

As used herein, and unless otherwise specified, the term "causalgia" refers to a syndrome of sustained burning, allodynia, and hyperpathia after a traumatic nerve lesion, often combined with vasomotor and sudomotor dysfunction and later trophic changes.

As used herein, and unless otherwise specified, the term "central pain" refers to pain initiated by a primary lesion or dysfunction in the central nervous system.

As used herein, and unless otherwise specified, the term "hyperesthesia" refers to increased sensitivity to stimulation, excluding the special senses.

As used herein, and unless otherwise specified, the term "hyperpathia" refers to a painful

SDI-116984v2 14 syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold. It may occur with allodynia, hyperesthesia, hyperalgesia, or dysesthesia.

As used herein, and unless otherwise specified, the term "dysesthesia" refers to an unpleasant abnormal sensation, whether spontaneous or evoked. In certain embodiments, dysesthesia include hyperalgesia and allodynia.

As used herein, and unless otherwise specified, the term "hyperalgesia" refers to an increased response to a stimulus that is normally painful. It reflects increased pain on suprathreshold stimulation.

As used herein, and unless otherwise specified, the term "allodynia" refers to pain due to a stimulus that does not normally provoke pain.

As used herein, and unless otherwise specified, the term "diabetic peripheral neuropathic pain" (DPNP), also called diabetic neuropathy, DN or diabetic peripheral neuropathy), refers to chronic pain caused by neuropathy associated with diabetes mellitus. The classic presentation of DPNP is pain or tingling in the feet that can be described not only as "burning" or "shooting" but also as severe aching pain. Less commonly, patients may describe the pain as itching, tearing, or like a toothache. The pain may be accompanied by allodynia and hyperalgesia and an absence of symptoms, such as numbness.

As used herein, and unless otherwise specified, the term "post-herpetic neuralgia", also called "postherpetic neuralgia" or PHN, refers to a painful condition affecting nerve fibers and skin.

Without being limited by a particular theory, it is a complication of shingles, a second outbreak of the varicella zoster virus (VZV), which initially causes chickenpox.

As used herein, and unless otherwise specified, the term "neuropathic cancer pain" refers to peripheral neuropathic pain as a result of cancer, and can be caused directly by infiltration or compression of a nerve by a tumor, or indirectly by cancer treatments such as radiation therapy and chemotherapy (chemotherapy- induced neuropathy).

As used herein, and unless otherwise specified, the term "HIV/AIDS peripheral neuropathy" or "HIV/AIDS related neuropathy" refers to peripheral neuropathy caused by HIV/AIDS, such as acute or chronic inflammatory demyelinating neuropathy (AIDP and CIDP, respectively), as well as peripheral neuropathy resulting as a side effect of drugs used to treat HIV/AIDS.

As used herein, and unless otherwise specified, the term "phantom limb pain" refers to pain appearing to come from where an amputated limb used to be. Phantom limb pain can also occur in limbs following paralysis (e.g., following spinal cord injury). Phantom limb pain is usually chronic in nature.

As used herein, and unless otherwise specified, the term "trigeminal neuralgia" (TN) refers to a disorder of the fifth cranial (trigeminal) nerve that causes episodes of intense, stabbing, electric- shock-like pain in the areas of the face where the branches of the nerve are distributed (lips, eyes,

SDI-116984v2 15 nose, scalp, forehead, upper jaw, and lower jaw). It is also known as the "suicide disease".

As used herein, and unless otherwise specified, the term "complex regional pain syndrome (CRPS)," formerly known as "reflex sympathetic dystrophy" (RSD), refers to a chronic pain condition whose key symptom is continuous, intense pain out of proportion to the severity of the injury, which gets worse rather than better over time. The term encompasses type 1 CRPS, which includes conditions caused by tissue injury other than peripheral nerve, and type 2 CRPS, in which the syndrome is provoked by major nerve injury, and is sometimes called causalgia.

As used herein, and unless otherwise specified, the terms "complex regional pain syndrome," "CRPS" and "CRPS and related syndromes" mean a chronic pain disorder characterized by one or more of the following: pain, whether spontaneous or evoked, including allodynia (painful response to a stimulus that is not usually painful) and hyperalgesia (exaggerated response to a stimulus that is usually only mildly painful); pain that is disproportionate to the inciting event (e.g., years of severe pain after an ankle sprain); regional pain that is not limited to a single peripheral nerve distribution; and autonomic dysregulation (e.g., edema, alteration in blood flow and hyperhidrosis) associated with trophic skin changes (hair and nail growth abnormalities and cutaneous ulceration).

The embodiments provided herein can be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments.

5.2 Cyclohexylmethanamines, Salts, and Solid Forms

In one embodiment, provided herein is a method of preparing a substituted

cyclohexylmethanamine. In one embodiment, the substituted cyclohexylmethanamines described herein include, but are not limited to:

c 5'-4-(aminomethyl)-4-(3,4-dichlorophenyl)- l-methylcyclohexanol;

c 5^,-4-(3,4-dichlorophenyl)- l -methyl-4-((methylamino)methyl)cyclohexanol;

c 5^,-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)- l-methylcyclohexanol;

?ranj'-4-(aminomethyl)-4-(3,4-dichlorophenyl)- l-methylcyclohexanol;

?ranj^,-4-(3,4-dichlorophenyl)- 1 -methyl-4-((methylamino)methyl)cyclohexanol; and

?ranj^,-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)- l-methylcyclohexanol;

which have the following chemical structures:

SDI-116984v2 16

In one embodiment, the substituted cyclohexylmethanamines described herein include, but limited to:

c 5'-4-(aminomethyl)-4-(3,4-dichlorophenyl)- l-methylcyclohexanol;

c s-4-(3,4-dichlorophenyl)- 1 -methyl-4-((methylamino)methyl)cyclohexanol; and

c 5^,-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)- l-methylcyclohexanol;

which have the following chemical structures:

In one embodiment, provided herein is a method of preparing cis-4-(aminomethyl)-4-(3,4- dichlorophenyl)-l-methylcyclohexanol. In one embodiment, provided herein is a method of preparing CM-4-(3,4-dichlorophenyl)- l -methyl-4-((methylamino)methyl) cyclohexanol. In one embodiment, provided herein is a method of preparing ci5'-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)- l- methylcyclohexanol. Other embodiments of substituted cyclohexylmethanamine compounds that may be prepared by a method disclosed herein are described in, for example, U.S. Patent Application No. 1 1/649,927, filed January 5, 2007 and U.S. Patent Application No. 12/688,474, filed January 15, 2010, both of which are incorporated by reference in their entireties. The substituted

cyclohexylmethanamines are useful in the treatment of various diseases and disorders, such as a CNS disease, including, but not limited to, depression (e.g., major depressive disorder, unipolar depression, bipolar disorder or bipolar depression, seasonal affective disorder, treatment-resistant depression, and dysthymia), cognitive deficit, fibromyalgia, pain (e.g., neuropathic pain), sleep disorder (e.g., sleep apnea), attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), restless leg syndrome, schizophrenia, anxiety, obsessive compulsive disorder, posttraumatic stress disorder, seasonal affective disorder (SAD), premenstrual dysphoria, and neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's disease).

In one embodiment, provided herein is a method of preparing a substituted

cyclohexylmethanamine, in which the 1- and 4-positions of the cyclohexyl ring are substituted.

In one embodiment, an exemplary method for the synthesis of 4-substituted cyclohexylamines is outlined in Scheme 1, which is disclosed in U.S. Patent Application No. 1 1/649,927, filed January 5, 2007 and U.S. Patent Application No. 12/688,474, filed January 15, 2010. In one embodiment, in Scheme 1 , Ar is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl,

SDI-116984v2 17 including a mono- or fused-ring system. In one embodiment, in Scheme 1 , R is a substituted or unsubstituted alkyl (e.g., C1-C4 alkyl, methyl).

Scheme 1:

16

μνν, 1

trans 1-E

Referring to Scheme 1, the acetonitrile 1-A is condensed with methyl acrylate to give the di- ester 1-B, which is cyclized via Dieckmann condensation to give the cyclic hydroxy ester 1-C. Conversion of 1-C to intermediate 1-D can, for example, be affected by heating the compound in the microwave to about 160 °C. Addition of an alkyl nucleophile (such as MeLi or EtLi) gives a mixture of the hydroxynitriles cis 1-E and trans 1-E, which may be separated by silica gel column chromatography. In an exemplary embodiment, in which Ar = 3,4-dichlorophenyl and in which propylmagnesium chloride is used as the nucleophile, only the cis analog 1-E was obtained.

Reduction of the nitrile group (e.g., using borane) affords the corresponding amines cis 1-F and trans 1-F. Subsequent alkylation of the amines as described herein, or using a method known in the art, give corresponding alkyl amines, such as methyl- and dimethyl-amines.

In one embodiment, provided herein are improved synthetic procedures for the synthesis of a substituted cyclohexylmethanamine. In one embodiment, the synthetic procedures described herein avoid cryogenic conditions (e.g., the reaction of intermediate 1-D with alkyl lithium at low temperature to produce intermediate 1-E) and/or eliminate the step of diastereoselective addition which may require discarding certain amounts of unwanted stereoisomers generated during the addition reaction. In one embodiment, the improved processes for the synthesis of a substituted cyclohexylmethanamine described herein are efficient and have improved overall yield.

In one embodiment, provided herein are processes for preparing a substituted

cyclohexylmethanamine, as depicted in Scheme 2, wherein R^a and R^b are defined herein elsewhere. In one embodiment, provided herein are processes for preparing a substituted

cyclohexylmethanamine, comprising any one, two, three, four, five, six, or seven, of Steps 1, 2, 3, 4,

SDI-116984v2 1 g 5, 6, and 7 as depicted in Scheme 2. In one embodiment, provided herein is a process for preparing a substituted cyclohexylmethanamine, comprising Step 7. In one embodiment, provided herein is a process for preparing a substituted cyclohexylmethanamine, comprising Steps 6 and 7. In one embodiment, provided herein is a process for preparing a substituted cyclohexyl-methanamine, comprising Steps 5, 6 and 7. In one embodiment, provided herein is a process for preparing a substituted cyclohexylmethanamine, comprising Steps 4, 5, 6 and 7. In one embodiment, provided herein is a process for preparing a substituted cyclohexylmethanamine, comprising Steps 3, 4, 5, 6 and 7. In one embodiment, provided herein is a process for preparing a substituted

cyclohexylmethanamine, comprising Steps 2, 3, 4, 5, 6 and 7. In one embodiment, provided herein is a process for preparing a substituted cyclohexylmethanamine, comprising Steps 1, 2, 3, 4, 5, 6 and 7. Scheme 2:

2-F 2-G 2-H

In one embodiment, R^a and R^b are each independently H or a substituted or unsubstituted alkyl. In one embodiment, R^a and R^b are each independently H or methyl. In one embodiment, one of R^a and R^b is H and the other of R^a and R^b is methyl. In one embodiment, R^a and R^b are both methyl.

Referring to Scheme 2, nitrile 2-A is condensed with methyl acrylate to give a substituted cyclohexyl 2-B, for example, upon treatment with KO?-Bu. Compound 2-B is de-carboxylated to give compound 2-C, for example, upon treatment with KOH in a protic solvent. Compound 2-C is treated with MeMgBr or MeMgCl, for example, at a temperature of, e.g., about 0 °C (e.g., between about 0 °C and about 15 °C) or at room temperature, to give nitrile 2-D-a and 2-D-b. Nitriles 2-D-a and 2-D-b are converted to the corresponding acids 2-E-a and 2-E-b, for example, upon treatment with KOH in a protic solvent and acidifying the product. A mixture comprising 2-E-a and 2-E-b is dehydrated, for example, under acidic condition, to give lactone 2-F, e.g., in the presence of Amberlyst 15 and heated

SDI-116984v2 19 to a temperature of, e.g. , about 110 °C in toluene to remove water azeotropically. Lactone 2-F is reacted with an amine, RTl'TNIH, e.g., in the presence of z^'-PrMgCl, to give amide 2-G. Amide 2-G is reduced to provide amine 2-H, e.g., via reduction with borane-THF or borane dimethyl sulfide complex. The resulting amine 2-H may be further converted to a suitable salt, as described herein elsewhere.

In one embodiment, provided herein is a process of preparing Compound 2-B, comprising contacting Compound 2-A with methyl acrylate:

2-B

In one embodiment, provided herein is a process of preparing Compound 2-C from

Compound 2-B:

In one embodiment, provided herein is a process of preparing Compound 2-D-a and Compound 2-D-b, comprising contacting Compound 2-C with one or more methyl Grignard reagent(s) (e.g., MeMgBr and/or MeMgCl):

2-C 2-D-a 2-D-b

In one embodiment, the reaction with the methyl Grignard reagent is carried out at a temperature of about -30 °C, about -25 °C, about -20 °C, about -15 °C, about -10 °C, about -5 °C, about 0 °C, about 5 °C, about 10 °C, about 15 °C, about 20 °C, or about 25 °C. In one embodiment, the reaction with the methyl Grignard reagent is carried out at a temperature of between about -20 °C and about 20 °C, between about -20 °C and about 0 °C, or between about 0 °C and about 20 °C.

In one embodiment, provided herein is a process of preparing Compound 2-E-a and/or Compound 2-E-b from Compound 2-D-a and/or Compound 2-D-b:

SDI-116984v2 20

2-D-a 2-D-b 2-E-a 2-E-b

In one embodiment, provided herein is a process of preparing lactone 2-F from Compound 2-

E-a and/or Compound 2-E-b:

2-E-a 2-E-b 2-F

In one embodiment, the reaction of preparing lactone 2-F from Compound 2-E-a has a yield of greater than about 40%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, or greater than about 97%. In one embodiment, the reaction of preparing lactone 2-F from Compound 2-E-b has a yield of greater than about 40%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, or greater than about 97%. In one embodiment, the reaction of preparing lactone 2-F from a mixture of Compound 2-E-a and Compound 2-E-b has a yield of greater than about 40%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, or greater than about 97%.

In one embodiment, provided herein is a process of preparing Compound 2-G, comprising contacting lactone 2-F with amine R^aR^bNH, wherein R^a and R^b are defined herein elsewhere:

2-F 2-G

In one embodiment, provided herein is a process of preparing Compound 2-H from

Compound 2-G, wherein R^a and R^b are defined herein elsewhere:

2-G 2-H

SDI-116984v2 21 In one embodiment, provided herein is a process of preparing lactone 2-F from one or more of the following: nitrile 2-D-a, nitrile 2-D-b, a mixture 2-D-a and 2-D-b, acid 2-E-a, acid 2-E-b, and a mixture of 2-E-a and 2-E-b. In one embodiment, provided herein is a process of preparing lactone 2-F from a mixture of nitriles (2-D-a and 2-D-b) or a mixture of acids (2-E-a and 2-E-b). Specific conditions are described herein elsewhere. In one embodiment, provided herein is a process of preparing lactone 2-F by cyclization or isomerization/cyclization of a mixture of acids (2-E-a and 2- E-b). In one embodiment, the yield of the isomerization/ cyclization reaction is greater than about 40%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, or greater than about 97%, relative to the total amount of 2-E-a and 2-E-b. In one embodiment, the mixture of nitriles (2-D-a and 2-D-b) comprises 2-D-a and 2-D-b in about 10: 1, about 5: 1, about 3: 1, about 1 :1, about 1:3, about 1 :5, or about 1 : 10 w/w ratio. In one embodiment, the mixture of acids (2-E-a and 2-E-b) comprises 2-E-a and 2-E-b in about 10: 1, about 5: 1, about 3: 1, about 1 : 1, about 1 :3, about 1 :5, or about 1 :10 w/w ratio.

In one embodiment, provided herein are processes for preparing a substituted

cyclohexylmethanamine, as depicted in Scheme 3, wherein R^a and R^b are defined herein elsewhere. In one embodiment, provided herein are processes for preparing a substituted

cyclohexylmethanamine, comprising any one, two, three, four, or five, of Steps 1, 2, 3, 4, and 5 as depicted in Scheme 3. In one embodiment, provided herein is a process for preparing a substituted cyclohexyl-methanamine, comprising Step 5. In one embodiment, provided herein is a process for preparing a substituted cyclohexylmethanamine, comprising Steps 4 and 5. In one embodiment, provided herein is a process for preparing a substituted cyclohexyl-methanamine, comprising Steps 3, 4 and 5. In one embodiment, provided herein is a process for preparing a substituted

cyclohexylmethanamine, comprising Steps 2, 3, 4 and 5. In one embodiment, provided herein is a process for preparing a substituted cyclohexylmethanamine, comprising Steps 1, 2, 3, 4 and 5.

Scheme 3:

SDI-116984v2 22 In one embodiment, Scheme 3 provides an efficient method of preparing a lactone intermediate 3-D via a Diels- Alder reaction between an unsaturated boronate ester and isoprene. The resulting alkene is cyclized to provide the desired lactone.

Referring to Scheme 3, 3,4-dichlorophenylacetic acid 3-A is converted to a vinyl compound 3-B, for example, upon treatment with n-BuLi in THF at a temperature of, e.g., about 0 °C, and reacting with paraformaldehyde, and heating the resulting product, e.g. , at a temperature of about 60 °C to about 80 °C. Compound 3-B is converted to a cyclic compound 3-C upon reaction with isoprene, for example, in the presence of borane-THF. Compound 3-C is heated in the presence of an acid, for example, >-toluenesulfonic acid, at a temperature of, e.g., about 1 15 °C (e.g., between about 100 °C and about 130 °C), to give lactone 3-D. Lactone 3-D is reacted with an amine, ^'TvfH, for example, in the presence of z^'-PrMgCl, to give amide 3-E. Amide 3-E is reduced to provide amine 3- F, e.g., via reduction with borane-THF or borane dimethyl sulfide complex. The resulting amine 3-F may be further converted to a suitable salt, as described herein elsewhere.

In one embodiment, provided herein is a process of preparing Compound 3-B from

Compound 3-A:

3-A 3-B

In one embodiment, provided herein is a process of preparing Compound 3-C, comprising contacting Compound 3-B with isoprene:

3-C

embodiment, provided herein is a process of preparing lactone 3-D from Compound 3-

C:

In one embodiment, provided herein is a process of preparing Compound 3-E, comprising contacting lactone 3-D with amine R^aR^bNH, wherein R^a and R^b are defined herein elsewhere:

SDI-116984v2 23

In one embodiment, provided herein is a process of preparing Compound 3-F from

Compound 3-E, wherein R^a and R^b are defined herein elsewhere:

In one embodiment, provided herein is a process for preparing cii-4-(3,4-dichlorophenyl)-4- ((dimethylamino)methyl)- 1 -methylcyclohexanol, comprising the steps:

a) reacting 4-(3,4-dichlorophenyl)- l-methyl-2-oxabicyclo[2.2.2]octan-3-one with dimethylamine or metalodimethylamide to yield c^-l-(3,4-dichlorophenyl)-4-hydroxy-4-methyl-N,N- dimethylcyclohexanecarboxamide:

b) converting cis- 1 -(3 ,4-dichlorophenyl)-4-hydroxy-4-methyl-N,N- dimethylcyclohexanecarboxamide to c i-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)- 1 - methylcyclohexanol:

In exemplary embodiments, the metalodimethylamide is magnesium dimethylamide. In exemplary embodiments, the metalodimethylamide is lithium dimethylamide. In exemplary embodiments, the metalodimethylamide is aluminium dimethylamide.

In one embodiment, provided herein is a process for preparing d,y-4-(3,4-dichlorophenyl)-l methyl-4-((methylamino)methyl)cyclohexanol, comprising the steps:

a) reacting 4-(3,4-dichlorophenyl)-l-methyl-2-oxabicyclo[2.2.2]octan-3-one with methylamine or metalomethylamide to yield ci^'s-l-(3,4-dichlorophenyl)-4-hydroxy-N,4- dimethylcyclohexanecarboxamide:

SDI-116984v2 24

b) converting cij'-l-(3,4-dichlorophenyl)-4-hydroxy-N,4-dimethylcyclohexanecarboxamide to c i-4-(3,4-dichlorophenyl)- 1 -methyl-4-((methylamino)methyl)cyclohexanol:

In exemplary embodiments, the metalomethylamide is magnesium methylamide. In exemplary embodiments, the metalomethylamide is lithium methylamide. In exemplary embodiments, the metalomethylamide is aluminium methylamide.

In one embodiment, provided herein is a process for preparing d,y-4-(3,4-dichlorophenyl)-4- ((dimethylamino)methyl)- 1 -methylcyclohexanol, comprising the steps:

a) reacting 4-(3,4-dichlorophenyl)- l-methyl-2-oxabicyclo[2.2.2]octan-3-one with dimethylamine to yield czs-l-(3,4-dichlorophenyl)-4-hydroxy-4-methyl-N,N- dimethylcyclohexanecarboxamide:

In one embodiment, provided herein is a process for preparing ci^'i-4-(3,4-dichlorophenyl)-l- methyl-4-((methylamino)methyl)cyclohexanol, comprising the steps:

a) reacting 4-(3,4-dichlorophenyl)-l-methyl-2-oxabicyclo[2.2.2]octan-3-one with methylamine to yield c«-l-(3,4-dichlorophenyl)-4-hydroxy-N,4-dimethylcyclohexanecarboxamide:

SDI-116984v2 25 b) converting c^-l-(3,4-dichlorophenyl)-4-hydroxy-N,4-dimethylcyclohexanecarboxamide to c i-4-(3,4-dichlorophenyl)- 1 -methyl-4-((methylamino)methyl)cyclohexanol:

In one embodiment, provided herein is a lactone compound having the following structure (e.g., Compound 2-F or Compound 3-D described herein elsewhere):

In one embodiment, provided herein is a process for the preparation of the lactone compound, e.g. , using one or more step s/re actions as depicted in Scheme 2 and Scheme 3.

In one embodiment, provided herein is a composition including a first stereoisomer and at least one additional stereoisomer of a compound provided herein. The first stereoisomer may be present in a diastereomenc or enantiomeric excess of at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99%. In particular embodiments, the first stereoisomer is present in a diastereomeric or enantiomeric excess of at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5%. Enantiomeric or diastereomeric excess may be determined relative to exactly one other stereoisomer, or may be determined relative to the sum of at least two other stereoisomers. In an exemplary embodiment, enantiomeric or diastereomeric excess is determined relative to all other detectable stereoisomers, which are present in the mixture. Stereoisomers are detectable if a concentration of such stereoisomer in the analyzed mixture can be determined using common analytical methods, such as chiral HPLC. In one embodiment, provided herein is a composition comprising one stereoisomer of a compound provided herein substantially free of other stereoisomers.

In one embodiment, provided herein is a salt of a substituted cyclohexyl-methanamine. In certain embodiments, a salt of a substituted cyclohexylmethanamine provided herein is a

pharmaceutically acceptable salt, as described herein elsewhere. In one embodiment, a salt of a substituted cyclohexylmethanamine provided herein, include, but is not limited to, a salt selected from the group consisting of acetate, benzoate, besylate, camphorsulfonate, citrate, fumarate, glutarate, hydrobromide, hydrochloride, L-malate, D-malate, maleate, malonate, mandelate, mesylate, oleate, oxalate, phosphate, pyroglutamate, salicylate, stearate, succinate, sulfate, L-tartrate, D-tartrate, and tosylate. In one embodiment, the salt is a besylate, fumarate, maleate, mesylate, succinate or tosylate salt. In one embodiment, the salt is a maleate salt.

embodiment, the salt provided herein is a hydrochloride salt.

SDI-116984v2 26 In one embodiment, the salt provided herein is not a hydrochloride salt.

In one embodiment, provided herein is a salt of c i-4-(3,4-dichlorophenyl)-4- ((dimethylamino)methyl)- 1 -methylcyclohexanol, wherein the acidic counterion is described herein elsewhere. In one embodiment, provided herein is a salt of c25^,-4-(3,4-dichlorophenyl)-l-methyl-4- ((methylamino)methyl)cyclohexanol, wherein the acidic counterion is described herein elsewhere. In one embodiment, provided herein is a salt of czs-4-(aminomethyl)-4-(3,4-dichlorophenyl)-l- methylcyclohexanol, wherein the acidic counterion is described herein elsewhere.

In one embodiment, provided herein is a salt of cz,y-4-(3,4-dichlorophenyl)-4- ((dimethylamino)methyl)- 1 -methylcyclohexanol, wherein the salt is selected from the group consisting of acetate, benzoate, besylate, camphorsulfonate, citrate, fumarate, glutarate, hydrobromide, hydroiodide, L-malate, D-malate, maleate, malonate, mandelate, mesylate, oleate, oxalate, phosphate, pyroglutamate, salicylate, stearate, succinate, sulfate, L-tartrate, D-tartrate, and tosylate salts.

In one embodiment, provided herein is a salt of cz^',y-4-(3,4-dichlorophenyl)-4- ((dimethylamino)methyl)- 1 -methylcyclohexanol, wherein the salt is selected from the group consisting of besylate, fumarate, mandelate, stearate, mesylate, maleate, L-malate, malonate, succinate, oxalate, and tosylate salts.

In one embodiment, provided herein is a salt of czs-4-(3,4-dichlorophenyl)-4- ((dimemylamino)methyl)- 1 -methylcyclohexanol, wherein the salt is selected from the group consisting of besylate, s-camsylate, glutarate, hydrobromide, maleate, L-malate, mesylate, oxalate, phosphate, salicylate, sulfate, L-tartrate, tosylate, and xinofoate salts.

In one embodiment, provided herein is a salt of c i-4-(3,4-dichlorophenyl)-4- ((dimethylamino)methyl)- 1 -methylcyclohexanol, wherein the salt is selected from the group consisting of besylate, s-camsylate, hydrobromide, maleate, L-malate, mesylate, oxalate, phosphate, salicylate, sulfate, L-tartrate, tosylate, and xinofoate salts.

In one embodiment, provided herein is a hydrochloride salt of cz,s'-4-(3,4-dichlorophenyl)-4- ((dimethylamino)methyl)- 1 -methylcyclohexanol.

In one embodiment, provided herein is a maleate salt of c/s-4-(3,4-dichlorophenyl)-4- ((dimethylamino)methyl)- 1 -methylcyclohexanol.

In one embodiment, provided herein is a fumarate salt of c/s-4-(3,4-dichlorophenyl)-4-

((dimethylamino)methyl)- 1 -methylcyclohexanol.

In one embodiment, provided herein is a besylate salt of c i-4-(3,4-dichlorophenyl)-4- ((dimethylamino)methyl)- 1 -methylcyclohexanol.

In one embodiment, provided herein is a mesylate salt of c s-4-(3,4-dichlorophenyl)-4- ((dimethylamino)methyl)- 1 -methylcyclohexanol.

In one embodiment, provided herein is a tosylate salt of c/s-4-(3,4-dichlorophenyl)-4- ((dimethylamino)methyl)- 1 -methylcyclohexanol.

SDI-116984v2 27 In one embodiment, provided herein is a salt of cz^'s-4-(3,4-dichlorophenyl)-l-methyl-4- ((methylamino)methyl)cyclohexanol, wherein the salt is selected from the group consisting of acetate, benzoate, besylate, camphorsulfonate, citrate, fumarate, glutarate, hydrobromide, L-malate, D-malate, maleate, malonate, mandelate, mesylate, oleate, oxalate, phosphate, pyroglutamate, salicylate, stearate, succinate, sulfate, L-tartrate, D-tartrate, and tosylate salts.

In one embodiment, provided herein is a salt of cz^',y-4-(3,4-dichlorophenyl)-l-methyl-4- ((methylamino)methyl)cyclohexanol, wherein the salt is selected from the group consisting of succinate, mesylate, and besylate salts.

In one embodiment, provided herein is a hydrochloride salt of cz,s-4-(3,4-dichlorophenyi)- l - methyl-4-((methylamino)methyl)cyclohexanol.

In one embodiment, provided herein is a succinate salt of cz,y-4-(3,4-dichlorophenyl)-l- methyl-4-((methylamino)methyl)cyclohexanol.

In one embodiment, provided herein is a mesylate salt of cz^'s-4-(3,4-dichlorophenyl)-l - methyl-4-((methylamino)methyl)cyclohexanol.

In one embodiment, provided herein is a besylate salt of cz^',y-4-(3,4-dichlorophenyl)-l-methyl-

4-((methylamino)methyl)cyclohexanol.

In one embodiment, a salt provided herein has unexpected and superior properties (e.g. , a maleate salt of czi'-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)- l -methylcyclohexanol), including, but not limited to, solubility, intrinsic dissolution, stability (e.g., chemical and/or polymorphic stability), and non-hygroscopicity.

In one embodiment, the salt provided herein is prepared from the corresponding free base of a substituted cyclohexylmethanamine and a suitable acid. Exemplary procedures for preparing the salt are provided herein, for example, in the Examples section.

In one embodiment, provided herein is a solid form of a substituted cyclohexyl-methanamine described herein, or a pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a solid form of a substituted cyclohexylmethanamine described herein. In one embodiment, provided herein is a solid form of a pharmaceutically acceptable salt of a substituted

cyclohexylmethanamine described herein. In one embodiment, the solid form is crystalline. In one embodiment, the solid form is amorphous. In one embodiment, the solid form comprises a crystal form of a substituted cyclohexylmethanamine, or a pharmaceutically acceptable salt thereof. In one embodiment, the solid form comprising a crystal form of a substituted cyclohexyl-methanamine, or a pharmaceutically acceptable salt thereof, is substantially free of other forms (e.g. , other crystal forms or amorphous forms). In one embodiment, the solid form comprising a crystal form of a substituted cyclohexylmethanamine, or a pharmaceutically acceptable salt thereof, is substantially pure. In one embodiment, provided herein is a solid form comprising a crystal form of a substituted

cyclohexylmethanamine, or a pharmaceutically acceptable salt thereof, which further comprises another crystal form of the substituted cyclohexylmethanamine, or the pharmaceutically acceptable

SDI-116984v2 28 salt thereof. In one embodiment, provided herein is a solid form comprising a crystal form of a substituted cyclohexylmethanamine, or a pharmaceutically acceptable salt thereof, which further comprises an amorphous form of the substituted cyclohexylmethanamine, or the pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a solid form of cz^'s^-^^-dichlorophenyl)^-

((dimethylamino)methyl)- 1 -methylcyclohexanol. In one embodiment, provided herein is a solid form of a pharmaceutically acceptable salt of c^-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)- l- methylcyclohexanol. In one embodiment, provided herein is a solid form of a maleate salt of cis-4- (3,4-dichlorophenyl)-4-((dimethylamino)methyl)-l -methylcyclohexanol. In one embodiment, provided herein is a crystal form of cis-4-(3 ,4-dichlorophenyl)-4-((dimethylamino)methyl)- 1 - methylcyclohexanol. In one embodiment, provided herein is a crystal form of a pharmaceutically acceptable salt of c i-4-(3,4-dichlorophenyl)-4-((dimethylamino)-methyl)-l -methylcyclohexanol. In one embodiment, provided herein is a crystal form of a maleate salt of cw-4-(3,4-dichlorophenyl)-4- ((dimethylamino)methyl)- 1 -methylcyclohexanol.

In one embodiment, provided herein is a solid form of czs-4-(3,4-dichlorophenyl)-l-methyl-4-

((methylamino)methyl)cyclohexanol. In one embodiment, provided herein is a solid form of a pharmaceutically acceptable salt of cz^' -4-(3,4-dichlorophenyl)-l-methyl-4-

((methylamino)methyl)cyclohexanol. In one embodiment, provided herein is a crystal form of cis-4- (3,4-dichlorophenyl)- l-methyl-4-((methylamino)methyl)cyclohexanol. In one embodiment, provided herein is a crystal form of a pharmaceutically acceptable salt of czs-4-(3,4-dichlorophenyl)-l-methyl- 4-((methylamino)methyl)cyclohexanol.

In one embodiment, the solid form or crystal form provided herein is substantially free of water (e.g., anhydrous). In one embodiment, the solid form or crystal form provided herein is substantially free of solvent (e.g., unsolvated). In one embodiment, the solid form or crystal form provided herein is hydrated (e.g., exists in a hydrated form). In one embodiment, the solid form or crystal form provided herein is solvated. In one embodiment, the solid form provided herein is a crystalline hydrate. In one embodiment, the solid form provided herein is a non-crystalline hydrate. In one embodiment, the solid form or crystal form provided herein comprises water as part of the crystal lattice. In one embodiment, the solid or crystal form provided herein does not contain water as part of the crystal lattice. In one embodiment, the solid form or crystal form provided herein comprises water on the surface of the crystal form.

In one embodiment, the solid form or crystal form provided herein comprises an acidic counterion (e.g., from the acid used to form the pharmaceutical salt) as part of the crystal lattice.

5.3 Pharmaceutical Compositions and Dosage Forms

In one embodiment, provided herein is a single unit dosage form suitable for oral administration to a human comprising: an amount equal to or greater than about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 125, 150, 200, or 250 mg of an active ingredient; and a pharmaceutically

SDI-116984v2 29 acceptable excipient or carrier; wherein the active ingredient is a substituted cyclohexylmethanamine provided herein, or a pharmaceutically acceptable salt or solid form thereof. In certain embodiments, when the active ingredient (e.g. , a substituted cyclohexylmethanamine provided herein) is present in the pharmaceutical composition as a salt, the amount of the active ingredient referred to herein is the amount of the corresponding free base (i.e., the effective strength of the active ingredient or the amount of the substituted cyclohexylmethanamine in the pharmaceutical composition).

In some embodiments, the amount of active ingredient is from about 0.1 to about 200 mg, from about 0.5 to about 100 mg, from, about 1 to about 50 mg, from about 1 mg to about 25 mg, from about 1 to about 5 mg, or from about 0.5 mg to about 5 mg. In one embodiment, the amount of the active ingredient is about 0.5 mg. In another embodiment, the amount of the active ingredient is about 1 mg. In another embodiment, the amount of the active ingredient is about 1.5 mg. In another embodiment, the amount of the active ingredient is about 2 mg. In another embodiment, the amount of the active ingredient is about 5 mg. In another embodiment, the amount of the active ingredient is about 7.5 mg. In another embodiment, the amount of the active ingredient is about 10 mg. In another embodiment, the amount of the active ingredient is about 15 mg. In another embodiment, the amount of the active ingredient is about 25 mg. In another embodiment, the amount of the active ingredient is about 30 mg. In another embodiment, the amount of the active ingredient is about 35 mg. In another embodiment, the amount of the active ingredient is about 40 mg. In another embodiment, the amount of the active ingredient is about 50 mg. In another embodiment, the amount of the active ingredient is about 60 mg. In another embodiment, the amount of the active ingredient is about 70 mg. In another embodiment, the amount of the active ingredient is about 75 mg. In another embodiment, the amount of the active ingredient is about 80 mg. In another embodiment, the amount of the active ingredient is about 90 mg. In another embodiment, the amount of the active ingredient is about 100 mg.

Pharmaceutical compositions and formulations provided herein can be presented as discrete dosage forms, such as capsules (e.g., gelcaps), caplets, tablets, troches, lozenges, dispersions, and suppositories each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in- water emulsion, or a water-in-oil liquid emulsion. Because of their ease of administration, tablets, caplets, and capsules represent a preferred oral dosage unit forms.

Tablets, caplets, and capsules typically contain from about 50 mg to about 500 mg of the pharmaceutical composition (i.e., active ingredient and excipient(s) or carrier(s)). Capsules can be of any size. Examples of standard sizes include #000, #00, #0, #1, #2, #3, #4, and #5. See, e.g., Remington 's Pharmaceutical Sciences, page 1658-1659 (Alfonso Gennaro ed., Mack Publishing Company, Easton Pennsylvania, 18th ed., 1990), which is incorporated by reference. Other examples of standard sizes include DB #AAA, #AA, #A, #B, #C, #D, and #E (e.g., manufactured by Capsugel Inc.). In some embodiments, capsules provided herein are of size #0 or larger, #1 or larger, #2 or larger, #3 or larger, or #4 or larger. In some embodiments, capsules provided herein are of size #A or

SDI-116984v2 30 larger, #B or larger, #C or larger, #D or larger, or #E or larger.

Also provided herein are anhydrous pharmaceutical compositions and dosage forms including an active ingredient, since water can facilitate the degradation of some compounds. For example, the addition of water {e.g., 5 percent) is widely accepted in the pharmaceutical arts as a means of simulating shelf-life, i.e., long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In effect, water and heat accelerate decomposition. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.

In one embodiment, an anhydrous pharmaceutical composition is prepared and stored such that the anhydrous nature is maintained. Accordingly, in some embodiments, anhydrous compositions are packaged using materials known to minimize or prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.

In this regard, also provided herein is a method of preparing a solid pharmaceutical formulation including an active ingredient through admixing the active ingredient and an excipient under anhydrous or low moisture/humidity conditions, wherein the ingredients are substantially free of water. The method can further include packaging the anhydrous or non-hygroscopic solid formulation under low moisture conditions. By using such conditions, the risk of contact with water is reduced and the degradation of the active ingredient can be prevented or substantially reduced.

Also provided herein are lactose-free pharmaceutical compositions and dosage forms.

Compositions and dosage forms that comprise an active ingredient that is a primary or secondary amine are preferably lactose-free (and/or free of other sugars, such as, dextrose, fructose, and mannose, e.g., dextrose-free, fructose-free, and/or mannose-free). As used herein, the term "lactose- free" means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient that is a primary or secondary amine. Lactose-free compositions provided herein can comprise excipients which are well known in the art and are listed in the USP (XXI)/NF (XVI), which is incorporated herein by reference.

In one embodiment, a substituted cyclohexylmethanamine provided herein, or a

pharmaceutically acceptable salt or solid form thereof, comprises from about 0.1 to about 50 weight percent of total weight of the composition. In another embodiment, a substituted

cyclohexylmethanamine provided herein, or a pharmaceutically acceptable salt or solid form thereof, comprises from about 0.1 to about 40 weight percent of total weight of the composition. In another embodiment, a substituted cyclohexylmethanamine provided herein, or a pharmaceutically acceptable salt or solid form thereof, comprises from about 0.1 to about 30 weight percent of total weight of the composition. In another embodiment, a substituted cyclohexylmethanamine provided herein, or a

SDI-116984v2 31 pharmaceutically acceptable salt or solid form thereof, comprises from about 0.1 to about 20 weight percent of total weight of the composition. In another embodiment, a substituted

cyclohexylmethanamine provided herein, or a pharmaceutically acceptable salt or solid form thereof, comprises from about 0.1 to about 15 weight percent of total weight of the composition. In another embodiment, a substituted cyclohexylmethanamine provided herein, or a pharmaceutically acceptable salt or solid form thereof, comprises from about 0.1 to about 10 weight percent of total weight of the composition. In another embodiment, a substituted cyclohexylmethanamine provided herein, or a pharmaceutically acceptable salt or solid form thereof, comprises from about 0.1 to about 5 weight percent of total weight of the composition. In another embodiment, a substituted

cyclohexylmethanamine provided herein, or a pharmaceutically acceptable salt or solid form thereof, comprises from about 0.5 to about 50 weight percent of total weight of the composition. In another embodiment, a substituted cyclohexylmethanamine provided herein, or a pharmaceutically acceptable salt or solid form thereof, comprises from about 5 to about 50 weight percent of total weight of the composition. In another embodiment, a substituted cyclohexylmethanamine provided herein, or a pharmaceutically acceptable salt or solid form thereof, comprises about 0.1 weight percent of total weight of the composition. In another embodiment, a substituted cyclohexylmethanamine provided herein, or a pharmaceutically acceptable salt or solid form thereof, comprises about 0.3 weight percent of total weight of the composition. In another embodiment, a substituted cyclohexylmethanamine provided herein, or a pharmaceutically acceptable salt or solid form thereof, comprises about 1 weight percent of total weight of the composition. In another embodiment, a substituted

cyclohexylmethanamine provided herein, or a pharmaceutically acceptable salt or solid form thereof, comprises about 1.5 weight percent of total weight of the composition. In another embodiment, a substituted cyclohexylmethanamine provided herein, or a pharmaceutically acceptable salt or solid form thereof, comprises about 3 weight percent of total weight of the composition. In another embodiment, a substituted cyclohexylmethanamine provided herein, or a pharmaceutically acceptable salt or solid form thereof, comprises about 10 weight percent of total weight of the composition. In another embodiment, a substituted cyclohexylmethanamine provided herein, or a pharmaceutically acceptable salt or solid form thereof, comprises about 15 weight percent of total weight of the composition. In another embodiment, a substituted cyclohexylmethanamine provided herein, or a pharmaceutically acceptable salt or solid form thereof, comprises about 20 weight percent of total weight of the composition. In another embodiment, a substituted cyclohexylmethanamine provided herein, or a pharmaceutically acceptable salt or solid form thereof, comprises about 25 weight percent of total weight of the composition. In another embodiment, a substituted cyclohexylmethanamine provided herein, or a pharmaceutically acceptable salt or solid form thereof, comprises about 30 weight percent of total weight of the composition. In another embodiment, a substituted

cyclohexylmethanamine provided herein, or a pharmaceutically acceptable salt or solid form thereof, comprises about 40 weight percent of total weight of the composition. In another embodiment, a

SDI-116984v2 32 substituted cyclohexylmethanamine provided herein, or a pharmaceutically acceptable salt or solid form thereof, comprises about 50 weight percent of total weight of the composition.

In one embodiment, the active ingredient and excipient, carrier, diluent, binder, or filler are directly blended as described herein elsewhere.

In one embodiment, the pharmaceutical composition provided herein comprises one or more diluent(s). In one embodiment, the pharmaceutical composition provided herein comprises one or more diluent(s), such as mannitol (e.g., Pearlitol™ 160C), microcrystalline cellulose (e.g., Avicel PH- 102), and/or starch (e.g., corn starch, pregelatinized starch, or Starch 1500).

In one embodiment, the pharmaceutical composition provided herein comprises one or more disintegrant(s). In one embodiment, the pharmaceutical composition provided herein comprises one or more disintegrant(s), such as starch (e.g., corn starch, pregelatinized starch, or Starch 1500). In one embodiment, the pharmaceutical composition provided herein comprises one or more

superdisintegrant(s), such as sodium starch glycolate (e.g., Primojel™).

In one embodiment, the pharmaceutical composition provided herein comprises one or more glidant(s) or anti-adherent agent(s). In one embodiment, the pharmaceutical composition provided herein comprises one or more glidant(s) or anti-adherent agent(s), such as talc.

In one embodiment, the pharmaceutical composition provided herein comprises one or more lubricant(s). In one embodiment, the pharmaceutical composition provided herein comprises one or more lubricant(s), such as magnesium stearate.

It is understood that an excipient in the pharmaceutical composition provided herein may server more than one function. For example, pregelatinized starch may serve both as a diluent and as a disintegrant in the composition.

In one embodiment, the pharmaceutical composition provided herein comprises mannitol (e.g., Pearlitol™ mannitol, or Pearlitol™ 160C). In one embodiment, the pharmaceutical composition provided herein comprises mannitol (e.g., Pearlitol™ mannitol, or Pearlitol™ 160C), in an amount of from about 10 to about 95, from about 20 to about 95, from about 30 to about 95, from about 40 to about 95, from about 50 to about 95, from about 40 to about 90, or from about 50 to about 80 weight percent of total weight of the composition. In one embodiment, the pharmaceutical composition provided herein comprises mannitol (e.g., Pearlitol™ mannitol, or Pearlitol™ 160C), in an amount of about 80 weight percent of total weight of the composition. In one embodiment, the pharmaceutical composition provided herein comprises mannitol (e.g., Pearlitol™ mannitol, or Pearlitol™ 160C), in an amount of about 50 weight percent of total weight of the composition.

In one embodiment, the pharmaceutical composition provided herein comprises starch (e.g., corn starch, pregelatinized starch, or Starch 1500). In one embodiment, the pharmaceutical composition provided herein comprises starch (e.g., corn starch, pregelatinized starch, or Starch

1500), in an amount of from about 3 to about 75 weight percent of total weight of the composition. In one embodiment, the pharmaceutical composition provided herein comprises starch (e.g., corn starch,

SDI-116984v2 33 pregelatinized starch, or Starch 1500), in an amount of from about 14 to about 16 weight percent of total weight of the composition. In one embodiment, the pharmaceutical composition provided herein comprises starch (e.g., corn starch, pregelatinized starch, or Starch 1500), in an amount of about 14, about 15, or about 16 weight percent of total weight of the composition.

In one embodiment, the pharmaceutical composition provided herein comprises talc. In one embodiment, the pharmaceutical composition provided herein comprises talc, in an amount of from about 1 to about 25, from about 1 to about 20, from about 1 to about 15, from about 1 to about 10, or from about 1 to about 5 weight percent of total weight of the composition. In one embodiment, the pharmaceutical composition provided herein comprises talc, in an amount of about 1, about 1.5, about 2, about 3, about 4, or about 5 weight percent of total weight of the composition.

In one embodiment, the pharmaceutical composition provided herein comprises magnesium stearate. In one embodiment, the pharmaceutical composition provided herein comprises magnesium stearate, in an amount of from about 0.2 to about 5, from about 0.2 to about 4, from about 0.2 to about 3, from about 0.2 to about 2, from about 0.2 to about 1, or from about 0.5 to about 1 weight percent of total weight of the composition. In one embodiment, the pharmaceutical composition provided herein comprises magnesium stearate, in an amount of about 1 weight percent of total weight of the composition.

In one embodiment, the pharmaceutical composition provided herein does not comprise microcrystalline cellulose (e.g., Avicel™ PH- 102).

In one embodiment, the pharmaceutical composition provided herein does not comprise sodium starch glycolate (e.g., Primojel™).

In one embodiment, the excipient, carrier, diluent, binder, or filler comprises mannitol and/or starch. In another embodiment, the excipient, carrier, diluent, binder, or filler comprises mannitol. In one embodiment, the mannitol is spray dried mannitol. In one embodiment, the mannitol is

Pearlitol™ mannitol. In another embodiment, the starch is pregelatinized starch. In another embodiment, the starch is corn starch.

In one embodiment, the excipient, carrier, diluent, binder, or filler comprises from about 50 to about 99 weight percent of total weight of the composition. In another embodiment, the excipient, carrier, diluent, binder, or filler comprises from about 60 to about 99 weight percent of total weight of the composition. In another embodiment, the excipient, carrier, diluent, binder, or filler comprises from about 70 to about 99 weight percent of total weight of the composition. In another embodiment, the excipient, carrier, diluent, binder, or filler comprises from about 80 to about 99 weight percent of total weight of the composition. In another embodiment, the excipient, carrier, diluent, binder, or filler comprises from about 85 to about 99 weight percent of total weight of the composition. In another embodiment, the excipient, carrier, diluent, binder, or filler comprises from about 90 to about 99 weight percent of total weight of the composition. In another embodiment, the excipient, carrier, diluent, binder, or filler comprises from about 95 to about 99 weight percent of total weight of the

SDI-116984v2 34 composition. In another embodiment, the excipient, carrier, diluent, binder, or filler comprises about 98 weight percent of total weight of the composition. In another embodiment, the excipient, carrier, diluent, binder, or filler comprises about 99 weight percent of total weight of the composition.

In one embodiment, the dosage forms provided herein comprise both mannitol and starch. In one embodiment, mannitol and starch comprise from about 50 to about 99 weight percent of total weight of the composition. In another embodiment, mannitol and starch comprise from about 60 to about 99 weight percent of total weight of the composition. In another embodiment, mannitol and starch comprise from about 70 to about 99 weight percent of total weight of the composition. In another embodiment, mannitol and starch comprise from about 75 to about 99 weight percent of total weight of the composition. In another embodiment, mannitol and starch comprise from about 80 to about 99 weight percent of total weight of the composition. In another embodiment, mannitol and starch comprise from about 85 to about 99 weight percent of total weight of the composition. In another embodiment, mannitol and starch comprise from about 90 to about 99 weight percent of total weight of the composition. In another embodiment, mannitol and starch comprise from about 95 to about 99 weight percent of total weight of the composition. In another embodiment, mannitol and starch comprise about 50 weight percent of total weight of the composition. In another embodiment, mannitol and starch comprise about 60 weight percent of total weight of the composition. In another embodiment, mannitol and starch comprise about 70 weight percent of total weight of the composition. In another embodiment, mannitol and starch comprise about 85 weight percent of total weight of the composition. In another embodiment, mannitol and starch comprise about 95 weight percent of total weight of the composition. In another embodiment, mannitol and starch comprise about 97 weight percent of total weight of the composition. In another embodiment, mannitol and starch comprise about 98 weight percent of total weight of the composition. In another embodiment, mannitol and starch comprise about 99 weight percent of total weight of the composition.

In one embodiment, the dosage forms provided herein comprise mannitol. In one embodiment, mannitol comprises from about 50 to about 99 weight percent of total weight of the composition. In another embodiment, mannitol comprises from about 50 to about 85 weight percent of total weight of the composition. In another embodiment, mannitol comprises from about 60 to about 99 weight percent of total weight of the composition. In another embodiment, mannitol comprises from about 70 to about 99 weight percent of total weight of the composition. In another embodiment, mannitol comprises from about 80 to about 99 weight percent of total weight of the composition. In another embodiment, mannitol comprises about 50 weight percent of total weight of the composition. In another embodiment, mannitol comprises about 60 weight percent of total weight of the composition. In another embodiment, mannitol comprises about 70 weight percent of total weight of the composition. In another embodiment, mannitol comprises about 80 weight percent of total weight of the composition. In another embodiment, mannitol comprises about 90 weight percent of total weight of the composition.

SDI-116984v2 35 In one embodiment, the ratio of mannitol: starch in the dosage form is from about 6: 1 to about 1 : 1. In one embodiment, the ratio of mannitol: starch in the dosage form is about 6: 1. In another embodiment, the ratio of mannitol: starch in the dosage form is about 5: 1. In another embodiment, the ratio of mannitol: starch in the dosage form is about 4:1. In another embodiment, the ratio of mannitol: starch in the dosage form is about 3: 1. In another embodiment, the ratio of mannitohstarch in the dosage form is about 2: 1. In another embodiment, the ratio of mannitol: starch in the dosage form is about 1 : 1.

In another embodiment, the dosage form comprises one or more lubricant(s). In one embodiment, the dosage form comprises about 0.1, 0.2, 0.3, 0.5, 0.6, 0.8, 1, 2, 3, 4, or 5 weight percent of lubricant.

In one embodiment, the dosage forms provided herein comprise magnesium stearate. In one embodiment, the dosage form comprises from about 1 to about 10 weight percent of magnesium stearate. In another embodiment, the dosage form comprises from about 1 to about 5 weight percent of magnesium stearate. In another embodiment, the dosage form comprises from about 1 to about 3 weight percent of magnesium stearate. In another embodiment, the dosage form comprises about 3 weight percent of magnesium stearate. In another embodiment, magnesium stearate comprises about 1 weight percent of total weight of the composition.

In one embodiment, the dosage forms provided herein comprise talc. In one embodiment, the dosage form comprises from about 1 to about 20 mg of talc. In another embodiment, the dosage form comprises from about 1 to about 15 mg of talc. In another embodiment, the dosage form comprises from about 1 to about 10 mg of talc. In another embodiment, the dosage form comprises from about 5 to about 15 mg of talc. In another embodiment, the dosage form comprises from about 5 to about 10 mg of talc. In another embodiment, the dosage form comprises about 4.5 mg of talc. In another embodiment, the dosage form comprises about 5 mg of talc. In another embodiment, the dosage form comprises about 10 mg of talc. In another embodiment, the dosage form comprises about 12 mg of talc. In another embodiment, talc comprises about 1 weight percent of total weight of the composition. In another embodiment, talc comprises about 1.5 weight percent of total weight of the composition. In another embodiment, talc comprises about 2 weight percent of total weight of the composition. In another embodiment, talc comprises about 3 weight percent of total weight of the composition. In another embodiment, talc comprises about 4 weight percent of total weight of the composition. In another embodiment, talc comprises about 5 weight percent of total weight of the composition.

In some embodiments, a pharmaceutically acceptable salt of a substituted

cyclohexylmethanamme is the active ingredient of a pharmaceutical composition provided herein, in which case, the formulations and dosage forms provided herein may be defined as compositions, formulations, or dosage forms comprising a substituted cyclohexyl-methanamine, or a

pharmaceutically acceptable salt or solid form thereof, at an amount that provides the potency of a

SDI-116984v2 36 specified amount of the corresponding free base of the substituted cyclohexylmethanamine.

In one embodiment, provided herein is a single unit dosage form comprising: 1) a substituted cyclohexylmethanamine, or a pharmaceutically acceptable salt or solid form thereof, present at an amount that provides about 0.5, 1, 3, 5, 10, 15, 20, 25, or 50 mg potency of the free base of the substituted cyclohexylmethanamine; and 2) one or more excipient, carrier, diluent, binder, or filler, present at an amount of about 1, 3, 5, 10, 12, 15, 30, 45, 50, 60, 75, 120, 150, 180, 200, 240, 250, or 300 mg.

In one embodiment, provided herein is a dosage form comprising: 1) a substituted cyclohexylmethanamine, or a pharmaceutically acceptable salt or solid form thereof, present at an amount that provides about 1 mg potency of the free base of the substituted cyclohexylmethanamine; and 2) a pharmaceutically acceptable excipient or carrier. In another embodiment, provided herein is a dosage form comprising: 1) a substituted cyclohexylmethanamine, or a pharmaceutically acceptable salt or solid form thereof, present at an amount that provides about 5 mg potency of the free base of the substituted cyclohexylmethanamine; and 2) a pharmaceutically acceptable excipient or carrier. In another embodiment, provided herein is a dosage form comprising: 1) a substituted

cyclohexylmethanamine, or a pharmaceutically acceptable salt or solid form thereof, present at an amount that provides about 10 mg potency of the free base of the substituted cyclohexylmethanamine; and 2) a pharmaceutically acceptable excipient or carrier. In another embodiment, provided herein is a dosage form comprising: 1) a substituted cyclohexylmethanamine, or a pharmaceutically acceptable salt or solid form thereof, present at an amount that provides about 15 mg potency of the free base of the substituted cyclohexylmethanamine; and 2) a pharmaceutically acceptable excipient or carrier. In another embodiment, provided herein is a dosage form comprising: 1) a substituted

cyclohexylmethanamine, or a pharmaceutically acceptable salt or solid form thereof, present at an amount that provides about 20 mg potency of the free base of the substituted cyclohexylmethanamine; and 2) a pharmaceutically acceptable excipient or carrier. In another embodiment, provided herein is a dosage form comprising: 1) a substituted cyclohexylmethanamine, or a pharmaceutically acceptable salt or solid form thereof, present at an amount that provides about 25 mg potency of the free base of the substituted cyclohexylmethanamine; and 2) a pharmaceutically acceptable excipient or carrier. In another embodiment, provided herein is a dosage form comprising: 1) a substituted

cyclohexylmethanamine, or a pharmaceutically acceptable salt or solid form thereof, present at an amount that provides about 50 mg potency of the free base of the substituted cyclohexylmethanamine; and 2) a pharmaceutically acceptable excipient or carrier. In another embodiment, provided herein is a dosage form comprising: 1) a substituted cyclohexylmethanamine, or a pharmaceutically acceptable salt or solid form thereof, present at an amount that provides about 75 mg potency of the free base of the substituted cyclohexylmethanamine; and 2) a pharmaceutically acceptable excipient or carrier. In another embodiment, provided herein is a dosage form comprising: 1) a substituted

cyclohexylmethanamine, or a pharmaceutically acceptable salt or solid form thereof, present at an

SDI-116984v2 37 amount that provides about 100 mg potency of the free base of the substituted

cyclohexylmethanamine; and 2) a pharmaceutically acceptable excipient or carrier.

In one embodiment, the total weight of the dosage form is about 300 mg. In one embodiment, the dosage form is suitable for administration as a tablet. In one embodiment, the dosage form is suitable for administration in a size 5 or larger capsule. In one embodiment, the dosage form is suitable for administration in a size 4 or larger capsule. In one embodiment, the dosage form is suitable for administration in a size 3 or larger capsule. In one embodiment, the dosage form is suitable for administration in a size 2 or larger capsule. In one embodiment, the dosage form is suitable for administration in a size 1 or larger capsule. In one embodiment, the excipient comprises a carrier, diluent, binder, or filler. In one embodiment, the excipients comprise a carrier, diluent, binder, or filler and a lubricant.

In one embodiment where the total fill weight of the dosage form is about 300 mg, the carrier, diluent, binder, or filler comprises mannitol and/or starch. In one embodiment, the excipient comprises both mannitol and starch. In one embodiment, the excipient comprises mannitol. In one embodiment, where both mannitol and starch are present in the dosage form, the dosage form comprises about 48 mg of starch, and about 150, about 200, or about 240 mg of mannitol. In one embodiment, the mannitol is spray dried mannitol. In one embodiment, the mannitol is Pearlitol™ mannitol. In another embodiment, the starch is pregelatinized starch.

In one embodiment, provided herein is a dosage form comprising: 1) a substituted cyclohexylmethanamine, or a pharmaceutically acceptable salt or solid form thereof, present at an amount that provides about 1 mg potency of the free base; 2) about 48 mg of pregelatinized starch; 3) about 4.5 mg of talc; 4) about 3 mg of magnesium stearate; and 5) mannitol at an amount that brings the total weight of the dosage form to 300 mg. In one embodiment, the dosage form is suitable for administration as a tablet. In one embodiment, the dosage form is suitable for administration as a capsule (e.g., a Size 1 capsule).

In one embodiment, provided herein is a dosage form comprising: 1) a substituted cyclohexylmethanamine, or a pharmaceutically acceptable salt or solid form thereof, present at an amount that provides about 5 mg potency of the free base; 2) about 48 mg of pregelatinized starch; 3) about 4.5 mg of talc; 4) about 3 mg of magnesium stearate; and 5) mannitol at an amount that brings the total weight of the dosage form to 300 mg. In one embodiment, the dosage form is suitable for administration as a tablet. In one embodiment, the dosage form is suitable for administration as a capsule (e.g., a Size 1 capsule).

In one embodiment, provided herein is a dosage form comprising: 1) a substituted cyclohexylmethanamine, or a pharmaceutically acceptable salt or solid form thereof, present at an amount that provides about 25 mg potency of the free base; 2) about 48 mg of pregelatinized starch;

3) about 10 mg of talc; 4) about 3 mg of magnesium stearate; and 5) mannitol at an amount that brings the total weight of the dosage form to 300 mg. In one embodiment, the dosage form is suitable for

SDI-116984v2 38 administration as a tablet. In one embodiment, the dosage form is suitable for administration as a capsule (e.g., a Size 1 capsule).

In one embodiment, provided herein is a dosage form comprising: 1) a substituted cyclohexylmethanamine, or a pharmaceutically acceptable salt or solid form thereof, present at an amount that provides about 50 mg potency of the free base; 2) about 44 mg of pregelatinized starch; 3) about 12 mg of talc; 4) about 2.75 mg of magnesium stearate; and 5) mannitol at an amount that brings the total weight of the dosage form to 275 mg. In one embodiment, the dosage form is suitable for administration as a tablet. In one embodiment, the dosage form is suitable for administration as a capsule (e.g., a Size 1 capsule).

In another embodiment, provided herein is a dosage form comprising a substituted cyclohexylmethanamine, or a pharmaceutically acceptable salt or solid form thereof, present at an amount that provides about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, or about 100 mg potency of the free base of the substituted

cyclohexylmethanamine, which is stable for a period of at least about 12, about 24, or about 36 months without refrigeration. In some embodiments, the dosage form comprises mannitol and/or starch. In some embodiments, the dosage form comprises mannitol. In one embodiment where both starch and mannitol are present in the dosage form, starch is present at an amount of about 48 mg, and mannitol is present at an amount that brings the total weight of composition to about 300 mg. In one embodiment where both starch and mannitol are present in the dosage form, starch is present at an amount of about 44 mg, and mannitol is present at an amount that brings the total weight of composition to about 275 mg. In some embodiments, the dosage form further comprises magnesium stearate at an amount of about 3 mg or about 2.75 mg. In some embodiments, the dosage form further comprises talc at an amount of about 4.5 mg, about 10 mg, or about 12 mg. In one embodiment, the dosage form is suitable for administration in a size 1 or larger capsule. In one embodiment, the dosage form is suitable for administration in a size 2 or larger capsule. In one embodiment, the dosage form is suitable for administration in a size 3 or larger capsule. In one embodiment, the dosage form is suitable for administration in a size 4 or larger capsule. In one embodiment, the dosage form is suitable for administration as a tablet.

5.3.1 Second Active Agents

In certain embodiments, provided herein are compositions and dosage form of a substituted cyclohexylmethanamine, or a pharmaceutically acceptable salt or solid form thereof, which may further comprise one or more secondary active ingredients. Certain combinations may work synergistically in the treatment of particular types of diseases or disorders, and conditions and symptoms associated with such diseases or disorders. A substituted cyclohexylmethanamine provided herein, or a pharmaceutically acceptable salt or solid form thereof, can also work to alleviate adverse effects associated with certain second active agents, and vice versa.

Specific second active compounds that can be contained in the formulations and dosage forms

SDI-116984v2 39 provided herein vary depending on the specific indication to be treated, prevented or managed.

Examples of second active agents that may be used for the treatment, prevention and/or management of pain include, but are not limited to, conventional therapeutics used to treat or prevent pain such as antidepressants, anticonvulsants, antihypertensives, anxiolytics, calcium channel blockers, muscle relaxants, non-narcotic analgesics, opioid analgesics, anti-inflammatories, COX-2 inhibitors, immunomodulatory agents, alpha-adrenergic receptor agonists or antagonists, immunosuppressive agents, corticosteroids, hyperbaric oxygen, ketamine, other anesthetic agents, NMDA antagonists, and other therapeutics found, for example, in the Physician 's Desk Reference 2003. Specific examples include, but are not limited to, salicylic acid acetate (Aspirin^®), celecoxib (Celebrex^®), Enbrel^®, ketamine, gabapentin (Neurontin^®), phenytoin (Dilantin^®), carbamazepine (Tegretol^®), oxcarbazepine (Trileptal^®), valproic acid (Depakene^®), morphine sulfate,

hydromorphone, prednisone, griseofulvin, penthonium, alendronate, dyphenhydramide, guanethidine, ketorolac (Acular^®), thyrocalcitonin, dimethylsulfoxide (DMSO), clonidine (Catapress^®), bretylium, ketanserin, reserpine, droperidol, atropine, phentolamine, bupivacaine, lidocaine, acetaminophen, nortriptyline (Pamelor^®), amitriptyline (Elavil^®), imipramine (Tofranil^®), doxepin (Sinequan^®), clomipramine (Anafranil^®), fluoxetine (Prozac^®), sertraline (Zoloft^®), naproxen, nefazodone (Serzone^®), venlafaxine (Effexor^®), trazodone (Desyrel^®), bupropion (Wellbutrin^®), mexiletine, nifedipine, propranolol, tramadol, lamotrigine, vioxx, ziconotide, ketamine, dextromethorphan, benzodiazepines, baclofen, tizanidine and phenoxybenzamine.

Additional examples of second active agents that may be used include, but are not limited to, immunomodulatory agents, immunosuppressive agents, antihypertensives, anticonvulsants, fibrinolytic agents, antiplatelet agents, antipsychotics {e.g., lurasidone, olanzapine, risperidone, aripiprazole, or donepezil), antidepressants (e.g., sertraline, or fluoxetine), benzodiazepines, buspirone, amantadine, and other known or conventional agents used in patients with CNS injury/damage and related syndromes. Specific examples include, but are not limited to: steroids (e.g. , glucocorticoids, such as, but not limited to, methylprednisolone, dexamethasone and betamethasone); an anti-inflammatory agent, including, but not limited to, naproxen sodium, diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone, refecoxib, methotrexate, leflunomide, sulfasalazine, gold salts, RHo-D Immune Globulin, mycophenylate mofetil, cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, dichlofenac, flurbinprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam, tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, apazone, zileuton, aurothioglucose, gold sodium thiomalate, auranofin, methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone and benzbromarone; a cAMP analog including, but not limited to, db-cAMP; an agent comprising a methylphenidate drug, which comprises 1-threo-

SDI-116984v2 40 methylphenidate, d-threo-methylphenidate, dl-threo-methylphenidate, 1-erythro-methylphenidate, d- erythro-methylphenidate, dl-erythro-methylphenidate, and a mixture thereof; and a diuretic agent such as, but not limited to, mannitol, furosemide, glycerol, and urea.

5.3.2 Process for Making Dosage Forms

Dosage forms provided herein can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the excipient, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly admixing (e.g. , direct blend) the active ingredient with liquid excipients or finely divided solid excipients or both, and then, if necessary, shaping the product into the desired presentation (e.g., compaction such as roller-compaction). If desired, tablets can be coated by standard aqueous or nonaqueous techniques.

A dosage form provided herein can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient as above and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Encapsulation of the dosage forms provided herein can be done using capsules of methylcellulose, calcium alginate, or gelatin.

In some embodiments, the active ingredients and excipients are directly blended and loaded into, for example, a capsule, or compressed directly into tablets. A direct-blended dosage form may be more advantageous than a compacted (e.g., roller-compacted) dosage form in certain instances, since direct-blending can reduce or eliminate the harmful health effects that may be caused by airborne particles of ingredients during the manufacture using compaction process.

Direct blend formulations may be advantageous in certain instances because they require only one blending step, that of the active and excipients, before being processed into the final dosage form, e.g., tablet or capsule. This can reduce the production of airborne particle or dust to a minimum, while roller-compaction processes may be prone to produce dust. In roller-compaction process, the compacted material is often milled into smaller particles for further processing. The milling operation can produce significant amounts of airborne particles, since the purpose for this step in manufacturing is to reduce the materials particle size. The milled material is then blended with other ingredients prior to manufacturing the final dosage form.

For certain active ingredients, in particular for a compound with a low solubility, the active ingredient's particle size is reduced to a fine powder in order to help increase the active ingredient's rate of solubilization. The increase in the rate of solubilization is often necessary for the active ingredient to be effectively absorbed in the gastrointestinal tract. However for fine powders to be directly-blended and loaded onto capsules, the excipients should preferably provide certain characteristics which render the ingredients suitable for the direct-blend process. Examples of such

SDI-116984v2 41 characteristics include, but are not limited to, acceptable flow characteristics. In one embodiment, therefore, provided herein is the use of, and compositions comprising, excipients which may provide characteristics, which render the resulting mixture suitable for direct-blend process, e.g., good flow characteristics.

In an exemplary embodiment, the process of preparing a pharmaceutical composition provided herein comprises any one, two, three, four, or five of the following steps:

1) Screening

In one embodiment, the process for making the pharmaceutical compositions provided herein includes the screening of the active ingredient and the excipient(s). In one embodiment, the active ingredient is passed through a screen having openings of about 200 microns to about 750 microns. In another embodiment, the active ingredient is passed through a screen with openings of about 200 microns to about 400 microns. In one embodiment, the active ingredient is passed through a screen having openings of about 300 to about 400 microns. Depending on the excipient(s) used, the screen openings vary. For example, disintegrants and binders are passed through openings of about 430 microns to about 750 microns, from about 600 microns to about 720 microns, or about 710 microns. Lubricants are typically passed through smaller openings, e.g., about 150 microns to about 250 microns screen. In one embodiment, the lubricant is passed through a screen opening of about 210 microns.

2) Pre-blending

After the ingredients are screened, the excipient and active ingredient are mixed in a diffusion mixer. In one embodiment, the mixing time is from about 1 minute to about 50 minutes, from about 5 minutes to about 45 minutes, from about 10 minutes to about 40 minutes, or from about 10 minutes to about 25 minutes. In another embodiment, the mixing time is about 15 minutes.

When more than one excipient is used, the excipients may be admixed in a tumble blender for about 1 minute to about 20 minutes, or for about 5 minutes to about 10 minutes, prior to mixing with the active ingredient.

3) Roller Compaction

In one embodiment, the pre -blend may optionally be passed through a roller compactor with a hammer mill or granulator mill attached at the discharge of the compactor.

4) Final Blend

When a lubricant, e.g., magnesium stearate, is used, the lubricant is mixed with the blend at the end of the process to complete the pharmaceutical composition. This additional mixing is from about 1 minute to about 10 minutes, or from about 3 minutes to about 5 minutes.

5) Encapsulation

The formulation mixture is then encapsulated into the desired size capsule shell using, for example, a manual, a semi-automatic, or automated capsule filling machine; or the formulation mixture is compressed using, for example, a rotary tablet press.

SDI-116984v2 42 Other examples of processes for preparing a dosage form provided herein are described herein elsewhere, e.g., in the Example Section below.

5.3.3 Oral Dosage Forms

Pharmaceutical compositions provided herein that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g. , chewable tablets), cap lets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington: The Science and Practice of Pharmacy, 20th ed. (2000).

Typical oral dosage forms are prepared by combining the active ingredients in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.

Large-scale production of pharmaceutical compositions or dosage forms in accordance with the present disclosure may require, in addition to the therapeutic drug ingredients, excipients or additives including, but not limited to, diluents, binders, lubricants, disintegrants, colorants, flavors, sweetening agents and the like or mixtures thereof. By the incorporation of these and other additives, a variety of dosage forms (e.g., tablets, capsules, caplets, troches and the like) may be made. These include, for example, hard gelatin capsules, caplets, sugar-coated tablets, enteric-coated tablets to delay action, multiple compressed tablets, prolonged-action tablets, tablets for solution, effervescent tablets, buccal and sublingual tablets, troches and the like.

Hence, unit dose forms or dosage formulations of a pharmaceutical composition provided herein, such as a troche, a tablet or a capsule, may be formed by combining a desired amount of each of the active ingredients with one or more pharmaceutically compatible or acceptable excipients, as described below, in pharmaceutically compatible amounts to yield a unit dose dosage formulation the desired amount of each active ingredient. The dose form or dosage formulation may be formed by methods well known in the art.

Tablets are often a preferred dosage form because of the advantages afforded both to the patient (e.g. , accuracy of dosage, compactness, portability, blandness of taste as well as ease of administration) and to the manufacturer (e.g., simplicity and economy of preparation, stability as well as convenience in packaging, shipping and dispensing). Tablets are solid pharmaceutical dosage forms containing therapeutic drug substances with or without suitable additives.

SDI-116984v2 43 Tablets are typically made by molding, by compression or by generally accepted tablet forming methods. Accordingly, compressed tablets are usually prepared by large-scale production methods while molded tablets often involve small-scale operations. For example, there are three general methods of tablet preparation: (1) the wet-granulation method; (2) the dry-granulation method; and (3) direct compression. These methods are well known to those skilled in the art. See, Remington: The Science and Practice of Pharmacy, 20th ed. (2000). See, also, U.S. Pharmacopeia XXI, U.S. Pharmacopeial Convention, Inc., ockville, Md. (1985).

Various tablet formulations may be made in accordance with the methods and compositions provided herein. These include tablet dosage forms such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, multiple-compressed tablets, prolonged action tablets and the like. Sugar- coated tablets (SCT) are compressed tablets containing a sugar coating. Such coatings may be colored and are beneficial in covering up drug substances possessing objectionable tastes or odors and in protecting materials sensitive to oxidation. Film-coated tablets (FCT) are compressed tablets that are covered with a thin layer or film of a water-soluble material. A number of polymeric substances with film-forming properties may be used. The film coating imparts the same general characteristics as sugar coating with the added advantage of a greatly reduced time period required for the coating operation. Enteric-coated tablets are also suitable for use in methods and compositions provided herein. Enteric-coated tablets (ECT) are compressed tablets coated with substances that resist dissolution in gastric fluid but disintegrate in the intestine. Enteric coating can be used for tablets containing drug substances that are inactivated or destroyed in the stomach, for those which irritate the mucosa or as a means of delayed release of the medication.

Multiple compressed tablets (MCT) are compressed tablets made by more than one compression cycle, such as layered tablets or press-coated tablets. Layered tablets are prepared by compressing additional tablet granulation on a previously compressed granulation. The operation may be repeated to produce multilayered tablets of two, three or more layers. Typically, special tablet presses are required to make layered tablets. See, for example, U.S. Pat. No. 5,213,738, incorporated herein in its entirety by reference thereto.

Press-coated tablets are another form of multiple compressed tablets. Such tablets, also referred to as dry-coated tablets, are prepared by feeding previously compressed tablets into a tableting machine and compressing another granulation layer around the preformed tablets. These tablets have all the advantages of compressed tablets, i.e., slotting, monogramming, speed of disintegration, etc., while retaining the attributes of sugar coated tablets in masking the taste of the drug substance in the core tablet. Press-coated tablets can also be used to separate incompatible drug substances. Further, they can be used to provide an enteric coating to the core tablets. Both types of tablets (i.e., layered tablets and press-coated tablets) may be used, for example, in the design of prolonged-action dosage forms.

Pharmaceutical compositions or unit dosage forms provided herein in the form of prolonged-

SDI-116984v2 44 action tablets may comprise compressed tablets formulated to release the drug substance in a manner to provide medication over a period of time. There are a number of tablet types that include delayed- action tablets in which the release of the drug substance is prevented for an interval of time after administration or until certain physiological conditions exist. Repeat action tablets may be formed that periodically release a complete dose of the drug substance to the gastrointestinal fluids. Also, extended release tablets that continuously release increments of the contained drug substance to the gastrointestinal fluids may be formed.

In order for medicinal substances or therapeutic ingredients provided herein, with or without excipients, to be made into solid dosage forms (e.g., tablets) with pressure, using available equipment, it is necessary that the material, either in crystalline or powdered form, possess a number of physical characteristics. These characteristics can include, for example, the ability to flow freely, as a powder to cohere upon compaction, and to be easily released from tooling. Since most materials have none or only some of these properties, methods of tablet formulation and preparation have been developed to impart these desirable characteristics to the material which is to be compressed into a tablet or similar dosage form.

As noted, in addition to the drugs or therapeutic ingredients, tablets and similar dosage forms may contain a number of materials referred to as excipients or additives. These additives are classified according to the role they play in the formulation of the dosage form such as a tablet, a caplet, a capsule, a troche or the like. One group of additives include, but are not limited to, binders, diluents (fillers), disintegrants, lubricants, and surfactants. In one embodiment the diluent, binder, disintegrant, and lubricant are not the same.

A binder is used to provide a free-flowing powder from the mix of tablet ingredients so that the material will flow when used on a tablet machine. The binder also provides a cohesiveness to the tablet. Too little binder will give flow problems and yield tablets that do not maintain their integrity, while too much can adversely affect the release (dissolution rate) of the drugs or active ingredients from the tablet. Thus, a sufficient amount of binder should be incorporated into the tablet to provide a free-flowing mix of the tablet ingredients without adversely affecting the dissolution rate of the drug ingredients from the tablet. With lower dose tablets, the need for good compressibility can be eliminated to a certain extent by the use of suitable diluting excipients called compression aids. The amount of binder used varies upon the type of formulation and mode of administration, and is readily discernible to those of ordinary skill in the art.

Binders suitable for use with dosage formulations provided herein include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone (povidone), methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose or mixtures

SDI-116984v2 45 thereof. Suitable forms of microcrystalline cellulose can include, for example, the materials sold as AVICEL™ PH-101, AVICEL™ PH-103 and AVICEL™ PH- 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa., U.S.A.).

Fillers or diluents are used to give the powder (e.g., in the tablet or capsule) bulk so that an acceptable size tablet, capsule or other desirable dosage form is produced. Typically, therapeutic ingredients are formed in a convenient dosage form of suitable size by the incorporation of a diluent therewith. As with the binder, binding of the drug(s) to the filler may occur and affect bioavailability. Consequently, a sufficient amount of filler should be used to achieve a desired dilution ratio without detrimentally affecting release of the drug ingredients from the dosage form containing the filler. Further, a filler that is physically and chemically compatible with the therapeutic ingredient(s) of the dosage form should be used. The amount of filler used varies upon the type of formulation and mode of administration, and is readily discernible to those of ordinary skill in the art. Examples of fillers include, but are not limited to, lactose, glucose, sucrose, fructose, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, xylitol, silicic acid, sorbitol, starch, pre-gelatinized starch, or mixtures thereof.

Disintegrants are used to cause the dose form (e.g., tablet) to disintegrate when exposed to an aqueous environment. Too much of a disintegrant will produce tablets which may disintegrate in the bottle due to atmospheric moisture. Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of drug(s) or active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the drug ingredients should be used to form the dosage forms provided herein. The amount of disintegrant used varies based upon the type of formulation and mode of administration, and is readily discernible to the skilled artisan. Examples of disintegrants include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, clays, other algins, other celluloses, gums, or mixtures thereof.

When a dose form that dissolves fairly rapidly upon administration to the subject, e.g., in the subject's stomach is desired, a super disintegrant can be used, such as, but not limited to, croscarmellose sodium or sodium starch glycolate. The term "super disintegrant," as used herein, means a disintegrant that results in rapid disintegration of drug or active ingredient in the stomach after oral administration. Use of a super disintegrant can facilitate the rapid absorption of drug or active ingredient(s) which may result in a more rapid onset of action.

Adhesion of the dosage form ingredients to blender walls, hoppers, screens, transfer containers, and all equipment surfaces, including but not limited to punches of the manufacturing machine (e.g., a tableting machine) and dosators of the capsule manufacturing machine must be minimized or ideally avoided. Adhesion is a particular issue for the composition provided herein. For example, when drug accumulates on the punch surfaces, it causes the tablet surface to become

SDI-116984v2 46 pitted and therefore unacceptable. Also, sticking of drug or excipients in this way requires unnecessarily high ejection forces when removing the tablet from the die. Excessive ejection forces may lead to a high breakage rate and increase the cost of production not to mention excessive wear and tear on the dies. In practice, it is possible to reduce sticking by wet-massing or by the use of lubricants, e.g., magnesium stearate, and other anti-adherent excipients. However, selection of a drug salt with good anti-adhesion properties can also minimize these problems.

As noted, the lubricant is used to enhance the flow of the tableting powder mix to the tablet machine and to prevent sticking of the tablet in the die after the tablet is compressed. Too little lubricant will not permit satisfactory tablets to be made and too much may produce a tablet with a water-impervious hydrophobic coating, which can form because lubricants are usually hydrophobic materials such as stearic acid, magnesium stearate, calcium stearate and the like. Further, a water- impervious hydrophobic coating can inhibit disintegration of the tablet and dissolution of the drug ingredient(s). Thus, a sufficient amount of lubricant should be used that readily allows release of the compressed tablet from the die without forming a water-impervious hydrophobic coating that detrimentally interferes with the desired disintegration and/or dissolution of the drug ingredient(s).

Example of suitable lubricants for use with the compositions provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.) or mixtures thereof.

Surfactants are used in dosage forms to improve the wetting characteristics and/or to enhance dissolution, and are particularly useful in pharmaceutical compositions or dosage forms containing poorly soluble or insoluble drug(s) or active ingredients. Examples of surfactants include, but are not limited to, polyoxyethylene sorbitan fatty acid esters, such as those commercially available as TWEENs (e.g. Tween 20 and Tween 80), polyethylene glycols, polyoxyethylene stearates, polyvinyl alcohol, polyvinylpyrrolidone, poly(oxyethylene)/ poly(oxypropylene) block co-polyers such as poloxamers (e.g. , commercially available as PLURONICs), and tetrafunctional block copolymers derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine, such as polyxamines (e.g., commercially as TETRONICs (BASF)), dextran, lecithin, dialkylesters of sodium sulfosuccinic acid, such as Aerosol OT, sodium lauryl sulfate, alkyl aryl polyether sulfonates or alcohols, such as TRITON X-200 or tyloxapol, p isononylphenoxypoly (glycidol) (e.g. Olin-lOG or

Surfactant 10-G (Olin Chemicals), or mixtures thereof. Other pharmaceutically acceptable surfactants are well known in the art, and are described in detail in the Handbook of Pharmaceutical Excipients.

SDI-116984v2 47 Other classes of additives for use with the pharmaceutical compositions or dosage forms provided herein include, but are not limited to, anti-caking or antiadherent agents, antimicrobial preservatives, coating agents, colorants, desiccants, flavors and perfumes, plasticizers, viscosity increasing agents, sweeteners, buffering agents, humectants and the like.

Examples of anti-caking agents include, but are not limited to, calcium silicate, magnesium silicate, silicon dioxide, colloidal silicon dioxide, talc, or mixtures thereof.

Examples of antimicrobial preservatives include, but are not limited to, benzalkonium chloride solution, benzethonium chloride, benzoic acid, benzyl alcohol, butyl paraben,

cetylpyridinium chloride, chlorobutanol, cresol, dehydroacetic acid, ethylparaben, methylparaben, phenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric nitrate, potassium sorbate, propylparaben, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimersol, thymol, or mixtures thereof.

Examples of colorants for use with compositions provided herein include, but are not limited to, pharmaceutically acceptable dyes and lakes, caramel, red ferric oxide, yellow ferric oxide or mixtures thereof. Examples of desiccants include, but are not limited to, calcium chloride, calcium sulfate, silica gel or mixtures thereof.

Flavors that may be used include, but are not limited to, acacia, tragacanth, almond oil, anethole, anise oil, benzaldehyde, caraway, caraway oil, cardamom oil, cardamom seed, compound cardamom tincture, cherry juice, cinnamon, cinnamon oil, clove oil, cocoa, coriander oil, eriodictyon, eriodictyon fluidextract, ethyl acetate, ethyl vanillin, eucalyptus oil, fennel oil, glycyrrhiza, pure glycyrrhiza extract, glycyrrhiza fluidextract, lavender oil, lemon oil, menthol, methyl salicylate, monosodium glutamate, nutmeg oil, orange flower oil, orange flower water, orange oil, sweet orange peel tincture, compound orange spirit, peppermint, peppermint oil, peppermint spirit, pine needle oil, rose oil, stronger rose water, spearmint, spearmint oil, thymol, tolu balsam tincture, vanilla, vanilla tincture, and vanillin or mixture thereof.

Examples of sweetening agents include, but are not limited to, acesulfame potassium, aspartame, dextrates, mannitol, saccharin, saccharin calcium, saccharin sodium, sorbitol, sorbitol solution, sucralose, or mixtures thereof.

Exemplary plasticizers for use with the compositions provided herein include, but are not limited to, castor oil, diacetylated monoglycerides, diethyl phthalate, glycerin, mono-and di-acetylated monoglycerides, polyethylene glycol, propylene glycol, and triacetin or mixtures thereof. Suitable viscosity increasing agents include, but are not limited to, acacia, agar, alamic acid, aluminum monostearate, bentonite, bentonite magma, carbomer 934, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carboxymethylcellulose sodium 12, carrageenan, cellulose, microcrystalline cellulose, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (Nos. 2208; 2906; 2910), magnesium aluminum silicate, methylcellulose, pectin, polyvinyl alcohol, povidone, silica gel, colloidal silicon dioxide, sodium

SDI-116984v2 48 alginate, tragacanth and xanthan gum or mixtures thereof.

Buffering agents that may be used in the compositions provided herein include, but are not limited to, magnesium hydroxide, aluminum hydroxide and the like, or mixtures thereof. Examples of humectants include, but are not limited to, glycerol, other humectants or mixtures thereof.

The dosage forms provided herein may further include one or more of the following: (1) dissolution retarding agents, such as paraffin; (2) absorption accelerators, such as quaternary ammonium compounds; (3) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (4) absorbents, such as kaolin and bentonite clay; (5) antioxidants, such as water soluble antioxidants (e.g., ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium

metabisulfate, sodium sulfite and the like), oil soluble antioxidants (e.g., ascorbyl palmitate, hydroxyanisole (BHA), butylated hydroxy toluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like); and (6) metal chelating agents, such as citric acid, ethylenediamine tetracetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.

Dosage forms provided herein, such as a tablet or caplet, may optionally be coated. Inert coating agents typically comprise an inert film-forming agent dispersed in a suitable solvent, and may further comprise other pharmaceutically acceptable adjuvants, such as colorants and plasticizers. Suitable inert coating agents, and methods for coating, are well known in the art, including without limitation aqueous or non-aqueous film coating techniques or microencapsulation. Examples of film- forming or coating agents include, but are not limited to, gelatin, pharmaceutical glaze, shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax, celluloses, such as methylcellulose, hydroxymethyl cellulose, carboxymethylcellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose (e.g., Nos.: 2208, 2906, 2910), hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate (e.g., Nos.: 200731 , 220824), hydroxyethylcellulose, methylhydroxyethylcellulose, ethylcellulose which may optionally be cross-linked, and sodium carboxymethyl cellulose; vinyls, such as polyvinyl pyrrolidione, polyvinyl acetate phthalate; glycols, such as polyethylene glycols; acrylics, such as dimethylaminoethyl methacrylate-methacrylate acid ester copolymer, and ethylacrylate-methylmethacrylate copolymer; and other carbohydrate polymers, such as

maltodextrins, and polydextrose, or mixtures thereof. The amount of coating agent and the carrier vehicle (aqueous or non-aqueous) used varies upon the type of formulation and mode of

administration, and is readily discernible to those of ordinary skill in the art.

A coating of a film forming polymer may optionally be applied to a tablet or caplet (e.g., a capsule shaped tablet) by using one of several types of equipment such as a conventional coating pan, Accelacota, High-Cota or Worster air suspension column. Such equipment typically has an exhaust- system to remove dust and solvent or water vapors to facilitate quick drying. Spray guns or other suitable atomizing equipment may be introduced into the coating pans to provide spray patterns conducive to rapid and uniform coverage of the tablet bed. Normally, heated or cold drying air is introduced over the tablet bed in a continuous or alternate fashion with a spray cycle to expedite

SDI-116984v2 49 drying of the film coating solution.

The coating solution may be sprayed by using positive pneumatic displacement or peristaltic pump systems in a continuous or intermittent spray-dry cycle. The particular type of spray application is selected depending upon the drying efficiency of the coating pan. In most cases, the coating material is sprayed until the tablets are uniformly coated to the desired thickness and the desired appearance of the tablet is achieved. Many different types of coatings may be applied such as enteric, slow release coatings or rapidly dissolving type coatings for fast acting tablets. Preferably, rapidly dissolving type coatings are used to permit more rapid release of the active ingredients, resulting in hastened onset. The thickness of the coating of the film forming polymer applied to a tablet, for example, may vary. However, it is preferred that the thickness simulate the appearance, feel (tactile and mouth feel) and function of a gelatin capsule. Where more rapid or delayed release of the therapeutic agent(s) is desired, one skilled in the art would easily recognize the film type and thickness, if any, to use based on characteristics such as desired blood levels of active ingredient, rate of release, solubility of active ingredient, and desired performance of the dosage form.

A number of suitable film forming agents for use in coating a final dosage form, such as tablets include, for example, methylcellulose, hydroxypropyl methyl cellulose (PHARMACOAT 606 6 cps), polyvinylpyrrolidone (povidone), ethylcellulose (ETHOCEL 10 cps), various derivatives of methacrylic acids and methacrylic acid esters, cellulose acetate phthalate or mixtures thereof.

The method of preparation and the excipients or additives to be incorporated into dosage form (such as a tablet or cap let) are selected in order to give the tablet formulation the desirable physical characteristics while allowing for ease of manufacture {e.g. , the rapid compression of tablets). After manufacture, the dose form preferably should have a number of additional attributes, for example, for tablets, such attributes include appearance, hardness, disintegration ability and uniformity, which are influenced both by the method of preparation and by the additives present in the tablet formulation.

Further, it is noted that tablets or other dosage forms of the pharmaceutical compositions provided herein should retain their original size, shape, weight and color under normal handling and storage conditions throughout their shelf life. Thus, for example, excessive powder or solid particles at the bottom of the container, cracks or chips on the face of a tablet, or appearance of crystals on the surface of tablets or on container walls are indicative of physical instability of uncoated tablets. Hence, the effect of mild, uniform and reproducible shaking and tumbling of tablets should be undertaken to insure that the tablets have sufficient physical stability. Tablet hardness can be determined by commercially available hardness testers. In addition, the in vitro availability of the active ingredients should not change appreciably with time.

The tablets, and other dosage forms of the pharmaceutical compositions provided herein, such as dragees, capsules, pills and granules, may optionally be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art.

SDI-116984v2 50 5.3.4 Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms provided herein are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the active ingredients (i.e., the compounds used in methods and compositions provided herein) disclosed herein can also be incorporated into the parenteral dosage forms.

5.3.5 Transdermal, Topical and Mucosal Dosage Forms

Transdermal, topical, and mucosal dosage forms provided herein include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton PA (1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Transdermal dosage forms include "reservoir type" or "matrix type" patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide transdermal, topical, and mucosal dosage forms provided herein are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied.

Depending on the specific tissue to be treated, additional components may be used prior to, in conjunction with, or subsequent to treatment with active ingredients provided herein. For example, penetration enhancers can be used to assist in delivering the active ingredients to the tissue.

The pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied, may also be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds such as stearates can also be added to

SDI-116984v2 51 pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery. In this regard, stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery- enhancing or penetration-enhancing agent. Different salts or solvates (e.g., hydrates) of the active ingredients can be used to further adjust the properties of the resulting composition.

5.3.6 Compositions with Enhanced Stability

The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of an active ingredient, e.g., a substituted cyclohexylmethanamine provided herein, or a pharmaceutically acceptable salt or solid form thereof, may be accelerated by certain excipients. Certain saccharides, particularly mono- or di-saccharides, may accelerate the decomposition of the active ingredient of a composition provided herein. For example, compositions comprising a compound provided herein or a pharmaceutically acceptable salt or solid form thereof should contain little, if any, lactose, mannose, or xylose.

Further provided are anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms provided herein may be anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are preferably packaged using materials known to minimize or prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

In one embodiment, also provided herein are pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

Specific non-limiting examples of stable pharmaceutical compositions are provided herein in the Examples Section below.

Like the amounts and types of excipients, the amounts and specific types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients.

SDI-116984v2 52 5.3.7 Delayed Release Dosage Forms

Active ingredients used in methods and compositions provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770;

3,916,899; 3,536,809; 3,598, 123; and 4,008,719, 5,674,533, 5,059,595, 5,591 ,767, 5, 120,548,

5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile 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 compounds used in methods and compositions provided herein. Thus, provided herein are single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

5.4. Kits

Pharmaceutical packs or kits which comprise pharmaceutical compositions or dosage forms provided herein are also provided. An example of a kit comprises notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

In some cases, active ingredients used in methods and compositions provided herein are

SDI-116984v2 53 preferably not administered to a patient at the same time or by the same route of administration. Therefore, in one embodiment, provided are kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a patient.

In one embodiment, the kit comprises a single unit dosage form of the compounds used in methods and composition provided herein, or a pharmaceutically acceptable salt or solid form thereof, and a single unit dosage form of another agent that may be used in combination with those compounds. Kits provided herein can further comprise devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers.

Kits provided herein can further comprise pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate - free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

5.5. Methods of Treatment, Prevention, and Management

Provided herein are methods of treating, preventing, and/or managing certain diseases or disorders using the formulations, compositions, or dosage forms provided herein.

In one embodiment, without being limited to a particular theory, provided herein is a method of inhibiting the binding of a monoamine transporter ligand to a monoamine transporter, such as, serotonin transporter, dopamine transporter, and norepinephrine transporter. In one embodiment, without being limited to a particular theory, provided herein is a method of binding a compound provided herein. In one embodiment, the method provided herein comprises contacting the monoamine transporter and a compound provided herein. In an exemplary embodiment, the monoamine transporter ligand is a monoamine, such as serotonin, dopamine, and norepinephrine. In an exemplary embodiment, the monoamine transporter ligand is an endogenous monoamine, such as serotonin, dopamine or norepinephrine. In another exemplary embodiment, the ligand is a drug molecule or another small molecule known to have binding affinity to a monoamine transporter. In another exemplary embodiment, the monoamine transporter ligand is a radioactively labeled compound, known to bind to the monoamine transporter.

In one embodiment, without being limited to a particular theory, provided herein is a method of modulating (e.g., inhibiting, augmenting) the activity of at least one monoamine transporter, such

SDI-116984v2 54 as, serotonin transporter, dopamine transporter, and norepinephrine transporter. The method includes contacting the monoamine transporter and a compound provided herein.

In one embodiment, without being limited to a particular theory, provided herein is a method of inhibiting the activity of at least one monoamine transporter, such as serotonin transporter, dopamine transporter, and norepinephrine transporter. The method includes contacting the monoamine transporter and a compound provided herein.

In an exemplary embodiment, the monoamine transporter is contacted with a compound provided herein, by administering to a subject a therapeutically effective amount of the compound provided herein, or a pharmaceutically acceptable salt or solid form thereof. In one embodiment, the subject is a human. In another exemplary embodiment, without being limited to a particular theory, the monoamine transporter is dopamine transporter (DAT), serotonin transporter (SERT) or norepinephrine transporter (NET). In another exemplary embodiment, without being limited to a particular theory, the compound provided herein inhibits the activity of at least two different monoamine transporters. Inhibition of monoamine transporter activity may be measured using assays known in the art. In an exemplary embodiment, the functional uptake assay utilizes an appropriate cell-line expressing a desired monoamine transporter. In another exemplary embodiment, the functional uptake assay utilizes synaptosomes isolated from brain tissue of an appropriate organism. Alternatively, inhibition of monoamine transporter activity may be assessed using receptor binding experiments known in the art, e.g., utilizing appropriate membrane preparations. In other embodiments, an assay involves treatment of a test subject (e.g., a rat) with a compound provided herein as well as a reference compound, followed by isolation of brain tissue and ex vivo analysis of receptor occupancy.

In yet another embodiment, without being limited to a particular theory, provided herein is a method of inhibiting the uptake of at least one monoamine, such as serotonin, dopamine, and norepinephrine, by a cell. The method includes contacting the cell with a compound provided herein. In an exemplary embodiment, the cell is a brain cell, such as, e.g. , a neuronal cell or a glial cell.

In one embodiment, inhibition of monoamine uptake occurs in vivo. Without being limited to a particular theory, in an organism, neuronal uptake (also termed reuptake) of a monoamine, such as dopamine or serotonin occurs, for example, from the synaptic cleft. In one embodiment, the neuronal cell is in contact with a synaptic cleft of a mammal. In another exemplary embodiment, inhibition of monoamine uptake occurs in vitro. In those methods, the cell may be a brain cell, such as a neuronal cell or a certain cell-type, which expresses a recombinant monoamine transporter.

In one embodiment, without being limited to a particular theory, a compound provided herein inhibits uptake of at least two different monoamines. This can, for example, be shown by performing various in vitro functional uptake assays utilizing a cell-type, which simultaneously expresses multiple different monoamine transporters (such as isolated synaptosomes), or may be shown by using two different cell types, each expressing a different monoamine transporter, such as a

SDI-116984v2 55 recombinant dopamine transporter, together with an appropriate, labeled monoamine. In one embodiment, inhibition of monoamine uptake is demonstrated when the inhibitor (e.g., a compound provided herein) has an IC₅₀ of between about 0.1 nM and about 10 μΜ, between about

1 nM and about 1 μΜ, between about 1 nM and about 500 nM, or between about 1 nM and about 100 nM in a functional monoamine uptake assay, such as those known in the art.

In one embodiment, without being limited by a particular theory, provided herein is a method of treating depression by inhibiting the activity at least one monoamine transporter. The method includes administering to a mammalian subject a compound provided herein, or a salt or solid form thereof. In one embodiment, without being limited to a particular theory, the compound provided herein inhibits the activity of at least two different monoamine transporters. In one embodiment, the mammalian subject is a human. For example, without being limited to a particular theory, a compound provided herein inhibits the activity of at least two of serotonin transporter, dopamine transporter and norepinephrine transporter. Inhibition of monoamine transporter activity may be shown by in vitro functional monoamine uptake assays. Demonstration of anti-depressant activity of a compound provided herein may be shown by utilizing an appropriate animal model of depression, such as, the Rat Forced Swim Test, the Mouse Tail Suspension Test, and the Rat Locomotor Activity Analyses. In some embodiments, the Rat Forced Swim Test is also suitable for the analysis of compounds having activities against more than one monoamine transporter (mixed monoamine transporter activity). For example, without being limited to a particular theory, an increase in swimming activity is indicative of serotonin reuptake inhibition, while an increase in climbing activity is indicative of norepinephrine reuptake inhibition. In one embodiment, a compound provided herein is active in at least one animal model, which can be used to measure anti-depressant- like activities, for instance those assessing immobility. In an exemplary embodiment, a compound provided herein is active when they inhibit mean immobility by between about 5% and about 90%, between about 10% and about 70 %, or between about 10% and about 50%, in at least one animal model, when compared to vehicle.

In yet another embodiment, provided herein is a method of effecting an anti-depressant- like effect. The method comprises administering to a mammalian subject in need thereof a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt or solid form thereof, or a pharmaceutical composition comprising the same. Anti-depressant-like effects may be measured using an animal model of disease, such as those described herein.

In one embodiment, provided herein is a method of treating, preventing, or managing a central nervous system disorder. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt or solid form thereof, or a pharmaceutical composition comprising the same. In one embodiment, the subject is a human.

Examples of diseases or disorders being treated, prevented, or managed using a method

SDI-116984v2 56 provided herein, include, but are not limited to, a neurological disorder or a CNS disorders. In one embodiment, the CNS disorder is depression (e.g., major depressive disorder, unipolar depression, bipolar depression, seasonal affective disorder, treatment-resistant depression, and dysthymia), cognitive deficit, fibromyalgia, pain (e.g., neuropathic pain), sleep disorder (e.g., sleep apnea), attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), restless leg syndrome, schizophrenia, anxiety, obsessive compulsive disorder, posttraumatic stress disorder, seasonal affective disorder (SAD), premenstrual dysphoria, and neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's disease).

In one embodiment, the CNS disorder being treated, prevented, or managed using a method provided herein, is selected from depression (e.g., major depressive disorder, bipolar disorder, unipolar disorder, dysthymia, treatment-resistant depression, and seasonal affective disorder), cognitive deficits, fibromyalgia, pain (e.g., neuropathic pain), a sleep disorder (e.g., sleep apnea, insomnia, narcolepsy, cataplexy, and a sleep disorder produced by psychiatric conditions), chronic fatigue syndrome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), restless leg syndrome, schizophrenia, anxieties (e.g., general anxiety disorder, social anxiety disorder, and panic disorder), obsessive compulsive disorder, posttraumatic stress disorder, seasonal affective disorder (SAD), premenstrual dysphoria, post-menopausal vasomotor symptoms (e.g., hot flashes and night sweats), a neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis), manic condition, dysthymic disorder, cyclothymic disorder, obesity, and substance abuse or dependency (e.g., cocaine addiction and nicotine addiction). In one embodiment, the CNS disorder is depression, such as, e.g., major depressive disorder or treatment- resistant depression. In one embodiment, the CNS disorder is fibromyalgia. In one embodiment, the CNS disorder is pain (e.g., neuropathic pain). In one embodiment, the CNS disorder is a sleep disorder (e.g., sleep apnea). In one embodiment, the CNS disorder is a neurodegenerative disease (e.g., Parkinson's disease). In one embodiment, the compounds provided herein are useful to treat at least two conditions/disorders described herein, which are comorbid, such as cognitive deficit and depression.

In one embodiment, CNS disorder includes cerebral function disorders, including, without limitation, senile dementia, Alzheimer's type dementia, cognition, memory loss, amnesia/amnestic syndrome, epilepsy, disturbances of consciousness, coma, lowering of attention, speech disorders, Lennox syndrome, autism, and hyperkinetic syndrome.

In one embodiment, examples of pain include, but are not limited to, nociceptive pain, neuropathic pain, mixed pain of nociceptive and neuropathic pain, visceral pain, migraine, headache and post-operative pain.

In one embodiment, examples of nociceptive pain include, but are not limited to, pain associated with chemical or thermal burns, cuts of the skin, contusions of the skin, osteoarthritis, rheumatoid arthritis, tendonitis, and myofascial pain.

SDI-116984v2 57 In one embodiment, examples of neuropathic pain include, but are not limited to, CRPS type I, CRPS type II, reflex sympathetic dystrophy (RSD), reflex neurovascular dystrophy, reflex dystrophy, sympathetically maintained pain syndrome, causalgia, Sudeck atrophy of bone, algoneurodystrophy, shoulder hand syndrome, post-traumatic dystrophy, trigeminal neuralgia, post herpetic neuralgia, cancer related pain, phantom limb pain, fibromyalgia, chronic fatigue syndrome, spinal cord injury pain, central post-stroke pain, radiculopathy, diabetic neuropathy, post-stroke pain, luetic neuropathy, and other painful neuropathic conditions such as those induced by drugs such as vincristine and velcade.

In one embodiment, neuropathic pain includes, without limitation, post herpetic (or post- shingles) neuralgia, reflex sympathetic dystrophy/causalgia or nerve trauma, phantom limb pain, carpal tunnel syndrome, and peripheral neuropathy (such as diabetic neuropathy or neuropathy arising from chronic alcohol use).

In one embodiment, examples of CNS disorders include, but are not limited to, CNS injuries, Amyotrophic Lateral Sclerosis, Alzheimer Disease, Parkinson Disease, Huntington's Disease, Multiple Sclerosis other neuroimmunological disorders such as Tourette Syndrome, delirium, or disturbances in consciousness that occur over a short period of time, and amnestic disorder, or discreet memory impairments that occur in the absence of other central nervous system impairments.

In one embodiment, examples of CNS injuries and related syndromes include, but are not limited to, CNS injury/damage and related syndromes, include, but are not limited to, primary brain injury, secondary brain injury, traumatic brain injury, focal brain injury, diffuse axonal injury, head injury, concussion, post-concussion syndrome, cerebral contusion and laceration, subdural hematoma, epidermal hematoma, post-traumatic epilepsy, chronic vegetative state, complete SCI, incomplete SCI, acute SCI, subacute SCI, chronic SCI, central cord syndrome, Brown-Sequard syndrome, anterior cord syndrome, conus medullaris syndrome, cauda equina syndrome, neurogenic shock, spinal shock, altered level of consciousness, headache, nausea, emesis, memory loss, dizziness, diplopia, blurred vision, emotional liability, sleep disturbances, irritability, inability to concentrate, nervousness, behavioral impairment, cognitive deficit, and seizure.

In one embodiment, examples of dysfunctional sleep (or sleep disorder) and related syndromes include, but are not limited to, snoring, sleep apnea, insomnia, narcolepsy, restless leg syndrome, sleep terrors, sleep walking sleep eating, and dysfunctional sleep associated with chronic neurological or inflammatory conditions.

In one embodiment, examples of chronic neurological or inflammatory conditions, include, but are not limited to, Complex Regional Pain Syndrome, chronic low back pain, musculoskeletal pain, arthritis, radiculopathy, pain associated with cancer, fibromyalgia, chronic fatigue syndrome, visceral pain, bladder pain, chronic pancreatitis, neuropathies (diabetic, post-herpetic, traumatic or inflammatory), and neurodegenerative disorders such as Parkinson's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's Disease, bradykinesia; muscle rigidity;

SDI-116984v2 58 parkinsonian tremor; parkinsonian gait; motion freezing; depression; defective long-term memory, Rubinstein-Taybi syndrome (RTS); dementia; postural instability; hypokinetic disorders; synuclein disorders; multiple system atrophies; striatonigral degeneration; olivopontocerebellar atrophy;

Shy-Drager syndrome; motor neuron disease with parkinsonian features; Lewy body dementia; Tau pathology disorders; progressive supranuclear palsy; corticobasal degeneration; frontotemporal dementia; amyloid pathology disorders; mild cognitive impairment; Alzheimer disease with parkinsonism; Wilson disease; Hallervorden-Spatz disease; Chediak-Hagashi disease; SCA-3 spinocerebellar ataxia; X-linked dystonia parkinsonism; prion disease; hyperkinetic disorders; chorea; ballismus; dystonia tremors; Amyotrophic Lateral Sclerosis (ALS); CNS trauma and myoclonus.

Other exemplary diseases and conditions that may be treated, prevented, or managed, using the methods provided herein include, but are not limited to, obesity; migraine or migraine headache; urinary incontinence, including without limitation involuntary voiding of urine, dribbling or leakage of urine, stress urinary incontinence (SUI), urge incontinence, urinary exertional incontinence, reflex incontinence, passive incontinence, and overflow incontinence; as well as sexual dysfunction, in men or women, including without limitation sexual dysfunction caused by psychological and/or physiological factors, erectile dysfunction, premature ejaculation, vaginal dryness, lack of sexual excitement, inability to obtain orgasm, and psycho-sexual dysfunction, including without limitation, inhibited sexual desire, inhibited sexual excitement, inhibited female orgasm, inhibited male orgasm, functional dyspareunia, functional vaginismus, and atypical psychosexual dysfunction.

In one embodiment, exemplary diseases and conditions that may be treated, prevented, or managed, using the methods provided herein are described below:

In one embodiment, the disorder is depression. In another embodiment, the disorder is anxiety disorder. In another embodiment, the disorder is pain. In another embodiment, the disorder is neuropathic pain. In another embodiment, the pain is diabetic neuropathy.

In one embodiment, the disorder is a neurodegenerative disease. In one embodiment, the neurodegenerative disease is Parkinson's disease. In another embodiment, the neurodegenerative disorder is Alzheimer's disease.

In one embodiment, the disorder is incontinence, for example, urinary incontinence. In another embodiment, the disorder is sexual dysfunction.

In one embodiment, the disorder is obesity, and the therapeutically effective amount of compound to supply to a patient is sufficient so that said patient feels satiated.

In one embodiment, the compounds described herein treat, prevent, or manage a CNS disorder, without causing addiction to said compounds.

In some embodiments, the methods provided herein may optionally comprise the administration of one or more of other active agents. Such other agents include, but are not limited to, those drugs or therapies conventionally used for the treatment, prevention, or management of neurological disorders or CNS disroders provided herein. In one embodiment, examples of such other

SDI-116984v2 59 active agents are provided herein elsewhere {e.g., those described in Section 5.3.1).

Any suitable route of administration can be employed for providing the patient with a therapeutically or prophylactically effective dose of an active ingredient. For example, oral, mucosal {e.g., nasal, sublingual, buccal, rectal, vaginal), parenteral {e.g., intravenous, intramuscular), transdermal, and subcutaneous routes can be employed. Exemplary routes of administration include oral, transdermal, and mucosal. Suitable dosage forms for such routes include, but are not limited to, transdermal patches, ophthalmic solutions, sprays, and aerosols. Transdermal compositions can also take the form of creams, lotions, and/or emulsions, which can be included in an appropriate adhesive for application to the skin or can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose. An exemplary transdermal dosage form is a "reservoir type" or "matrix type" patch, which is applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredient. The patch can be replaced with a fresh patch when necessary to provide constant administration of the active ingredient to the patient.

The amount to be administered to a subject {e.g., patient) to treat, prevent, or manage the disorders described herein will depend upon a variety of factors including the activity of the particular compound employed, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health, and prior medical history of the patient being treated, and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount required. For example, the physician or veterinarian could start doses of the compounds employed 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.

In general, a suitable daily dose of a compound provided herein will be that amount of the compound which is the lowest dose effective to produce a therapeutic or prophylactic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds provided herein for a patient will range from about 0.005 mg per kilogram to about 5 mg per kilogram of body weight per day. In one embodiment, the oral dose of a compound provided herein will range from about 0.05 mg to about 5 g per day. In one embodiment, the oral dose of a compound provided herein will range from about 0.1 mg to about 3 g per day. In one embodiment, the oral dose of a compound provided herein will range from about 0.25 mg to about 2 g per day. In one embodiment, the oral dose of a compound provided herein will range from about 0.5 mg to about 1 g per day. In one embodiment, the oral dose of a compound provided herein will range from about 1 mg to about 500 mg per day. In another embodiment, the oral dose of a compound provided herein will range from about 2 mg to about 250 mg per day. In another embodiment, the oral dose of a compound provided herein will range from

SDI-116984v2 60 about 3 mg to about 300 mg per day. In one embodiment, the oral dose of a compound provided herein will range from about 5 mg to about 300 mg per day. In another embodiment, the oral dose of a compound provided herein will range from about 10 mg to about 100 mg per day. In another embodiment, the oral dose of a compound provided herein will range from about 25 mg to about 50 mg per day. In another embodiment, the oral dose of a compound provided herein will range from about 30 mg to about 200 mg per day. Each of the above-recited dosage ranges may be formulated as a single or multiple unit dosage formulations.

Certain embodiments are exemplified in the following non-limiting examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be practiced without departing from the spirit and scope of this disclosure.

6. EXAMPLES

Embodiments provided herein may be more fully understood by reference to the following examples. These examples are meant to be illustrative of processes, salts, pharmaceutical compositions, and dosage forms provided herein, but are not in any way limiting.

6.1. Example 1: Synthesis of 4-(3,4-dichlorophenyl)-l-methyl-2- oxabicyclo [2.2.2] octan-3-one

2-D-a 2-D-b 2-E-a 2-E-b 2-F 6.1.1 Synthesis of cis-\ -(3,4-dichlorophenyl)-4-hydroxy-4- methylcyclohexanecarbonitrile and trans- 1 -(3,4-dichlorophenyl)-4-hydroxy- 4-methylcyclohexanecarbonitrile

A solution of l-(3,4-dichlorophenyl)-4-oxocyclohexanecarbonitrile 2-C (302 g, 1.13 mol) (prepared, for example, from 2-(3,4-dichlorophenyl)acetonitrile and methyl acrylate, or following a procedure disclosed in U.S. Pat. Appl. No. 11/649,927 and U.S. Pat. Appl. No. 12/688,474; see also, WO 2007/081857 at page 255) in THF (3 L) was added to a solution of methylmagnesium chloride in THF (0.42 L, 3.0 M, 1.26 mol), while the mixture was maintained at a temperature of 0-15 °C during the addition of the ketone solution. Once the reaction was complete, the mixture was added to 2000 g of 22 % w/w aqueous citric acid at a rate so as to maintain the temperature below 30 °C during the

SDI-116984v2 \ addition and stirred for a brief time. Methyl tert-butyl ether (MTBE, 2 L) was added and the mixture was stirred for a brief time. The phases were allowed to settle and the organic phase was washed with 1.5 L of water. The phases were allowed to settle and the organic phase was concentrated by rotary evaporation to give a mixture of cyanoalcohols 2-D-a and 2-D-b as a brown oil that was used in the next step without further purification.

Cis isomer 2-D-a: ¾ NMR (400 MHz, CDC1₃) δ 7.54 (1H, d, 2.2 Hz), 7.46 (1H, d, 8.4 Hz), 7.32 (1H, dd, 8.4, 2.2 Hz), 2.19 (2H, m), 1.92 (4H, m), 1.80 (2H, m), 1.30 (3H, s). ¹³C NMR (100 MHz. CDCI₃) δ 139.84, 133.20, 132.38, 130.91, 127.88, 125.29, 121.47, 69.00, 42.48, 36.94, 34.30, 25.70.

Trans isomer 2-D-b: ¾ NMR (400 MHz, CDC1₃) δ 7.60 (1H, d, 2.2 Hz), 7.45 (1H, d, 8.5

Hz), 7.33 (1H, dd, 8.5, 2.2 Hz), 2.22 (2H, ddd, 14.3, 14.3, 4.0 Hz), 1.92 (4H, m), 1.79 (2H, m), 1.35 (3H, s). ¹³C NMR (100 MHz, CDCl₃) 5 141.01, 133.04, 132.11, 130.75, 127.82, 125.14, 121.47, 67.64, 43.29, 35.91, 32.48, 31.22. 6.1.2 Synthesis of cis-l -(3,4-dichlorophenyl)-4-hydroxy-4- methylcyclohexanecarboxylic acid and Zra«5-l-(3,4-dichlorophenyl)-4- hydroxy-4-methylcyclohexanecarboxylic acid

155 g (0.546 mol) of a mixture of 2-D-a and 2-D-b (about 1 :3 w/w ratio) was dissolved in 1 L of ethanol. To the stirred solution was added 100 g of potassium hydroxide dissolved in 150 g of water (approximately a 40 % w/w solution). The mixture was heated to 80 °C until the reaction was considered complete. The mixture was cooled and concentrated to a volume of about 500 mL. To the concentrated solution was added 1.6 L of MTBE. With stirring, to this solution was added 6 N hydrochloric acid to adjust the pH of the mixture to < 1. The mixture was stirred at 25-45 °C and the phases were allowed to settle. The organic (upper) phase was concentrated by rotary evaporation to give a mixture of 2-E-a and 2-E-b that was diluted with 1 L of toluene, and the mixture was concentrated to give a brown oil that was diluted with 1.5 L of toluene (60 °C). Upon cooling the mixture became an off-white suspension. This suspension was estimated to contain approximately 165 g of an about 1 :3 w/w mixture of 2-E-a and 2-E-b and was used in the next step without further purification.

6.1.3 Synthesis of 4-(3,4-dichlorophenyl)- 1 -methyl-2-oxabicyclo[2.2.2]octan-3- one

A 165 g mixture of 2-E-a and 2-E-b (about 1 :3 w/w ratio) was stirred in 1.5 L of toluene. To the stirred solution was added 150 g of Amberlyst 15 beads (50 % water content). The mixture was heated to 1 10 °C to remove water azeotropically until the reaction was considered complete. Then the mixture was cooled and the mixture was filtered to remove the Amberlyst 15 beads. The beads were washed with 0.2 L of toluene and the combined filtrate was concentrated to give approximately 100 g

SDI-116984v2 62 of lactone 2-F as a brown solid. ^l NMR (400 MHz, DMSO-d₆) δ 7.58 (1H, d, 8.2 Hz), 7.57 (1H, d, 1.6 Hz), 7.33 (1H, dd, 8.2, 1.6 Hz), 2.19 (2H, ddd, 1 1.4, 1 1.2, 2.5 Hz), 2.036 (2H, ddd, 12.2, 12.2, 5.4 Hz), 1.92 (2H, ddd, 12.2, 12.2, 5.4 Hz), 1.82 (2H, ddd, 1 1.4, 1 1.2, 2.5 Hz), 1.36 (3H, s). ¹³C NMR (100 MHz, DMSO-d₆) δ 175.56, 142.40, 131.16, 130.72, 130.46, 130.26, 128.81, 81.83, 44.79, 31.86, 30.22, 25.74.

Example 2: Synthesis of 4-(3,4-dichlorophenyl)-l-niethyl-2- oxabicyclo [2.2.2] octan-3-one

6.2.1 Synthesis of 2-(3,4-dichlorophenyl)acrylic acid

46 mL of «-BuLi (2.5 M) was added over 30 min to a solution of 10 g of 3,4- dichlorophenylacetic acid 3-A, in 150 mL of THF at 0 °C. The solution was stirred for 40 min at 20 °C and then cooled to 0 °C. Solid paraformaldehyde (5.5 g, 183 mmol) was added in one portion and the reaction was allowed to warm to RT overnight. The mixture was concentrated and diluted with 150 mL of THF. This mixture was heated to 65 °C for 18 h. The reaction was then cooled to RT and quenched with water and 6 M HC1. The aqueous layer was extracted (3X) with EtOAc and dried with MgSO/μ The mixture was filtered through celite and concentrated to yield 2-(3,4- dichlorophenyl)acrylic acid 3-B as a yellow solid (10.1 g, 94% crude yield). 6.2.2 Synthesis of l-(3,4-dichlorophenyl)-4-methylcyclohex-3-enecarboxylic acid

2-(3,4-dichlorophenyl)acrylic acid 3-B (9.26 g, 42.6 mmol) was dissolved in toluene (90 mL) and cooled to 0 °C. The reaction was charged with BH₃-THF (12.8 mL, 1.0 M in THF) and stirred for 20 min at 0 °C and 20 min at RT. 8.6 mL of isoprene was added to the mixture and the mixture was stirred at 45 °C for 18 h. The reaction was cooled and concentrated. The residue was dissolved in 40 mL of MTBE and washed with 10 % aqueous citric acid. The organic layer was removed and the aqueous layer was extracted with 20 mL of dichloromethane. The combined organic layer was dried over MgSC , filtered and concentrated to afford 11.03 g of 3-C as a yellow solid (90%).

6.2.3 Synthesis of 4-(3,4-dichlorophenyl)-l-methyl-2-oxabicyclo[2.2.2]octan-3- one

11.03 g of l-(3,4-dichlorophenyl)-4-methylcyclohex-3-enecarboxylic acid 3-C was dissolved in 100 mL of toluene and 1.1 g of >-toluenesulfonic acid was added. The mixture was stirred at 115 °C for 18 h. The reaction was cooled to RT and diluted with 20 mL of MTBE. The organic layer was

SDI-116984v2 63 washed with dilute KHC0₃ and dried over MgS0₄. The resulting mixture was filtered and concentrated to give 8.4 g of the desired lactone 3-D.

110 g of crude lactone 3-D was suspended in 350 mL of ethanol and heated to 80 °C to obtain a solution that was then cooled to 15-25 °C. The suspension was stirred at 15-25 °C and then filtered. The product cake was washed with approximately 90 mL of ethanol and dried at 40-50 °C to give 87.1 g of lactone 3-D as an off-white solid.

6.3. Example 3: Synthesis of cis-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-l- methylcyclohexanol and a maleate salt thereof

3-^D

6.3.1 Synthesis of cis- 1 -(3,4-dichlorophenyl)-4-hydroxy-4-methyl-N,N- dimethylcyclohexanecarboxamide

60 mL of 2.0 M isopropylmagnesium chloride (0.120 mol) in THF was added to 70 mL of 2.0 M dimethylamine (0.140 mol) in tetrahydrofuran. The resulting solution was added to a solution of 18.2 g of lactone 3-D (0.0638 mol) in 75 mL of THF and was stirred at 0-20 °C until the reaction was considered complete. The reaction mixture was added to 30 mL of 6 N hydrochloric acid and stirred for a brief time. 100 mL of MTBE was added and the mixture was stirred again for a brief time. The phases were allowed to settle, organic phase removed and the aqueous phase was extracted with 100 mL of MTBE. The organic phase was combined with the original organic phase and washed with 100 mL of water. The organic phase was concentrated to give the amide product as a tan solid. The solid was heated to 85-95 °C in 1 10 mL of toluene to yield 18 g of the amide product as a white solid.

6.3.2 Synthesis of c;,y-4-(3,4-dichlorophenyl)-4-((dimethylamino)-methyl)- 1 - methylcyclohexanol and a maleate salt thereof

161 mL of 1.0 M borane in tetrahydrofuran (0.1610 mol) was added to 12.1 g of cis-l-(3,4- dichlorophenyl)-4-hydroxy-4-methyl-N,N-dimethylcyclohexanecarboxamide (0.0366 mol) in 60 mL of THF. The reaction was stirred at 15-40 °C until complete and then was added to methanol while maintaining the solution at a temperature of 15-25 °C. The solution was stirred at 15-25 °C for at least one hour then stirred at 40-50 °C. The solution was concentrated and 200 mL methanol was added. The solution was concentrated to a final volume of approximately 30 mL and then treated with 5.1 g of maleic acid (0.0439 mol) in 13 mL of methanol. The mixture was stirred for 15 min and 300 mL of MTBE was added to give a suspension that was stirred for at least one hour at 15-25 °C.

SDI-116984v2 64 The suspension was filtered and the product cake washed with 30 mL of MTBE to give the crude product of the maleate salt as a solid.

10 g of the crude product of the maleate salt was stirred in 20 mL of methanol at 35-45 °C to obtain a solution. To the solution was added 1 10 mL of ethyl acetate to obtain a suspension. After stirring for one hour at 15-25 °C, more ethyl acetate (220 mL) was added and stirring was continued at 15-25 °C for at least an additional hour. The slurry was filtered and the product was washed with 20 mL of ethyl acetate and dried in vacuo to give the desired maleate salt.

6.4. Example 4: Synthesis of ci^'s-4-(3,4-dichlorophenyl)-4-((dimethylamino)methy])-l- methylcyclohexanol and a maleate salt thereof

3-D

6.4.1 Synthesis of cis- 1 -(3,4-dichlorophenyl)-4-hydroxy-4-methyl-N,N- dimethylcyclohexanecarboxamide

41 mL of 2.0 M isopropylmagnesium chloride (0.082 mol) in THF was added to 47.3 mL of 2.0 M dimethylamine in tetrahydrofuran (0.095 mol) at 0° C. The resulting solution was added to

18.0 g of lactone 3-D (0.0638 mol) in 75 mL of THF and was stirred at 0-20 °C until the reaction was considered complete. The reaction mixture was added to 119 mL of 1 N hydrochloric acid and 120 mL of toluene, and the mixture was stirred. The phases were allowed to settle, organic phase removed and the aqueous phase was extracted with 60 mL of toluene. The organic phase was combined with the original organic phase and washed with 100 mL of water. The organic phase was concentrated to give the amide product as a tan solid. The solid was heated to reflux in 100 mL of toluene and the solution was cooled to room temperature. The slurry was filtered, washed with 32 mL of toluene and dried to yield 18.41 g of the desired amide as a white solid. H NMR (400 MHz, DMSO-d₆) δ 7.56 (1H, d, 8.4 Hz), 7.42 (1H, d, 2.2 Hz), 7.20 (1H, dd, 8.4, 2.2 Hz), 2.63 (6H, br s), 2.20 (2H, m), 1.73 (2H, dd, 10.8, 10.8 Hz), 1.61 (2H, dd, 10.8, 10.8 Hz), 1.37 (2H m), 1.09 (3H, s). ¹ C NMR (400 MHz, DMSO-d₆) δ 173.36, 146.42, 132.84, 131.52, 129.67, 128.29, 127.09. 68.08,

50.45, 38.16, 37.33, 32.97, 28.08.

6.4.2 Synthesis of c;,y-4-(3,4-dichlorophenyl)-4-((dimethylamino)-methyl)-l- methylcyclohexanol and a maleate salt thereof

141 mL of 1.0 M borane in tetrahydrofuran was added to 21.16 g of cis-l-(3,4- dichlorophenyl)-4-hydroxy-4-methyl-N,N-dimethylcyclohexanecarboxamide (0.064 mol) in 115 mL of THF at 0 °C. The reaction was stirred at 40 °C for 3 h and 74 g of 1.0 M borane in tetrahydrofuran

SDI-116984v2 65 was added. The mixture was stirred for an additional 2 h and cooled to 20° C. 350 mL of methanol was added and the solution was stirred at 15-25 °C for 3 days. The solution was concentrated. 350 mL of methanol was added and the solution was reconcentrated. The solid was dissolved in 80 mL of ethyl acetate and 8.9 g of maleic acid in 23 mL of methanol was added. The mixture was stirred for 15 min and 525 mL of MTBE was added to give a suspension. The suspension was filtered and the product cake washed with 50 mL of MTBE to give 24.32 g of the product. ¾ NMR (400 MHz, DMSO-d₆) δ 7.70 (1H, d, 1.8 Hz), 7.64 (1H, d, 8.4 Hz), 7.48 (1H, dd, 8.4, 1.8 Hz), 6.02 (2H, s), 4.18 (1H, br s), 3.24 (2H, br s), 2.47 (6H, s), 2.08 (2H, d, 13.2 Hz), 1.88 (2H, dd, 13.5, 11.0 Hz), 1.42 (2H, d, 13.5 Hz), 1.06 (2H, dd, 12.8, 11.4 Hz), 0.95 (3H, s). ¹³C NMR (100 MHz, DMSO-d₆) δ 167.16, 135.70, 131.66, 130.79, 130.06, 129.71, 128.39, 66.45, 45.88, 40.88, 34.04, 30.65, 28.86.

Alternatively, a flask was charged with 20.0 g of czs-l-(3,4-dichlorophenyl)-4-hydroxy-4- methyl-N,N-dimethylcyclohexanecarboxamide and 56.9 g (64 mL) of tetrahydrofuran at 20 °C followed by addition of borane dimethyl sulfide complex (2.0 M solution in tetrahydrofuran, 59.6 g, 70 mL) at a rate such that the internal temperature did not exceed 30 °C. The reaction was then stirred at 50 to 60 °C until reaction was complete, then the mixture was cooled to 25 °C. The mixture was then slowly added to methanol (142.2 g, 180 mL) and warmed to 30 °C. The mixture was stirred at 45 to 50 °C until all the borane complex was broken. The solution was concentrated to 100 mL then methanol (237 g, 300 mL) was added. This addition and concentration sequence was then repeated once more. The solution was again concentrated to 100 mL and isopropanol (237 g, 300 mL) was added. This addition and concentration sequence was then repeated once more. The solution was then concentrated to a final volume of approximately 100 mL, and cooled to 20 °C followed by addition of 94.2 g (120 mL) of isopropanol.

The maleate salt of c 5-4-(3,4-dichlorophenyl)-4-((dimethylamino)-methyl)-l- methylcyclohexanol was made by contacting maleic acid with czs-4-(3,4-dichlorophenyl)-4- ((dimethylamino)-methyl)- 1 -methylcyclohexanol and isolating the salt. The solution from the second procedure described above was charged with a solution of maleic acid (7.7 g) in isopropanol (47.1 g, 60 mL) at 30 °C. The mixture was cooled to 0 °C and stirred for 1 h. The slurry was filtered and the cake was washed with cold isopropanol (25 g, 32mL). The cake was then dried to yield 21.9 g of crude product as a maleate salt.

The c 5^,-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)- 1 -methylcyclohexanol maleate salt (25.01 g) obtained and isopropanol (200.5 g) was charged to a flask and the mixture was heated to 81.5 °C to dissolve the salt. The solution was then cooled to 70 °C and seeded with c i-4-(3,4- dichlorophenyl)-4-((dimethylamino)methyl)-l -methylcyclohexanol maleate salt (1.26 g) and stirred for 45 minutes at 70 °C before cooling to 0 °C and filtering the slurry. The wet cake was washed with cold isopropanol (2 x 31.3 g). The wet cake was then dried to yield 22.99 g of c i-4-(3,4- dichlorophenyl)-4-((dimethylamino)methyl)-l -methylcyclohexanol maleate salt. H NMR (400 MHz, MeOH-o ): δ 7.72 (1H, d, J= 2.2 Hz), 7.61 (1H, d, J= 8.4 Hz), 7.49 (1H, dd, J= 8.4, 2.2 Hz), 6.26

SDI-116984v2 66 (2H, s), 4.9 (IH, br s), 3.38 (2H, br s), 2.65 (6H, s), 2.21 (2H, d, J= 13.2 Hz), 2.00 (2H, ddd, J= 13.5, 13.5, 3.3 Hz), 1.58 (2H, d, J= 13.0 Hz), 1.30 (2H, ddd, J= 14.0, 13.6, 2.9 Hz), 1.08 (3H, s). ¹³C NMR (100 MHz, MeOH-d4): δ 169.62, 140.76, 135.56, 133.31, 131.59, 131.27, 130.18, 127.85, 71.19, 67.65, 45.85, 41.04, 33.83, 29.66, 29.17.

6.5. Example 5: Synthesis of ci's-4-(3,4-dichlorophenyl)-l-methyl-4-

((methylamino)methyl)cyclohexanol and a HCI salt thereof

3-D

6.5.1 Synthesis of cis- 1 -(3,4-dichlorophenyl)-4-hydroxy-N,4- dimethylcyclohexanecarboxamide

64.4 mL of 2.0 M isopropylmagnesium chloride (0.129 mol) in THF was added to 71 mL of 2.0 M methylamine in tetrahydrofuran (0.142 mol) at 0° C. A solution of 20.4 g of lactone 3-D

(0.0638 mol) in 200 mL of THF and was added to the amine mixture. The mixture was stirred at 20 °C overnight and the reaction was complete as indicated by HPLC. The reaction was concentrated to 100 mL and diluted with 400 mL of a 1 : 1 mixture of MTBE and ethyl acetate. The organic layer was washed with 230 mL of 1 M aqueous HCI and 100 mL of water. The organic phase was then concentrated to give 23.8 g of the amide product as a solid. ^:H NMR (400 MHz, CDC1₃) δ 7.48 (IH, d, 2.4 Hz), 7.43 (IH, d, 8.4 Hz), 7.26 (IH, dd, 8.4, 2.4 Hz), 2.68 (3H, d, 4.8 Hz), 2.42 (2H, ddd, 14.4, 14.4, 3.6 Hz), 2.06 (2H, m), 1.95 (2H, s), 1.63 (2H, m), 1.39 (2H, ddd, 14.4, 14.4, 3.6 Hz), 1.14 (3H, s). ¹³C NMR (100 MHz, CDC 1₃) δ 175.75, 141.72, 133.34, 131.51, 131.07, 129.60, 127.08, 69.00, 50.00, 35.49, 29.91, 29.49, 27.09.

6.5.2 Synthesis of ds-4-(3,4-dichlorophenyl)-l-methyl-4-

((methylamino)methyl)cyclohexanol and a HCI salt thereof

180 mL of 1.0 M borane in tetrahydrofuran (0.180 mol) was added to 20.0 g of czs-l-(3,4- dichlorophenyl)-4-hydroxy-N,4-dimethylcyclohexanecarboxamide (0.0366 mol) in 200 mL of THF. The reaction was stirred at 20 °C for 16 h. An additional 60 mL of 1.0 M borane in tetrahydrofuran was added and the solution was stirred at 40 °C for 8 h. 60 mL of methanol was carefully added at 40 °C. The solution was stirred at 40 °C for 3 h and the solution was concentrated to dryness. 200 mL methanol and 50 mL of 2 M HCI in diethyl ether were then added. The mixture was stirred for 1 h and concentrated to dryness. The solid was dissolved in 300 mL of ethyl acetate at reflux, cooled to ambient temperature and stirred at 20 °C. The resulting slurry was filtered and the solid was washed with ethyl acetate (2 x 50 mL). The solid was dissolved into 200 mL of hot methanol (reflux) and cooled to 20 °C. The mixture was stirred overnight at room temperature, filtered and the solid was

SDI-116984v2 7 washed with 40 mL of methanol. The solid was dried in vacuo to yield the crude salt of the desired amine compound. The crude salt was dissolved in 300 mL of ethyl acetate at reflux. The mixture was cooled to ambient temperature and the solid was filtered and washed with ethyl acetate (2 x 50 mL) to yield 17.3 g of solid. The solid was dissolved into 200 mL of hot methanol and cooled to ambient temperature. The resulting slurry was filtered, washed with methanol (40 mL), and dried to yield 8.0 g of the desired salt product as a white solid. ^!H NMR (400 MHz, CD₃OD) δ 7.65 (1H, d, 2.0 Hz), 7.60 (1H, d, 8.8 Hz), 7.43 (1H, dd, 8.8, 2.0 Hz), 4.86 (2H, s), 3.11 (2H, s), 2.60 (3H, s), 2.19 (2H, d, 13.6 Hz), 1.98 (2H, ddd, 13.6, 13.6, 2.8 Hz), 1.59 (2H, d, 13.6 Hz), 1.27 (2H, ddd, 13.6, 13.6, 2.8 Hz), 1.08 (3H, s). ¹³C NMR (100 MHz, CD₃OD) 5 141.69, 134.40, 132.60, 132.47, 131.07, 128.81, 68.95. 63.01, 41.82, 35.32, 35.1 1, 30.86, 29.77.

6.6. Example 6: Synthesis of c s-4-(3,4-dichlorophenyl)-4-((dimethylamino)methy])-l- methylcyclohexanol and a maleate salt thereof

3-D

6.6.1 Synthesis of ds-l-(3,4-dichlorophenyl)-4-hydroxy-4-methyl-N,N- dimethylcyclohexanecarboxamide

222 g of 2.0 M isopropylmagnesium chloride in THF was added to 222 g of 2.0 M dimethylamine in tetrahydrofuran (0.095 mol) below 10 °C. To this solution was added 100 g of lactone 3-D in 267 g of THF and the mixture was stirred at 0-20 °C until the reaction was considered complete. The reaction mixture was added to 712 g of 1 N hydrochloric acid. To this was added 606 g of toluene and the mixture was stirred. The phases were allowed to settle, organic phase removed and the aqueous (lower) phase was extracted with 303 g of toluene. The organic phase was combined with the original organic phase and the combined organic phase was concentrated to 700 mL. 250 mL of toluene was added and the mixture was concentrated to 700 mL. The slurry was heated to 77 °C and the solution was cooled to room temperature over 2 h. The slurry was filtered, washed with 160 g of toluene and dried to yield 104.7 g of c i-l-(3,4-dichlorophenyl)-4-hydroxy-4-methyl-N,N- dimethylcyclohexanecarboxamide as a white solid. ¾ NMR (400 MHz, DMSO-d₆) δ 7.56 (1H, d, 8.4 Hz), 7.42 (1H, d, 2.2 Hz), 7.20 (1H, dd, 8.4, 2.2 Hz), 2.63 (6H, br s), 2.20 (2H, m), 1.73 (2H, dd, 10.8, 10.8 Hz), 1.61 (2H, dd, 10.8, 10.8 Hz), 1.37 (2H, m), 1.09 (3H, s). ¹ C NMR (100 MHz, DMSO-d₆) δ 173.36, 146.42, 132.84, 131.52, 129.67, 128.29, 127.09, 68.08, 50.45, 38.16, 37.33, 32.97, 28.08.

SDI-116984v2 68 6.6.2 Synthesis of ci,y-4-(3,4-dichlorophenyl)-4-((dimethylamino)-methyl)-l- methylcyclohexanol and a maleate salt thereof

A 500 mL reactor containing 20 g of cz^'s-l-(3,4-dichlorophenyl)-4-hydroxy-4-methyl-N,N- dimethylcyclohexanecarboxamide and 35.6 g of tetrahydrofuran was charged with 132.9 g of 1 M borane in tetrahydrofuran at 20 °C. The mixture was stirred at ambient temperature until < 1% of the starting material remained. The mixture was added to 180 mL of cooled (0 °C) methanol. The resulting solution was stirred at 20 °C until hydrogen evolution ceased and then stirred at 40 °C for 10 hours. The mixture was concentrated to 100 mL. 300 mL of methanol was added and the mixture was concentrated to 100 mL. 300 mL of methanol was added and the mixture was concentrated to 100 mL. 300 mL of isopropanol was added and the mixture was concentrated to 100 mL. 300 mL of isopropanol was added and the mixture was concentrated to 100 mL. 120 mL of isopropanol was added, the temperature was adjusted to 30 °C and 7.7 g of maleic acid in 60 mL of isopropanol was added. The mixture was cooled to 0 °C over 1 h and stirred at 0 °C for 1 h. The slurry was filtered and the solid washed with 25 g of isopropanol. The solid was dried at 50 °C to yield 21.1 g of the desired product. ¾ NMR (400 MHz, DMSO-d₆) δ 7.70 (IH, d, 1.8 Hz), 7.64 (IH, d, 8.4 Hz), 7.48

(IH, dd, 8.4, 1.8 Hz), 6.02 (2H, s), 4.18 (IH, br s), 3.24 (2H, br s), 2.47 (6H, s), 2.08 (2H, d, 13.2 Hz), 1.88 (2H, dd, 13.5, 1 1.0 Hz), 1.42 (2H, d, 13.5 Hz), 1.06 (2H, dd, 12.8, 11.4 Hz), 0.95 (3H, s). ¹ C NMR (100 MHz, DMSO-d₆) δ 167.16, 135.70, 131.66, 130.79, 130.06, 129.71, 128.39, 66.45, 45.88, 40.88, 34.04, 30.65, 28.86.

6.6.3 Purification of cz^'i-4-(3,4-dichlorophenyl)-4-((dimethylamino)-methyl)- 1 - methylcyclohexanol maleate salt

A 500 mL reactor was charged with 25 g of ds-4-(3,4-dichlorophenyl)-4-((dimethylamino)- methyl)- 1 -methylcyclohexanol maleate salt and 185 g of isopropanol. The mixture was heated to 81 °C and the resulting solution was cooled to 70 °C. To the mixture was added 0.5 g of solid cis-4-(3,4- dichlorophenyl)-4-((dimethylamino)-methyl)- 1 -methylcyclohexanol maleate salt as seeds, and the mixture was stirred for 45 min. The slurry was cooled 0 °C over 160 min and stirred at 0 °C for 1 h. The mixture was filtered, washed with 30 g of isopropanol and dried to yield 22.8 g of the desired product.

6.7. Example 7: Synthesis of salts of ds-4-(3,4-dichlorophenyl)-l-methyl-4- ((methylamino)methyl)cyclohexanol

Several salts of c 5-4-(3,4-dichlorophenyl)- 1 -methyl-4-((methylamino)-methyl)cyclohexanol were synthesized and characterized.

6.7.1 Succinate salt

1.36 g of cii'-4-(3,4-dichlorophenyl)-l-methyl-4-((methylamino)methyl) cyclohexanol, 608 mg of succinic acid, and 34.1 g of isopropanol were stirred at reflux for 10 min and stirred at 20 °C for

SDI-116984v2 69 16 h. The resulting slurry was filtered and the solid washed with 8.5 g of isopropanol to yield 1.44 g of the salt. ¾NMR (400 MHz, DMSO-d₆) δ 7.55 (IH, d), 7.52 (IH, d), 7.33 (IH, dd), 2.59 (2H, s), 2.27 (2H, s), 2.19 (3H, s), 1.98 (2H, d), 1.83 (2H, dd), 1.39 (2H, d), 1.07 (2H, dd), 0.93 (3H, s).

6.7.2 Mesylate salt

1.62 g of cii'-4-(3,4-dichlorophenyl)-l-methyl-4-((inethylamino)methyl) cyclohexanol, 565 mg of methanesulfonic acid, and 30.2 g of isopropanol were stirred at 20 °C for 16 h. The resulting slurry was filtered and the solid washed with 4 mL of isopropanol to yield 1.97 g of the salt. ¾ NMR (400 MHz, DMSO-d₆) δ 7.82 (2H, s), 7.65 (IH, d), 7.60 (IH, d), 7.38 (IH, dd), 4.18 (H, s), 3.00 (2H, s), 2.44 (3H, s), 2.30 (3H, s), 2.06 (2H, d), 1.85 (2H, dd), 1.42 (2H, d), 1.05 (2H, dd), 0.94 (3H, s).

6.7.3 Besylate salt

2.20 g of cii'-4-(3,4-dichlorophenyl)-l-methyl-4-((inethylamino)methyl) cyclohexanol, 1.26 g of benzenesulfonic acid, and 20 g of isopropanol were stirred at 20 °C for 16 h. The resulting slurry was filtered and the solid washed with 4 mL of isopropanol to yield 3.1 g of the salt. ^XH NMR (400 MHz, DMSO-d₆) δ 7.77 (2H, s), 7.63 (IH, d), 7.57 (4H, m), 7.38 (IH, dd), 7.31 (4H, m), 4.18 (H, br s), 3.00 (2H, dd), 2.43 (3H, dd), 2.06 (2H, d), 1.84 (2H, dd), 1.42 (2H, d), 1.05 (2H, dd), 0.94 (3H, s).

6.8. Example 8: Synthesis of Salts of c/s-4-(3,4-dichlorophenyl)-4- ((dimethylamino)methyl)-l-methylcyclohexanol

Several salts of c«-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)- l-methylcyclohexanol were synthesized and characterized.

6.8.1 Experiment 1 : Overview

c i-4-(3,4-Dichlorophenyl)-4-((dimethylamino)methyl)- 1 -methylcyclohexanol was mixed with one of sixteen different acids (including besylate, benzoate, fumarate, mandelate, oleate, stearate, mesylate, maleate, L-malate, malonate, succinate, citrate, oxalate, hydrochloride, L-tartrate, and tosylate) in one of six different solvents (isopropanol, diethyl ether, acetone, toluene, methanol, ethanol). Several of the acids rendered crystalline salt products. Some of the salts were scaled up and compared to the hydrochloride salt (Table 1). The analysis indicated that the maleate salt has unexpected overall superior properties. Crystallization studies were performed on the maleate salt, and the maleate salt was further scaled up.

Table 1

SDI-116984v2 70 Salt Hygroscopicity Karl Thermal Properties Water

(VTI) Max. Ads. at Fisher DSC/Hotstage Solubility

25°C/95% RH (%) (°C) (mgA/mL)⁶

HC1 1 1.0⁴ , 10.4⁵ 0.09 255 °C² (sublimate melt)

Mesylate 15.5 0.03 162 °C (15 J/g)

210 °C (74 J/g)²

Tosylate 10.8 0.01 185 °C (72 J/g)²

Malonate

Freebase 0.1 0.01 102 °C (74 J/g)² < 0.3³

HC1 1 1.3⁴ 0.08 -160 °C^l (sublimes)

Fumarate 0.7 0.01 -135 °C^! (sublimes) 75³

178 °C (107 J/g)²

Besylate 0.1 0.03 -180 °C ¹ (melt start) >100³

188 °C (77 J/g)²

Hemi- 0.13 0.03 175 °C (126 J/g)²

fumarate

¹ based upon hotstage microscopy analysis

² based upon DSC analysis

³ Visual estimate of solubility

⁴ VTI analysis at 25°C

5 Analysis at 40 °C %RH cycled 5% to 95%

⁶ Solubility is expressed in terms of free base (mgA = milligrams of activity)

6.8.2 Preparation of Fumarate Salt of czs-4-(3,4-dichlorophenyl)-4- ((dimethylamino)methyl)- 1 -methylcyclohexanol

400 mg of fumaric acid was added to a solution of 1.0 g of c»-4-(3,4-dichlorophenyl)-4-

((dimethylamino)methyl)- 1 -methylcyclohexanol in 40 mL acetone at 40 °C. The mixture was stirred at 40 °C until dissolution then cooled to ambient temperature. The mixture was stirred at 20 °C for 3 h and the resulting slurry was filtered. The solid was washed with cold acetone and dried in vacuo at 45-50 °C to yield the desired salt in 73% yield.

6.8.3 Preparation of Besylate Salt of cw-4-(3,4-dichlorophenyl)-4-

((dimethylamino)methyl)- 1 -methylcyclohexanol

A solution of 550 mg of benzenesulfonic acid in 10 mL toluene and 10 mL acetone was added to a solution of 1.0 g of c/s-4-(3,4-dichlorophenyl)-4-((dimethylamino) methyl)-l- methylcyclohexanol in 20 mL acetone. The mixture was stirred at 40 °C until dissolution then cooled to ambient temperature. The mixture was stirred at 20 °C for 3 h and the resulting slurry was filtered. The solid was washed with cold acetone and dried in vacuo at 45-50 °C to yield the desired salt in 78% yield.

6.8.4 Preparation of Maleate Salt of c 5'-4-(3,4-dichlorophenyl)-4- ((dimethylamino)methyl)- 1 -methylcyclohexanol

A solution of 400 mg of maleic acid in 20 mL of isopropanol was added to a solution of 1.0 g of czs-4-(3,4-dichlorophenyl)-4-((dimethylamino) methyl)- 1 -methylcyclohexanol in 20 mL of acetone. The mixture was stirred at 40 °C until dissolution then cooled to ambient temperature. The

SDI-116984v2 71 mixture was stirred at 20 °C for 3 h and the resulting slurry was filtered. The solid was washed with cold acetone and dried in vacuo at 45-50 °C to yield the desired salt in 69% yield.

6.8.5 Preparation of Mesylate Salt of c s-4-(3,4-dichlorophenyl)-4- ((dimethylamino)methyl)- 1 -methylcyclohexanol

99 mg of methanesulfonic acid was added to a solution of 300 mg of ds-4-(3,4- dichlorophenyl)-4-((dimethylamino) methyl)- 1 -methylcyclohexanol in 4 mL of acetone at 40 °C. The mixture was stirred at 20 °C for 3 h and the resulting slurry was filtered. The solid was washed with cold acetone and dried in vacuo at 45-50 °C to yield the desired salt in 80% yield.

6.8.6 Preparation of Tosylate Salt of di-4-(3,4-dichlorophenyl)-4- ((dimethylamino)methyl)- 1 -methylcyclohexanol

A solution of 180 mg of p-toluenesulfonic acid in 3 mL of acetone was added to a solution of 300 mg of czs-4-(3,4-dichlorophenyl)-4-((dimethylamino) methyl) -1 -methylcyclohexanol in 3 mL of acetone at 40 °C. The mixture was then cooled to ambient temperature. The mixture was stirred at 20 °C for 3 h and the resulting slurry was filtered. The solid was washed with cold acetone and dried in vacuo at 45-50 °C to yield the desired salt in 56% yield.

6.8.7 Experiment 2: Overview

Various ci,y-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)- 1 -methylcyclohexanol salts were formed using a microplate method or a manual method as described below. A greater selection of acids were found to form salts with c i'-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-l- methylcyclohexanol, as shown in Table 2.

Table 2

SDI-116984v2 72

Microplate Method

6.8.8 Experiment 2: Manual Method

Solutions of the acid and free base were prepared and combined in one to one molar ratios. In some cases, the salt precipitated and was harvested. In cases where precipitation was not observed, the sample was cooled in order to induce precipitation (slow cools) or evaporated in order to produce solids (fast evaporation).

6.8.9 Experiment 2: Microplate Method

The free base of API compound was dissolved in methanol, to provide a 0.1 M solution. Using the Symyx platform, specified amounts of the API host solution were distributed into 72 wells

SDI-116984v2 73 in each of two 96-well microplates. Selected carboxylic acid, strong mineral acid, and sulfonic acid guest molecules were dissolved in methanol to provide 0.1 M solutions. Stoichiometric amounts of each guest solution were then auto-dispensed on the Symyx platform into the wells of each microplate containing the host solution. The last well in the first three dispensed rows of each microplate contained API and solvent only (as control). Observations were made for signs of precipitation:

Slow Evaporation Plate: The guest: host molar ratio was 1 :1.

Sonic Slurry Plate: The guest: host molar ratio was 1 :1.

The solvents were removed from the microplates using a centrifugal vacuum evaporator at a nominal temperature of 40 °C for approximately 45 min.

Three different solvents were auto-dispensed by row on the Symyx platform into the wells of the slow evaporation plate. The microplate was sealed and heated in an oven at 40 °C for approximately 1 h, agitated on an orbital shaker for approximately 0.5 h, then transferred under aluminum foil cover to a fume hood.

Three different solvents were manually distributed by row to the remaining Sonic Slurry microplate, and the microplate was sonicated. The solvents were removed using a centrifugal vacuum evaporator at ambient temperature for approximately 0.5 h. The microplate was sealed with an aluminum foil seal.

6.9. Example 9: Capsule Formulation of c s-4-(3,4-dichlorophenyl)-4- ((dimethylamino)methyl)-l-methylcyclohexanol

Formulation experiments were performed to discover dosage forms of czs-4-(3,4- dichlorophenyl)-4-((dimethylamino)methyl)-l-methylcyclohexanol maleate salt that can meet the following criteria:

• Acceptable physical and chemical stability of the formulation for at least 12 months,

preferably 3 years or longer;

• Manufacturability on automated equipment that is commonly used in the pharmaceutical industry;

• Ease of dosing to subjects and/or patients, in-clinic or out-of-clinic; and

• Blinding across strengths.

Excipients were studied such that the formulations would have the following characteristics: physical and chemical stability of the dry blend and the final capsule formulation, ease of handling of the dry blend during manufacture, and suitability of using the dry blend to manufacture capsules formulations on a high speed machine. The various excipients studied include Mannitol (Pearlitol™ 160C), Microcrystalline cellulose (Avicel™ PH-102), Pregelatinized starch (Starch 1500), Sodium starch glycolate (Primojel™), Talc, and Magnesium Stearate. Size 1 Swedish Orange #41-88 hard gelatin capsule shells were selected to encapsulate the formulations. Final formulation selection was based on initial testing and stability in PVC/PVDC//Alu blisters and handling properties of the dry

SDI-116984v2 74 powder blend. Table 3 and 4 lists the composition of various capsule formulations of cis-4-(3,4- dichlorophenyl)-4-((dimethylamino)methyl)-l-methylcyclohexanol maleate salt (API in these formulations). As shown in Table 3, various combinations of excipients were evaluated.

Combination A was selected for further study. As shown in Table 4, various capsule strength and amount of ingredients were evaluated.

Table 3:

Table 4:

* 1.37 mg of the maleate salt is equivalent to 1 mg of the free base of czs-4-(3,4- dichlorophenyl)-4-((dimethylamino)methyl)- l-methylcyclohexanol

A flow chart of the dry blending and encapsulation process for capsule formulation, for example, for capsule formulation of c^-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-l- methylcyclohexanol maleate salt, using automated equipment is shown in Scheme 4.

SDI-116984v2 75 Scheme 4:

1. API;

MIX

Talc;

(API and Talc, then 1 part diluent)

Pearlitol 160C (diluent, divide into 4 parts)

SIEVE (50 mesh)

Blend from Step 1

1 part Pearlitol 160C

Blend from Step 2

Starch 1500

Remainder of Pearlitol 160C

4. Blend from Step 3

SIEVE (30 mesh)

Magnesium Stearate

BLEND (2 min)

A.

5. Withdraw Samples

Blend from Step 4

Size 1 Swedish Orange Opaque Hard

Gelatin Capsule Shells

Data were obtained from Assay and Impurity analyses, and from moisture content analyses of c;j'-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)- 1 -methylcyclohexanol maleate salt capsules, which are shown in Tables 5 and 6. Table 7 summarizes the percent weight of excipients used in two dosage forms described herein and the percent weight ranges for each particular ingredient that may be used in a pharmaceutical composition.

Table 5: Assay and impurity of capsules packaged in PVC/P-VDC//Alu Blisters

SDI-116984v2 76

* Time in months, Condition A = 25°C/60%RH, B = 40°C/75%RH, C = 30°C/65%RH

Table 6: Moisture content of capsules packaged in PVC/P-VDC//Alu Blisters

* Time in months, Condition A = 25°C/60%RH, B = 40°C/75%RH, C = 30°C/65%RH

Table 7:

SDI-116984v2 77 All of the patents, patent applications and publications referred to in this application are incorporated herein in their entireties. Moreover, citation or identification of any reference in this application is not an admission that such reference is available as prior art.

SDI-116984v2 78

Claims

What is claimed is:

1. A pharmaceutical composition comprising cz^'s-4-(3,4-dichlorophenyl)- 1 -methyl-4- ((methylamino)methyl)cyclohexanol or c 5'-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)- 1 - methylcyclohexanol or a pharmaceutically acceptable salt or solid form thereof, and mannitol.

2. The pharmaceutical composition of claim 1, further comprising at least one of starch, talc, and magnesium stearate.

3. The pharmaceutical composition of claim 1, further comprising starch, talc, and magnesium stearate.

4. The pharmaceutical composition of claim 1 , comprising a maleate salt of cz^',y-4-(3,4- dichlorophenyl)-4-((dimethylamino)methyl)-l -methylcyclohexanol or a solid form thereof.

5. The pharmaceutical composition of claim 1 , which is a tablet or a capsule.

6. The pharmaceutical composition of claim 1, wherein the composition comprises at least 10% by weight of mannitol.

7. The pharmaceutical composition of claim 3, wherein the mannitol is present at an amount of from about 40 to about 95 weight percent of total weight of the composition.

8. The pharmaceutical composition of claim 3, wherein the starch is present at an amount of from about 14 to about 16 weight percent of total weight of the composition.

9. The pharmaceutical composition of claim 3, wherein the talc is present at an amount of from about 1 to about 5 weight percent of total weight of the composition.

10. The pharmaceutical composition of claim 3, wherein the magnesium stearate is present at an amount of from about 0.5 to about 1 weight percent of total weight of the composition.

11. A maleate salt of c i-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-l- methylcyclohexanol or a solid form thereof.

12. A process for preparing ci,y-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-l- methylcyclohexanol, comprising the steps:

a) reacting 4-(3,4-dichlorophenyl)-l-methyl-2-oxabicyclo[2.2.2]octan-3-one with dimethylamine or metalodimethylamide to yield cz,s-l-(3,4-dichlorophenyl)-4-hydroxy-4-methyl-N,N- dimethylcyclohexanecarboxamide:

SDI-116984v2 79 b) converting cis- 1 -(3 ,4-dichlorophenyl)-4-hydroxy-4-methyl-N,N- dimethylcyclohexanecarboxamide to c i-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)- 1 - methylcyclohexanol:

13. A process for preparing d,y-4-(3,4-dichlorophenyl)- 1 -methyl-4- ((methylamino)methyl)cyclohexanol, comprising the steps:

a) reacting 4-(3,4-dichlorophenyl)-l-methyl-2-oxabicyclo[2.2.2]octan-3-one with methylamine or metalomethylamide to yield ds-l-(3,4-dichlorophenyl)-4-hydroxy-N,4- dimethylcyclohexanecarboxamide:

b) converting c^-l-(3,4-dichlorophenyl)-4-hydroxy-N,4-dimethylcyclohexanecarboxamide to c i-4-(3,4-dichlorophenyl)- 1 -methyl-4-((methylamino)methyl)cyclohexanol:

A compound having the following formula:

SDI-116984v2 80