US 2008/0234257 A1 Gant Et Al

Home , Sodium deuteroxide

US 20080234257A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0234257 A1 Gant et al. (43) Pub. Date: Sep. 25, 2008

(54) SUBSTITUTED PHENETHYLAMINES WITH (52) U.S. Cl...... 514/230.5:564/287: 514/643; SEROTONNERGIC AND/OR 564/355; 514/649; 54.4/71; 530/409 NOREPINEPHRINERGIC ACTIVITY (57) ABSTRACT Chemical syntheses and medical uses of novel inhibitors of (75) Inventors: Thomas G. Gant, Carlsbad, CA the uptake of monoamine neurotransmitters and pharmaceu (US); Sepehr Sarshar, Cardiff by tically acceptable salts and prodrugs thereof, for the treatment the Sea, CA (US); Soon Hyung and/or management of psychotropic disorders, anxiety disor Woo, Vista, CA (US) der, generalized anxiety disorder, depression, post-traumatic stress disorder, obsessive-compulsive disorder, panic disor Correspondence Address: der, hot flashes, senile dementia, migraine, hepatopulmonary GLOBAL PATENT GROUP - APX syndrome, chronic pain, nociceptive pain, neuropathic pain, Ms. LaVern Hall painful diabetic retinopathy, bipolar depression, obstructive 10411 Clayton Road, Suite 304 sleep apnea, psychiatric disorders, premenstrual dysphoric ST. LOUIS, MO 63131 (US) disorder, Social phobia, Social anxiety disorder, urinary incontinence, anorexia, bulimia nervosa, obesity, ischemia, head injury, calcium overload in brain cells, drug depen (73) Assignee: AUSPEX dence, attention deficit hyperactivity disorder, fibromyalgia, PHARMACEUTICALS, INC., irritable bowel syndrome, and/or premature ejaculation are Vista, CA (US) described. (21) Appl. No.: 12/048,012 Formula I (22) Filed: Mar. 13, 2008 Related U.S. Application Data (60) Provisional application No. 60/895,049, filed on Mar 15, 2007, provisional application No. 60/944,399, filed on Jun. 15, 2007.

Publication Classification (51) Int. C. A 6LX 3/537 (2006.01) C07C 2 II/27 (2006.01) A6 IK 3/4 (2006.01) C07K I4/705 (2006.01) A6 IK3I/37 (2006.01) CO7D 265/6 (2006.01)

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SUBSTITUTED PHENETHYLAMINES WITH it can act as an inhibitor of CYP2D6, its application in polyp SEROTONNERGIC AND/OR harmacy is necessarily complex and has potential for adverse NOREPINEPHRINERGIC ACTIVITY events. These CYPs are involved in the metabolism of medi cations that are typically prescribed concurrently with ven lafaxine. This phenomenon increases inter-patient variability 0001. This application claims the benefit of priority of in response to polypharmacy. An example of the critical need U.S. provisional applications No. 60/895,049, filed Mar. 15, for improvement of Venlafaxine is the observed interpatient 2007, and No. 60/944,399, filed Jun. 15, 2007, the disclosures variability in “poor metabolizers” having either defective of which are hereby incorporated by reference as if written CYP2D6 alleles or total lack of CYP2D6 expression. These herein in its entirety. patients fail to convert Venlafaxine to its equipotent metabo lite, O-desmethylvenlafaxine. Venlafaxine also suffers from a FIELD short half-life relative to the majority of serotonin reuptake 0002 The present invention is directed to inhibitors of the inhibitors. The half-life of venlafaxine inhumans is ~5 hours, uptake of monoamine neurotransmitters and pharmaceuti while its active metabolite has a T of ~11 hours. As a cally acceptable salts and prodrugs thereof, the chemical Syn consequence of its 5-11 hour pharmacological half-life, those thesis thereof, and the medical use of such compounds for the taking Venlafaxine are at significant risk of SRI discontinua treatment and/or management of psychotropic disorders, tion symptoms if the drug is abruptly discontinued. Further anxiety disorder, generalized anxiety disorder, depression, more, in order to overcome its short half-life, the drug must be post-traumatic stress disorder, obsessive-compulsive disor taken 2 (BID) or 3 (TID) times a day. An extended release der, panic disorder, hot flashes, senile dementia, migraine, formulation of Venlafaxine is also available; however, it does hepatopulmonary syndrome, chronic pain, nociceptive pain, not significantly increase the carryover of drug to the next neuropathic pain, painful diabetic retinopathy, bipolar day. Most other serotonin reuptake inhibitors (SRIs) have depression, obstructive sleep apnea, psychiatric disorders, half-lives 224 hours. The half-life of the primary active premenstrual dysphoric disorder, Social phobia, Social anxi metabolite, O-desmethylvenlafaxine (“ODV), is longer than ety disorder, urinary incontinence, anorexia, bulimia nervosa, that of the parent compound; however, it is still desirable and obesity, ischemia, head injury, calcium overload in brain beneficial to increase the half-life of ODV. cells, drug dependence, attention deficit hyperactivity disor der, fibromyalgia, irritable bowel syndrome, and/or prema ture ejaculation.

BACKGROUND 0003 Venlafaxine (Effexor(R) (1-2-dimethylamino-1-(4- methoxy-phenyl)-ethyl-cyclohexanol) is a therapeutic agent HO whose efficacy is hypothesized to act through inhibition of serotonin reuptake and, potentially, norepinephrine reuptake HO in neuronal cells. Norepinephrine activity modulation is pur O-desmethylvenlafaxine ported to occur at higher doses of Venlafaxine than those required for serotonin activity modulation. Venlafaxine also has the potential to modulate dopamine activity, though the SUMMARY OF THE INVENTION interaction in vitro is weak and the clinical relevance of this interaction is unknown. The drug substance is sold as a 50/50 0005 Disclosed herein is a pharmaceutically acceptable racemic mixture of R- and S-enantiomers. acid addition salt of a compound having structural formula I:

(I)

HO No Wenlafaxine

0004 Venlafaxine is converted in vivo by oxidative and conjugative degradation to multiple metabolites, at least 48 of which are documented. The major metabolic pathways include phase I metabolism leading to demethylation at the oxygen and/or nitrogen centers and cyclohexyl ring hydroxy lation, as well as phase II metabolism including glucuronida tion of the hydroxylated metabolites. Because venlafaxine is metabolized by polymorphically-expressed isozymes of wherein R. R2, Rs. R4, Rs. R6. R7. Rs. R9. Rio. R11, R12. R1s. cytochrome Paso including CYPs 2C19 and 2D6, and because R14. R1s. R16. R17, R1s. R19. R20. R21. R22. R R R R US 2008/02342.57 A1 Sep. 25, 2008 and R27 are independently selected from the group consisting 0012. Further disclosed herein is a compound having of hydrogen and deuterium; and structural formula IV: 0006 at least one of R. R. R. R. Rs. Re, R7Rs, Ro Ro, R11, R12, R13, R14, R1s. R16, R17, Ris, R19, R20 R2, R22, R2s.

R2, R2s, R2, and R27 is deuterium. (IV) 0007 Further disclosed herein is a compound having structural formula II:

(II)

wherein Rss. Rs4 Rss. Rs6. Rs7, Rss. Rs.9, Roo. Ro1, Ro2, Ros. R94. Ros, R96. R97. Ros, Roo. Roo. Ro1, Ro2. Rios. R 104. Ros, Roe, and Ro, are independently selected from the group consisting of hydrogen and deuterium; and I0013 at least one of Rss. Rs. Rss. Rs6, R87, R8s, R89. Roo, wherein R2s, R29, Rao Rs1, R32, R3s. R34, R3s. R36, R37, R3s, Rol, Ro2, Ros, Ro4. Ros, Roo Ro7, Ros. Roo Roo Rio, Rio2 R39, Rao, R41, R42, R43; R44 R4s. R46. R47, R4s. Rao, Rso Rs1, Rios, Ro4, Rios, Rios, and Roz is deuterium. Rs. Rs. Rs. Rss. Rs, and Rs 7 are independently selected 0014. Also disclosed herein are pharmaceutical composi from the group consisting of hydrogen and deuterium; tions comprising at least one compound as disclosed herein or 0008 at least one of Rs. Ro Ro, R. R. R. R. Rs. a pharmaceutically acceptable salt, Solvate, or prodrug R36, R37, Ras, R39, Rao, R41, R42, R43, R44 R4s. Ra6. R47, R4s. thereof; in combination with one or more pharmaceutically R49. Rso Rs1, Rs.2, Rss. Rs4 Rss. Rs6, and Rs7 is deuterium; acceptable excipients or carriers. and 0015. Further disclosed herein is a method for treating, 0009 X is a leaving group anion. preventing, or ameliorating one or more symptoms of a 0010 Further disclosed herein is a compound having monoamine-mediated disorder, which comprises administer structural formula III: ing to a subject a therapeutically effective amount of at least one compound as disclosed herein or a pharmaceutically acceptable salt, Solvate, or prodrug thereof. (III)

0016. Additionally provided herein is a method for treat ing, preventing, or ameliorating one or more symptoms of the following disorders, including, but not limited to: psychotro pic disorders, anxiety disorders, generalized anxiety disorder, depression, post-traumatic stress disorder, obsessive-com pulsive disorder, panic disorder, hot flashes, senile dementia, migraine, hepatopulmonary syndrome, chronic pain, nocice ptive pain, neuropathic pain, painful diabetic retinopathy, bipolar depression, obstructive sleep apnea, psychiatric dis orders, premenstrual dysphoric disorder, social phobia, Social anxiety disorder, urinary incontinence, anorexia, bulimia ner Vosa, obesity, ischemia, head injury, calcium overload in brain cells, drug dependence, Gilles de la Tourette syndrome, Shy Drager syndrome, vasomotor flushing, chronic fatigue syndrome, cognition enhancement, attention deficit hyperac tivity disorder, fibromyalgia, irritable bowel syndrome, and/ or premature ejaculation, which comprises administering to a wherein Rss. Rso Roo Roi, Ro2, Ros. Ro4. Ros. Rog. Rg7 Rg8. subject a therapeutically effective amount of at least one R69. R70 R-71, R72. R73. R74. R.7s. R76. R77, R7s. R79. Rso Rs1, compound as disclosed herein or a pharmaceutically accept and Rs are independently selected from the group consisting able salt, Solvate, or prodrug thereof. of hydrogen and deuterium; and 0017. Further, disclosed herein are methods of modulating 0011 at least one of Rss. Rso, Roo, R, R2, R. R. Ros. a target selected from the group consisting of a serotonin R66. R67. R6s. R69. R70 R-71, R72. R73. R74. R.7s. R76. R77, R7s. receptor, a norepinephrine receptor, a serotonin transporter, R79. Rso, Rs, and Rs2 is deuterium. and a norepinephrine transporter. US 2008/02342.57 A1 Sep. 25, 2008

0.018. In another aspectare processes for preparing a com able for injectable dosage forms. Furthermore, the hydrochlo pound having structural formula I as serotonin and/or nore ride salt Forms A-F of the compound of formula I with pinephrine receptor and/or transporter modulators, or other enhanced solubility characteristics facilitate the dissolution pharmaceutically acceptable derivatives Such as prodrug of solid dosage forms in a timely manner. All of these advan derivatives, or individual isomers and mixture of isomers or tages are specifically described herein for all of the pharma enantiomers thereof. ceutical dosage forms, treatment regimens and therapeutic 0019. In another aspectare processes for preparing a phar uses described hereinform compounds of formula I. maceutically acceptable salt of a compound having structural 0027. The hydrochloride salt Forms A-F of the compound formula I. of formula I have greater kinetic solubility than the free base 0020. In another aspectare processes for preparing a com of the compound of formula I. Additionally, the hydrochlo pound having structural formula II. ride salt Forms A-F of the compound of formula I are more 0021. In another aspectare processes for preparing a com stable in air and can be used without deliquescence. In one pound having structural formula III. aspectare compounds of formula I which can be stored in air 0022. Additionally disclosed herein is the use of a com and used without deliquescence, including for periods of pound having structural formula II for the manufacture of a more than 1 week, more than 2 weeks, more than 1 month, compound having structural formula I. more than 2 months, more than 3 months and more than 6 0023. Additionally disclosed herein is the use of a com months. pound having structural formula III for the manufacture of a compound having structural formula I. BRIEF DESCRIPTION OF THE DRAWINGS 0024. Also disclosed herein are articles of manufacture 0028 FIG. 1 is an X-ray powder diffraction spectrum of and kits containing compounds as disclosed herein. By way do-1-(2-dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclo of example only, a kit or article of manufacture can include a hexanol hydrochloride (d-venlafaxine hydrochloride. Form container (such as a bottle) with a desired amount of at least A) which was prepared and isolated according to the process one compound (or pharmaceutical composition of a com disclosed in Example 34. pound) as disclosed herein. Further, such a kit or article of 0029 FIG. 2 is an X-ray powder diffraction spectrum of manufacture can further include instructions for using said do-1-(2-dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclo compound (or pharmaceutical composition of a compound) hexanol hydrochloride (d-venlafaxine hydrochloride, Form as disclosed herein. The instructions can be attached to the B) which was prepared and isolated according to the process container, or can be included in a package (such as a box or a disclosed in Example 35. plastic or foil bag) holding the container. 0030 FIG. 3 is an X-ray powder diffraction spectrum of 0025. In another aspect is the use of at least one compound do-1-(2-dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclo as disclosed herein in the manufacture of a medicament for hexanol hydrochloride (d-venlafaxine hydrochloride, Form treating a disorder in an animal in which serotonin and/or C) which was prepared and isolated according to the process norepinephrine receptors contribute to the pathology and/or disclosed in Example 36. symptomology of the disorder. In a further or alternative 0031 FIG. 4 is an X-ray powder diffraction spectrum of embodiment, said disorder is, but is not limited to, a psycho do-1-(2-dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclo tropic disorder, anxiety disorder, generalized anxiety disor hexanol hydrochloride (d-venlafaxine hydrochloride, Form der, depression, post-traumatic stress disorder, obsessive D) which was prepared and isolated according to the process compulsive disorder, panic disorder, hot flashes, senile disclosed in Example 37. dementia, migraine, hepatopulmonary syndrome, chronic 0032 FIG. 5 is an X-ray powder diffraction spectrum of pain, nociceptive pain, neuropathic pain, painful diabetic ret do-1-(2-dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclo inopathy, bipolar depression, obstructive sleep apnea, psychi hexanol hydrochloride (d-venlafaxine hydrochloride, Form atric disorders, premenstrual dysphoric disorder, social pho E) which was prepared and isolated according to the process bia, Social anxiety disorder, urinary incontinence, anorexia, disclosed in Example 38. bulimia nervosa, obesity, ischemia, head injury, calcium over 0033 FIG. 6 is an X-ray powder diffraction spectrum of load in brain cells, drug dependence, Gilles de la Tourette do-1-(2-dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclo syndrome, Shy Drager syndrome, vasomotor flushing, hexanol hydrochloride (d-venlafaxine hydrochloride, Form chronic fatigue syndrome, cognition enhancement, attention F) which was prepared and isolated according to the process deficit hyperactivity disorder, fibromyalgia, irritable bowel disclosed in Example 39. syndrome, and/or premature ejaculation. 0034 FIG. 7 is a solid state infrared absorption spectrum 0026. It has been found that the hydrochloride salt Forms of do-1-(2-dimethylamino-1-(4-methoxyphenyl)-ethyl-cy A-F of the compound of formula I have high crystallinity, i.e., clohexanol hydrochloride (do-Venlafaxine hydrochloride, substantially free of amorphous material. Such salts have the Form A) which was prepared and isolated according to the advantage that they provide more reproducible dosing results. process disclosed in Example 34. The hydrochloride salt Forms A-F of the compound of for 0035 FIG. 8 is a solid state infrared absorption spectrum mula I are substantially hygroscopically stable, which allevi of do-1-(2-dimethylamino-1-(4-methoxyphenyl)-ethyl-cy ates potential problems associated with weight changes of the clohexanol hydrochloride (do-Venlafaxine hydrochloride, active ingredient during the manufacture of capsules or tab Form B) which was prepared and isolated according to the lets. The hydrochloride Forms A-F of the compound of for process disclosed in Example 35. mula I have the additional advantage that they have a low 0036 FIG. 9 is a solid state infrared absorption spectrum tendency for concentrated aqueous solution to form viscous of do-1-(2-dimethylamino-1-(4-methoxyphenyl)-ethyl-cy mixtures upon standing. The hydrochloride salt Forms A-F of clohexanol hydrochloride (do-Venlafaxine hydrochloride, the compound of formula I have rapid kinetic aqueous solu Form C) which was prepared and isolated according to the bility which simplifies aqueous dosing and make them Suit process disclosed in Example 36. US 2008/02342.57 A1 Sep. 25, 2008

0037 FIG. 10 is a solid state infrared absorption spectrum hamsters, ferrets, and the like), lagomorphs, Swine (e.g., pig, of do-1-(2-dimethylamino-1-(4-methoxyphenyl)-ethyl-cy miniature pig), equine, canine, feline, and the like. The terms clohexanol hydrochloride (do-Venlafaxine hydrochloride, “subject' and “patient” are used interchangeably herein in Form D) which was prepared and isolated according to the reference, for example, to a mammalian Subject, such as a process disclosed in Example 37. human patient. 0038 FIG. 11 is a solid state infrared absorption spectrum 0047. The terms “treat,” “treating,” and “treatment” are of do-1-(2-dimethylamino-1-(4-methoxyphenyl)-ethyl-cy meant to include alleviating or abrogating a disorder; or one clohexanol hydrochloride (do-Venlafaxine hydrochloride, or more of the symptoms associated with the disorder; or Form E) which was prepared and isolated according to the alleviating or eradicating the cause(s) of the disorder itself. process disclosed in Example 38. 0048. The terms “prevent.” “preventing, and “preven 0039 FIG. 12 is a solid state infrared absorption spectrum tion” refer to a method of delaying or precluding the onset of of do-1-(2-dimethylamino-1-(4-methoxyphenyl)-ethyl-cy a disorder, and/or its attendant symptoms, barring a subject clohexanol hydrochloride (do-Venlafaxine hydrochloride, from acquiring a disorder or reducing a subject's risk of Form F) which was prepared and isolated according to the acquiring a disorder. process disclosed in Example 39. 0049. The term “therapeutically effective amount” refers 0040 FIG. 13 is a thermogravimetric analysis (TGA) of to the amount of a compound that, when administered, is do-1-2-dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclo sufficient to prevent development of, or alleviate to some hexanol hydrochloride (d-venlafaxine hydrochloride, Form extent, one or more of the symptoms of the disorder being B) which was prepared and isolated according to the process treated. The term “therapeutically effective amount” also disclosed in Example 35, heated at 10°C/min from ambient refers to the amount of a compound that is sufficient to elicit temperature to approximately 700° C. and then in regular the biological or medical response of a cell, tissue, system, mode to 1000°C., in a nitrogen atmosphere (25 cc/min). animal, or human that is being sought by a researcher, Veteri 0041 FIG. 14 is a thermogravimetric analysis (TGA) of narian, medical doctor, or clinician. do-1-2-dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclo 0050. The term “pharmaceutically acceptable carrier.” hexanol hydrochloride (d-venlafaxine hydrochloride, Form “pharmaceutically acceptable excipient,” “physiologically C) which was prepared and isolated according to the process acceptable carrier,” or “physiologically acceptable excipient’ disclosed in Example 36, heated at 10°C/min from ambient refers to a pharmaceutically-acceptable material, composi to approximately 700° C. and then in regular mode to 1000 tion, or vehicle, such as a liquid or Solid filler, diluent, excipi C., in a nitrogen atmosphere (25 cc/min). ent, solvent, or encapsulating material. Each component must 0042 FIG. 15 is a thermogravimetric analysis (TGA) be “pharmaceutically acceptable' in the sense of being com spectrum of do-1-(2-dimethylamino-1-(4-methoxyphenyl)- patible with the other ingredients of a pharmaceutical formu ethyl-cyclohexanol hydrochloride (d-venlafaxine hydro lation. It must also be suitable for use in contact with the tissue chloride. Form E) which was prepared and isolated according or organ of humans and animals without excessive toxicity, to the process disclosed in Example 38, heated at 10°C./min irritation, allergic response, immunogenecity, or other prob from ambient to approximately 700° C. and then in regular lems or complications, commensurate with a reasonable ben mode to 1000°C., in a nitrogen atmosphere (25 cc/min). efit/risk ratio. See, Remington. The Science and Practice of Pharmacy, 21st Edition; Lippincott Williams & Wilkins: INCORPORATION BY REFERENCE Philadelphia, Pa., 2005, Handbook of Pharmaceutical 0043 All publications (including WO07064697A1 and Excipients, 5th Edition; Rowe et al., Eds. The Pharmaceuti US200701:49.622A1) and references cited herein, including cal Press and the American Pharmaceutical Association: those in the background section, are expressly incorporated 2005; and Handbook of Pharmaceutical Additives, 3rd Edi herein by reference in their entirety. However, with respect to tion; Ash and Ash Eds. Gower Publishing Company: 2007; any similar or identical terms found in both the incorporated Pharmaceutical Preformulation and Formulation, Gibson publications or references and those explicitly put forth or Ed., CRC Press LLC: Boca Raton, Fla., 2004). defined in this document, then those terms definitions or 0051. The term “deuterium enrichment” refers to the per meanings explicitly put forth in this document shall control in centage of incorporation of deuterium at a given position in a all respects. molecule in the place of hydrogen. For example, deuterium enrichment of 1% at a given position means that 1% of mol DETAILED DESCRIPTION ecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deu 0044) To facilitate understanding of the disclosure set terium is about 0.0156%, deuterium enrichment at any posi forth herein, a number of terms are defined below. Generally, tion in a compound synthesized using non-enriched starting the nomenclature used herein and the laboratory procedures materials is about 0.0156%. The deuterium enrichment can in organic chemistry, medicinal chemistry, and pharmacol be determined using conventional analytical methods known ogy described herein are those well known and commonly to one of ordinary skill in the art, including mass spectrometry employed in the art. In the event that there is a plurality of and nuclear magnetic resonance spectroscopy. definitions for a term used herein, those in this section prevail 0052. The term “is/are deuterium, when used to describe unless stated otherwise. a given position in a molecule such as R. R. R. R. R. R. 0045. As used herein, the singular forms “a,” “an and R7, Rs. Ro. Rio, R1, R12, R13, R14, R1s. R16, R17, R1s. R19. “the may refer to plural articles unless specifically stated Ro, R. R. R. R. R.2s and R2 or the Symbol "D. When otherwise. used to represent a given position in a drawing of a molecular 0046. The term “subject” refers to an animal, including, structure, means that the specified position is enriched with but not limited to, a primate (e.g., human, monkey, chimpan deuterium above the naturally occurring distribution of deu Zee, gorilla, and the like), rodents (e.g., rats, mice, gerbils, terium. In one embodiment deuterium enrichment is of no US 2008/02342.57 A1 Sep. 25, 2008

less than about 1%, in another no less than about 5%, in fying the duration or place of release of the active Substance another no less than about 10%, in another no less than about from a dosage form as compared with a conventional imme 20%, in another no less than about 50%, in another no less diate release dosage form. than about 70%, in another no less than about 80%, in another 0062. The term “pharmaceutically acceptable acid addi no less than about 90%, and in another no less than about 98% tion salt” refers to a salt prepared by contacting a compound of deuterium at the specified position. having a basic functional group with a pharmaceutically 0053. The term “isotopic enrichment” refers to the per acceptable acid. centage of incorporation of a less prevalent isotope of an 0063. The term “SNRI” and “serotonin and/or norepi element at a given position in a molecule in the place of the nephrine receptor and/or transporter modulator are inter more prevalent isotope of the element. changeable and refer to a compound that can act as an inhibi 0054 The term “non-isotopically enriched’ refers to a tor, oran antagonist of a serotonin receptor and/or transporter, molecule in which the percentages of the various isotopes are and/or norepinephrine receptor and/or transporter. Substantially the same as the naturally occurring percentages. 0064. The term “monoamine-mediated disorder” refers to 0055. The terms “substantially pure” and “substantially a disorder that is characterized by abnormal serotonin and/or homogeneous' mean Sufficiently homogeneous to appear norepinephrine levels, and when the levels of these neu free of readily detectable impurities as determined by stan rotransmitters are modified, leads to the amelioration of other dard analytical methods used by one of ordinary skill in the abnormal biological processes. A monoamine-mediated dis art, including, but not limited to, thin layer chromatography order may be completely or partially mediated by abnormal (TLC), gel electrophoresis, high performance liquid chroma serotonin, and/or norepinephrine receptors and/or transport tography (HPLC), infrared spectroscopy (IR), gas chroma ers. In particular, a monoamine-mediated disorder is one in tography (GC), Ultraviolet Spectroscopy (UV), nuclear mag which modulation of serotonin-norepinephrine reuptake netic resonance (NMR), atomic force spectroscopy and mass activity results in Some effect on the underlying condition, spectroscopy (MS); or sufficiently pure such that further puri disorder, or disease, e.g., administration of an SNRI results in fication would not detectably alter the physical and chemical Some improvement in at least some of the patients being properties, or biological and pharmacological properties, treated. Such as enzymatic and biological activities, of the Substance. 0065. The term “halogen”, “halide' or “halo' includes In certain embodiments, “substantially pure' or “substan fluorine, chlorine, bromine, and iodine. tially homogeneous” refers to a collection of molecules, 0066. The term “leaving group’ (LG) refers to any atom wherein at least about 50%, at least about 70%, at least about (or group of atoms) that is stable in its anion or neutral form 80%, at least about 90%, at least about 95%, at least about after it has been displaced by a nucleophile and as such would 98%, at least about 99%, or at least about 99.5% of the be obvious to one of ordinary skill and knowledge in the art. molecules are a single compound, including a racemic mix The definition of “leaving group” includes but is not limited ture or single stereoisomer thereof, as determined by standard to: water, methanol, ethanol, chloride, bromide, iodide, an analytical methods. alkyl Sulfonate, for example methanesulfonate, ethane Sul 0056. The term “about' or “approximately means an fonate and the like, an arylsulfonate, for example benzene acceptable error for a particular value, which depends in part Sulfonate, tolylsulfonate and the like, a perhaloalkane on how the value is measured or determined. In certain Sulfonate, for example trifluoromethanesulfonate, embodiments, “about can mean 1 or more standard devia trichloromethanesulfonate and the like, an alkylcarboxylate, tions. for example acetate and the like, a perhaloalkylcarboxylate, for example trifluoroacetate, trichloroacetate and the like, an 0057 The terms “active ingredient” and “active sub arylcarboxylate, for example benzoate and the like, an N-hy stance' refer to a compound, which is administered, alone or droxyimide anion, for example N-hydroxyrnaleimide anion, in combination with one or more pharmaceutically accept Nhydroxysuccinimide anion, N-hydroxyphthalimide anion, able excipients or carriers, to a Subject for treating, prevent N-hydroxysulfosuccinimide anion and the like. ing, or ameliorating one or more symptoms of a disorder. 0067. The term “protecting group' or “removable protect 0058. The terms “drug.” “therapeutic agent,” and “chemo ing group' refers to a group which, when bound to a func therapeutic agent” refer to a compound, or a pharmaceutical tionality, Such as the oxygen atom of a hydroxyl or carboxyl composition thereof, which is administered to a subject for group, or the nitrogen atom of an amino group, prevents treating, preventing, or ameliorating one or more symptoms reactions from occurring at that functional group, and which of a disorder. can be removed by a conventional chemical or enzymatic step 0059. The term “disorder as used herein is intended to be to reestablish the functional group (Greene and Wuts, Protec generally synonymous, and is used interchangeably with, the tive Groups in Organic Synthesis, 3" Ed., John Wiley & Sons, terms “disease.” “syndrome,” and “condition' (as in medical New York, N.Y., 1999). condition), in that all reflect an abnormal condition of the 0068. In light of the purposes described in the present body or of one of its parts that impairs normal functioning and disclosure, all references to “alkyl and “aryl groups or any is typically manifested by distinguishing signs and Symp groups ordinarily containing C-H bonds may include par tOmS. tially or fully deuterated versions as required to affect the 0060. The term “release controlling excipient” refers to an improvements outlined herein. excipient whose primary function is to modify the duration or I0069. When the notation R-R is used to represent a place of release of the active Substance from a dosage form as span of consecutive R groups, what is mean is that all R compared with a conventional immediate release dosage groups between and including said R groups are comprised form. by said notation. For example, R-R-7 is equivalent to R, R2, 0061 The term “nonrelease controlling excipient” refers Rs. R4 Rs. Rs. R-7, Rs. Ro, Rio, R1, R12, R13, R14, Ris, R16, to an excipient whose primary function do not include modi R17, Ris, R19, R20 R2, R22, R23, R24. R2s, R26, and R27. US 2008/02342.57 A1 Sep. 25, 2008

0070. When the term “increased' is used to compare a 0074. A carbon-hydrogen bond is by nature a covalent certain effect or property of an isotopically enriched (e.g., chemical bond. Suchabond forms when two atoms of similar deuterated) compound to a corresponding non-isotopically electronegativity share some of their valence electrons, enriched compound, what is meant is that said effect or prop thereby creating a force that holds the atoms together. This erty is increased by greater than about 5%, greater than about force or bond strength can be quantified and is expressed in 10%, greater than about 20%, greater than about 30%, greater units of energy, and as Such, covalent bonds between various than about 40%, or by greater than about 50% as compared to atoms can be classified according to how much energy must the corresponding non-isotopically enriched compound. be applied to the bond in order to break the bond or separate Similarly, when the term “decreased' is used to compare a the two atoms. certain effect or property of an isotopically enriched (e.g., 0075. The bond strength is directly proportional to the deuterated) compound to a corresponding non-isotopically absolute value of the ground-state vibrational energy of the enriched compound, what is meant is that said effect or prop bond. This vibrational energy, which is also known as the erty is decreased by greater than about 5%, greater than about Zero-point vibrational energy, depends on the mass of the 10%, greater than about 20%, greater than about 30%, greater atoms that form the bond. The absolute value of the Zero-point than about 40%, or by greater than about 50% as compared to vibrational energy increases as the mass of one or both of the the corresponding non-isotopically enriched compound. atoms making the bond increases. Since deuterium (D) has twice the mass of hydrogen (H), it follows that a C-D bond is Deuterium Kinetic Isotope Effect stronger than the corresponding C-H bond. Compounds 0071. In an attempt to eliminate foreign substances, such with C-D bonds are frequently indefinitely stable in HO, and as therapeutic agents, from its circulation system, the animal have been widely used for isotopic studies. If a C H bond is body expresses various enzymes, such as the cytochrome Paso broken during a rate-determining step in a chemical reaction enzymes or CYPs, esterases, proteases, reductases, dehydro (i.e. the step with the highest transition State energy), then genases, and monoamine oxidases, to react with and convert Substituting a deuterium for that hydrogen will cause a these foreign substances to more polar intermediates or decrease in the reaction rate and the process will slow down. metabolites for renal excretion. Some of the most common This phenomenon is known as the Deuterium Kinetic Isotope metabolic reactions of pharmaceutical compounds involve Effect (DKIE). The magnitude of the DKIE can be expressed the oxidation of a carbon-hydrogen (C-H) bond to either a as the ratio between the rates of a given reaction in which a carbon-oxygen (C-O) or carbon-carbon (C-C) JU-bond. C–H bond is broken, and the same reaction where deuterium The resultant metabolites may be stable or unstable under is substituted for hydrogen. The DKIE can range from about physiological conditions, and can have Substantially different 1 (no isotope effect) to very large numbers, such as 50 or pharmacokinetic, pharmacodynamic, and acute and long more, meaning that the reaction can be fifty, or more, times term toxicity profiles relative to the parent compounds. For slower when deuterium is substituted for hydrogen. High most drugs, such oxidations are generally rapid and ulti DKIE values may be due in part to a phenomenon known as mately lead to administration of multiple or high daily doses. tunneling, which is a consequence of the uncertainty prin 0072 The relationship between the activation energy and ciple. Tunneling is ascribed to the Small mass of a hydrogen the rate of reaction may be quantified by the Arrhenius equa atom, and occurs because transition states involving a proton tion, k=Ae', where E is the activation energy, T is can sometimes form in the absence of the required activation temperature, R is the molar gas constant, k is the rate constant energy. Because deuterium has more mass than hydrogen, it for the reaction, and A (the frequency factor) is a constant statistically has a much lower probability of undergoing this specific to each reaction that depends on the probability that phenomenon. Substitution of tritium for hydrogen results in the molecules will collide with the correct orientation. The yet a stronger bond than deuterium and gives numerically Arrhenius equation states that the fraction of molecules that larger isotope effects have enough energy to overcome an energy barrier, that is, (0076 Discovered in 1932 by Urey, deuterium (D) is a those with energy at least equal to the activation energy, stable and non-radioactive isotope of hydrogen. It was the depends exponentially on the ratio of the activation energy to first isotope to be separated from its element in pure form and thermal energy (RT), the average amount of thermal energy has twice the mass of hydrogen, and makes up about 0.02% of that molecules possess at a certain temperature. the total mass of hydrogen (in this usage meaning all hydro 0073. The transition state in a reaction is a short lived state gen isotopes) on earth. When two deuterium atoms bond with (on the order of 10-14 sec) along the reaction pathway during one oxygen, deuterium oxide (DO or “heavy water) is which the original bonds have stretched to their limit. By formed. DO looks and tastes like HO, but has different definition, the activation energy E for a reaction is the physical properties. It boils at 101.41° C. and freezes at 3.79 energy required to reach the transition state of that reaction. C. Its heat capacity, heat of fusion, heat of vaporization, and Reactions that involve multiple steps will necessarily have a entropy are all higher than H2O. It is more viscous and has number of transition states, and in these instances, the acti different solubilizing properties than H.O. Vation energy for the reaction is equal to the energy difference 0077. When pure DO is given to rodents, it is readily between the reactants and the most unstable transition state. absorbed and reaches an equilibrium level that is usually Once the transition state is reached, the molecules can either about eighty percent of the concentration of what was con revert, thus reforming the original reactants, or new bonds Sumed. The quantity of deuterium required to induce toxicity form giving rise to the products. This dichotomy is possible is extremely high. When 0% to as much as 15% of the body because both pathways, forward and reverse, result in the water has been replaced by D.O, animals are healthy but are release of energy. A catalyst facilitates a reaction process by unable to gain weight as fast as the control (untreated) group. lowering the activation energy leading to a transition state. When about 15% to about 20% of the body water has been Enzymes are examples of biological catalysts that reduce the replaced with DO, the animals become excitable. When energy necessary to achieve a particular transition state. about 20% to about 25% of the body water has been replaced US 2008/02342.57 A1 Sep. 25, 2008

with DO, the animals are so excitable that they go into 0081. The novel approach to designing and synthesizing frequent convulsions when stimulated. Skinlesions, ulcers on new analogs of Venlafaxine and related compounds through the paws and muzzles, and necrosis of the tails appear. The incorporation of deuterium disclosed herein may generate animals also become very aggressive; males becoming novel monoamine reuptake inhibitors with unexpected and almost unmanageable. When about 30%, of the body water non-obvious improvements of pharmacological, pharmaco has been replaced with DO, the animals refuse to eat and kinetic and toxicological properties in comparison to the non become comatose. Their body weight drops sharply and their isotopically enriched monoamine reuptake inhibitors. metabolic rates drop far below normal, with death occurring I0082 Both N-methyl groups, the single O-methyl, and at about 30 to about 35% replacement with D.O. The effects several sites on the cyclohexyl ring of Venlafaxine are now are reversible unless more than thirty percent of the previous known to be sites of cytochrome Paso metabolism. The tox body weight has been lost due to D.O. Studies have also icities of all resultant metabolites are not known. Further shown that the use of DO can delay the growth of cancer cells more, because polymorphically expressed CYPs such as and enhance the cytotoxicity of certain antineoplastic agents. 2C19 and 2D6 oxidize Venlafaxine, and because Venlafaxine 0078 Tritium (T) is a radioactive isotope of hydrogen, inhibits the polymorphically expressed CYP2D6, the preven used in research, fusion reactors, neutron generators and tion of Such interactions decreases interpatient variability, radiopharmaceuticals. Mixing tritium with a phosphor pro decreases drug-drug interactions, increases T, decreases vides a continuous light source, a technique that is commonly the necessary C, and improves several other ADMET used in wristwatches, compasses, rifle sights and exit signs. It parameters. For example, the half-life of Venlafaxine ranges was discovered by Rutherford, Oliphant and Harteck in 1934, from 3–7 hours. The equipotent metabolite, O-demethylated and is produced naturally in the upper atmosphere when venlafaxine (ODV), has a half-life averaging 11 hours. Vari cosmic rays react with H molecules. Tritium is a hydrogen ous deuteration patterns can be used to a) alter the ratio of atom that has 2 neutrons in the nucleus and has an atomic active metabolites, b) reduce or eliminate unwanted metabo weight close to 3. It occurs naturally in the environment in lites, c) increase the half-life of the parent drug, and/or d) very low concentrations, most commonly found as TO, a increase the half-life of active metabolites and create a more colorless and odorless liquid. Tritium decays slowly (half effective drug and a safer drug for polypharmacy, whether the life=12.3 years) and emits a low energy beta particle that polypharmacy be intentional or not. High doses of VenalX cannot penetrate the outer layer of human skin. Internal expo afine are often prescribed in order to reach levels capable of Sure is the main hazard associated with this isotope, yet it inhibiting norepinephrine reuptake. Unfortunately, high must be ingested in large amounts to pose a significant health doses are also associated with hypertension. Since these phe risk. As compared with deuterium, a lesser amount of tritium nomena are linked by the pharmaceutical agent rather than the must be consumed before it reaches a hazardous level. pharmacological target, they are theoretically separable by 0079 Deuteration of pharmaceuticals to improve pharma increasing the half-life, thus allowing dosing in a range that cokinetics (PK), pharmacodynamics (PD), and toxicity pro lowers the Cand thus may avoid triggering the mechanism files, has been demonstrated previously with some classes of leading to hypertension. Further illustrating this point, ven drugs. For example, the DKIE was used to decrease the hepa lafaxine is known to display linear kinetics at the low end of totoxicity of halothane by presumably limiting the production the dose range, 75 mg/day, but displays non-linear kinetics at of reactive species such as trifluoroacetylchloride. However, the high end of the dose range, 400 mg/day, as a result of the this method may not be applicable to all drug classes. For saturation of clearance mechanisms. This non-linearity pro example, deuterium incorporation can lead to metabolic duces an ascending, rather than a flat, dose-response curve for Switching. The concept of metabolic Switching asserts that Venlafaxine. The deuteration approach has strong potential to Xenogens, when sequestered by Phase I enzymes, may bind slow metabolism through the previously saturated mecha transiently and re-bind in a variety of conformations prior to nism allowing linear, more predictable ADMET responses the chemical reaction (e.g., oxidation). This hypothesis is throughout the dose range (which would also be lower via this supported by the relatively vast size of binding pockets in invention). This leads to lesser interpatient variability of the many Phase I enzymes and the promiscuous nature of many type that can lead to the hypertensive effects. metabolic reactions. Metabolic Switching can potentially lead I0083. The compounds disclosed herein have the potential to different proportions of known metabolites as well as alto to uniquely maintain the beneficial aspects of the non-isoto gether new metabolites. This new metabolic profile may pically enriched drugs while Substantially increasing the half impart more or less toxicity. Such pitfalls are non-obvious life (T), lowering the maximum plasma concentration and are not predictable a priori for any drug class. (C) of the minimum efficacious dose (MED), lowering the efficacious dose and thus decreasing the non-mechanism Deuterated Phenethylamine Derivatives related toxicity, and/or lowering the probability of drug-drug interactions. These drugs also have strong potential to reduce 0080 Venlafaxine is a substituted phenethylamine-based the cost-of-goods (COG) owing to the ready availability of SNRI. The carbon-hydrogen bonds of Venlafaxine contain a inexpensive sources of deuterated reagents combined with naturally occurring distribution of hydrogenisotopes, namely previously mentioned potential for lowering the therapeutic 1H or protium (about 99.984.4%), 2H or deuterium (about dose. It has been discovered that deuteration at the N-methyl 0.0156%), and 3H or tritium (in the range between about 0.5 and the O-methyl groups alone, deuteration at the N-methyl and 67 tritium atoms per 1018 protium atoms). Increased and the O-methyl groups in combination, or deuteration of levels of deuterium incorporation may produce a detectable additional sites found to be labile as a result of metabolic Kinetic Isotope Effect (KIE) that could affect the pharmaco Switching are effective in achieving some of the objectives kinetic, pharmacologic and/or toxicologic profiles of Such disclosed herein. SNRIs in comparison with the compound having naturally I0084. In the following embodiments below, further occurring levels of deuterium. embodiments of each are provided, wherein each compound US 2008/02342.57 A1 Sep. 25, 2008

may be substantially a single enantiomer, a mixture of about 0100. In yet another embodiment, at least one of R. R. 90% or more by weight of the (-)-enantiomer and about 10% and R is deuterium; and R, R2, R. R. Rio, and Ra-R27 are or less by weight of the (+)-enantiomer, a mixture of about hydrogen. 90% or more by weight of the (+)-enantiomer and about 10% 0101. In yet another embodiment, R, R2, and R are or less by weight of the (-)-enantiomer, Substantially an indi deuterium; and R. R. R. Ra-Ro, and R-R-7 are hydrogen. vidual diastereomer, or a mixture of about 90% or more by 0102. In yet another embodiment, at least one of R. R. Rs. R, R2, and R is deuterium; and Ra-Rio and Ra-R27 weight of an individual diastereomer and about 10% or less are hydrogen. by weight of any other diastereomer. 0103) In yet another embodiment, R. R. R. R. R. 0085 Also in the following embodiments below, further and Rare deuterium; and Ra-Ro and Ra-R, are hydrogen. embodiments of each are provided, wherein at least one of 0104. In yet another embodiment, at least one of R. R. each R group designated to be deuterium independently has R. R. Ris, and R is deuterium; and R-Ro and R7-R27 deuterium enrichment of no less than about 1%, no less than are hydrogen. about 5%, no less than about 10%, no less than about 20%, no 0105. In yet another embodiment, R. R. R. R. Rs. less than about 50%, no less than about 70%, no less than and Rare deuterium; and R-Ro and R,-R, are hydrogen. about 80%, no less than about 90%, no less than about 95%, 0106. In yet another embodiment, at least one of R. R. or no less than about 98%. R. R. R. R. R. Ris, and R is deuterium; and Ra-Rio I0086. In one embodiment, disclosed herein is a pharma and R17-R27 are hydrogen. ceutically acceptable acid addition salt of a compound having 0107. In yet another embodiment, R. R. R. R. R. structural formula I: R. R. Ris, and Rare deuterium; and Ra-Rio and R7-R27 are hydrogen. 0108. In yet another embodiment, a pharmaceutically (I) acceptable acid addition salt of a compound has a structural formula selected from the group consisting of

H Cl N Y 1.

HO DCO

1. H C 1N wherein R-R-7 are independently selected from the group HO consisting of hydrogen and deuterium; and DCO 0087 at least one of R-R-7 is deuterium. H 0088. In yet another embodiment, at least one of R. R. Y and R is deuterium. C 1 N N. 0089. In yet another embodiment, R. R. and R are deu terium. 0090. In yet another embodiment, at least one of R. R. and R is deuterium. HO 0091. In yet another embodiment, R. R. and R are DCO deuterium. H 0092. In yet another embodiment, at least one of R. R. Y Rs. R, R2, and R1 is deuterium. C 1N D 0093. In yet another embodiment, R. R. R. R. R. D and Rs are deuterium. 0094. In yet another embodiment, at least one of R. R. HO R. R. Ris, and R is deuterium. 0.095. In yet another embodiment, R. R. R. R. Rs. DCO and R are deuterium. H 0096. In yet another embodiment, at least one of R. R. 1. R. R. R. R. R. Ris, and R is deuterium. C 1N D 0097. In yet another embodiment, R. R. R. R. R. D R. R. Ris, and R are deuterium. 0098. In yet another embodiment, at least one of R. R. HO and R is deuterium; and Ra-R, are hydrogen. 0099. In yet another embodiment, R. R. and R are deu DCO terium; and R-R-7 are hydrogen.

US 2008/02342.57 A1 Sep. 25, 2008 12

0123. In yet another embodiment, Ras, Rao, Rio, Rao, Rso -continued Rs. Rs.2, Rss. Rs4 Rss. Rs6, and Rs7 are deuterium; and R-Rs are hydrogen. I0124. In one embodiment, X is selected from the group consisting of halogen, alkylsulfonate, arylsulfonate, perha loalkanesulfonate, CHOSO, and CDOSOs. 0.125. In another embodiment, X is iodide. 0.126 Inyet another embodiment, a compound has a struc HO tural formula selected from the group consisting of DCO

0109. In one embodiment, disclosed herein is a compound having structural formula II:

(II) HO

DCO s

wherein Ras-Rs, are independently selected from the group consisting of hydrogen and deuterium; 0110 at least one of Rs-Rs, is deuterium; and HO 0111 X is a leaving group anion. 0112. In yet another embodiment, at least one of Rs. R. DCO s and Rio is deuterium. 0113. In yet another embodiment, Ras, R, and Ro are deuterium. 0114. In yet another embodiment, at least one of Rao, Rso Rs. Rs.2, Rss. Rs. Rss. Rs6, and Rs7 is deuterium. 0115. In yet another embodiment, Rao, Rso, Rs. Rs. Rs HO Rs. Rss. Rs, and Rs 7 are deuterium. 0116. In yet another embodiment, at least one of Rs. Ro, DCO s Rao R49. Rso Rs1, Rs.2, Rss, RS4 Rss. Rs6, and Rs7 is deute rium. 0117. In yet another embodiment, Ras, Rao, Rio, Rao, Rso Rs. Rs.2, Rss. Rs. Rss. Rs6, and Rs 7 are deuterium. 0118. In yet another embodiment, at least one of Rs. R. and Rio is deuterium; and R-Rs, are hydrogen. HO 0119. In yet another embodiment, Rs. Rao, and Ro are DCO , and deuterium; and R —Rs, are hydrogen. 0120 In yet another embodiment, at least one of Rao, Rso Rs. Rs.2, Rss. Rs. Rss. Rs6, and Rs7 is deuterium; and R Ras are hydrogen. 0121. In yet another embodiment, Rao, Rso, Rs. Rs. Rs Rs. Rss. Rs, and Rs 7 are deuterium; and Ras-Ras are hydro HO gen. 0122. In yet another embodiment, at least one of Rs. Ro, DCO Rao R49. Rso Rs1, Rs.2, Rss, RS4 Rss. Rs6, and Rs7 is deute rium; and Ral-Ras are hydrogen. US 2008/02342.57 A1 Sep. 25, 2008

0127. In one embodiment, disclosed herein is a compound having structural formula III: -continued CH

(III) D.

Dr.O,

DCO CD3 D SK, O

DCO CD3 wherein Rss-Rs are independently selected from the group consisting of hydrogen and deuterium; and D D 0128 at least one of Rss-Rs is deuterium. Dr SK, 0129. In yet another embodiment, at least one of Rss, Rs. O and Reo is deuterium. 0130. In yet another embodiment, Riss Rs, and Reo are deuterium. DCO 0131. In yet another embodiment, at least one of Rs. Roo, CD3 Rso Rs1, and Rs2 is deuterium. 0132. In yet another embodiment, Res R. R.so, Rs, and D Rs are deuterium. K, and 0133. In yet another embodiment, at least one of Rss, Rs. O Roo, Ros, Roo, Rso Rs1, and Rs2 is deuterium. 0134. In yet another embodiment, Riss, Rs. Reo Rs. R. Rso Rs1, and Rs are deuterium. H3CO I0135) In yet another embodiment, at least one of Rs. Rs. and Roo is deuterium; and Re-Rs are hydrogen. CD3 0136. In yet another embodiment, Rss Rso, and Reo are D D deuterium; and Re-Rs are hydrogen. 0.137 In yet another embodiment, at least one of Rs. R. D SK, Rso Rs1, and Rs2 is deuterium; and Rss-R7 and R-7o-R-79 are O hydrogen. 0138. In yet another embodiment, Res R. R.so, Rs, and Rs are deuterium; and Rss-R, and Rzo-R79 are hydrogen. H3CO 0.139. In yet another embodiment, at least one of Rss, Rs. Roo, Ros, Roo, Rso Rs1, and Rs2 is deuterium; and Roll-R67 0142. In one embodiment, disclosed herein is a compound and Rzo-R79 are hydrogen. having structural formula IV: 0140. In yet another embodiment, Rss Rso, Rao, Rs. Roo, (IV)

Rso Rs1, and Rs are deuterium; and Re-R7 and R-7o-R79 are R103 hydrogen. 0141. In yet another embodiment, a compound has a struc tural formula selected from the group consisting of

DCO US 2008/02342.57 A1 Sep. 25, 2008

0143 or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein Rs-Ro, are independently -continued selected from the group consisting of hydrogen and deute p rium; and N 0144 at least one of Rs-Ro, is deuterium. YCD, 0145. In yet another embodiment, at least one of Ro, Ros, and Roa is deuterium. 0146 In yet another embodiment, Rio, Ros, and Roa are HO deuterium. 0147 In yet another embodiment, at least one of Ro, HO Rios, Ro4, Rios, Rios, and Roz is deuterium. 0148. In yet another embodiment, Rio, Ros, Rio, Ros, Ros, and Ro, are deuterium. D N 0149. In yet another embodiment, at least one of Roo and D N Ro is deuterium. 0150. In yet another embodiment, Roo and Ro are deu terium. 0151. In yet another embodiment, at least one of Roo, HO Rio Rio, Rios, and Roa is deuterium. HO 0152. In yet another embodiment, Roo, Ro Ro, Ros, and Roa are deuterium. 0153. In yet another embodiment, at least one of Roo, CD3 Rio, Rio2, Rios. Ro4, Rios. Roo, and Rio 7 is deuterium. R 0154 In yet another embodiment, Roo, Ro Ro, Ros, D N Ro4, Rios. Rios, and Roz are deuterium. 0155. In yet another embodiment, at least one of Ro, Rios, and Rio is deuterium, and Rss-Roi, Rios, Roo, and HO Rare hydrogen. 0156. In yet another embodiment, Rio, Ros, and Roa are HO deuterium, and Rss-Roi, Rios, Rog, and Roz. 0157. In yet another embodiment, at least one of Ro, Rios, Ro4, Rios. Rios, and Rio, is deuterium, and Rss-Rio CD3 are hydrogen. D N 0158. In yet another embodiment, Rio, Ros, Rio, Ros, D NCD, Ros, and Ro, are deuterium, and Rs-Ro are hydrogen. 0159. In yet another embodiment, at least one of Roo and Ro is deuterium, and Rss-Roo and Ro-Ro, are hydrogen. HO 0160 In yet another embodiment, Roo and Ro are deu HO terium, and Rs-Roo and Ro-Ro, are hydrogen. 0161 In yet another embodiment, at least one of Roo, N Rio Rio2, Rios, and Roa is deuterium, and Rss-Roo, Rios, N Ros, and Rio, are hydrogen. D 0162. In yet another embodiment, Roo, Rio, Rio, Ros, and Rio are deuterium, and Rss-Roo. Rios. Rios, and Rio, are HO hydrogen. 0163. In yet another embodiment, at least one of Roo-Ro, HO is deuterium, and Rs-R are hydrogen. p 0164. In yet another embodiment, Roc-Ro, are deute N N rium, and Rss-Roo are hydrogen. D 0.165. In yet another embodiment, a compound has a struc tural formula selected from the group consisting of HO

HO CD3 CD3 N N YCD, D

HO HO

HO HO US 2008/02342.57 A1 Sep. 25, 2008 15

-continued -continued

D N D N D

HO HO R CD3 D N

HO CD3 D N D YCD, D

HO N Sn D

HO D D p N SN D

HO D D CD3

HO US 2008/02342.57 A1 Sep. 25, 2008 16

-continued -continued CD3 R CD3 R D SN D D N D D D D HO HO

HO D D HO D D D D D

CD3 CD3 D N D N D SCD, D NCD, D D D D HO HO D HO D D HO D D D D

N N N N D D D

HO HO

HO HO D D p NP N N N D D D

HO HO

D D CD3 CD3 N YCD, N NCD, D D D

HO HO

D D

D N D N D N D N D D D

HO HO

HO HO D

US 2008/02342.57 A1 Sep. 25, 2008

-continued -continued CD3 CD3 D D l N D D N SN D D D D D

HO D D HO HO D

US 2008/02342.57 A1 Sep. 25, 2008 20

mula II, wherein Ras-Rs, are independently selected from the -continued group consisting of hydrogen and deuterium, and X is a CD3 leaving group anion, under conditions suitable to form a D compound having structural formula I, as set forth below:

(II) or a pharmaceutically acceptable salt, Solvate, or prodrug thereof. 0166 In yet another embodiment, a compound has the structural formula:

CD3 YCD,

HO (I) or a pharmaceutically acceptable salt, Solvate, or prodrug 0172 Compounds having structural formula II can be pre thereof. pared by methods known to one of skill in the art or following 0167. In a further embodiment, said compound contains procedures similar to those described in the Example section about 50% or more by weight of the (-)-enantiomer of said herein and routine modifications thereof. Compound II is compound and about 50% or less by weight of (+)-enantiomer contacted with a nucleophile at an elevated temperature. of said compound or about 50% or more by weight of the Nucleophiles contemplated for use in the practice of this (+)-enantiomer of said compound and about 50% or less by particular disclosure include, but are not limited to, 2-amino weight of (-)-enantiomer of said compound. ethanol, 3-aminopropanol. 1,8-diazabicyclo5.4.0]undec 0168 In another aspectare processes for preparing a com 7ene, 1,4-diazabicyclo2.2.2]octane, trialkylamine, sodium pound having structural formula I as serotonin and/or nore borohydride, lithium borohydride, lithium trialkylborohy pinephrine receptor and/or transporter modulators, or other dride, lithium hydride, potassium hydride, and Sodium pharmaceutically acceptable derivatives Such as prodrug hydride. Solvents contemplated for use in the practice of this derivatives, or individual isomers and mixture of isomers or particular disclosure include, but are not limited to, polar enantiomers thereof. Solvents such as 1,4-dioxane, acetone, acetonitrile, dimethyl 0169. In another embodiment are disclosed processes for formamide, dimethylacetamide, N-methylpyrrolidone, dim preparing a compound having structural formula II, or indi ethyl sulfoxide, or suitable mixtures thereof. The process is vidual isomers and mixture of isomers or enantiomers carried out at a temperature from about 0°C. to about 500°C., thereof. for about 0.01 to about 240 hours, at a pH from about 1 to 0170 In another embodiment is provided the use of a about 14, at a pressure from about 1 mBar to about 350 Bar. compound having structural formula II for the manufacture of 0173. In certain embodiments, compounds having struc a compound having structural formula I. tural formula II are contacted with a nucleophile at an 0171 In one embodiment, disclosed herein is a process for elevated temperature in the presence of microwave radiation. preparing a compound having structural formula I wherein Nucleophiles contemplated for use in the practice of this R-R2, are independently selected from the group consisting particular disclosure include, but are not limited to, 2-amino of hydrogen and deuterium. Such a process can be performed, ethanol, 3-aminopropanol. 1,8-diazabicyclo5.4.0]undec for example, by reacting a compound having structural for 7ene, 1,4-diazabicyclo2.2.2]octane, trialkylamine, sodium US 2008/02342.57 A1 Sep. 25, 2008

borohydride, lithium borohydride, lithium trialkylborohy include, but are not limited to, lithium deuteroxide, lithium dride, lithium hydride, potassium hydride, and sodium hydroxide, Sodium deuteroxide, sodium hydroxide, potas hydride. Solvents contemplated for use in the practice of this sium deuteroxide, potassium hydroxide, lithium formate, particular disclosure include, but are not limited to, polar potassium formate, and sodium formate. Solvents contem Solvents such as 1,4-dioxane, acetone, acetonitrile, dimethyl plated for use in the practice of this particular disclosure formamide, dimethylacetamide, N-methylpyrrolidone, dim include, but are not limited to, polar solvents such as water, ethyl sulfoxide, or suitable mixtures thereof. The process is deuterium oxide, methanol, d-methanol, formic acid, d-for carried out in the presence of focused microwave radiation mic acid, 1,4-dioxane, acetone, acetonitrile, dimethylforma using a quartz reactor at a pressure from about 1 Bar to about mide, dimethylacetamide, N-methylpyrrolidone, dimethyl 25 Bar, a power setting from about 1 W per liter of solvent to sulfoxide, or any suitable mixtures thereof. The process is about 900 W per liter of solvent, at a temperature from about carried out at a temperature from about 0°C. to about 500°C., 0° C. to about 500° C., for about 0.01 to about 5 hours, at a pH for about 0.01 to about 240 hours, at a pH from about 1 to from about 1 to about 14. about 14, at a pressure from about 1 mBar to about 350 Bar. 0.174. In another embodiment is provided the use of a 0177. In certain embodiments, compounds having struc compound having structural formula III for the manufacture tural formula III are contacted with a nucleophile at an of a compound having structural formula I. elevated temperature in the presence of microwave radiation. 0.175. In one embodiment, disclosed herein is a process for Additives contemplated for use in the practice of this particu preparing a compound having structural formula I wherein lar disclosure include, but are not limited to, lithium deuteroX R-R-7 are independently selected from the group consisting ide, lithium hydroxide, sodium deuteroxide, sodium hydrox of hydrogen and deuterium. Such a process can be performed, ide, potassium deuteroxide, potassium hydroxide, lithium for example, by reacting a compound having structural for formate, potassium formate, and sodium formate. Solvents mula III, wherein Rss-Rs are independently selected from contemplated for use in the practice of this particular disclo the group consisting of hydrogen and deuterium, under con Sure include, but are not limited to, polar solvents such as ditions suitable to form a compound having structural for water, deuterium oxide, methanol, da-methanol, formic acid, mula I, as set forth below: d-formic acid, 1,4-dioxane, acetone, acetonitrile, dimethyl formamide, dimethylacetamide, N-methylpyrrolidone, dim ethylsulfoxide, or any suitable mixtures thereof. The process is carried out in the presence of focused microwave radiation using a quartz, reactor at a pressure from about 1 Bar to about 25 Bar, a power setting from about 1 W per liter of solvent to about 900 W per liter of solvent, at a temperature from about 0° C. to about 500° C., for about 0.01 to about 5 hours, at a pH from about 1 to about 14. 0178. In certain embodiments, a compound as disclosed herein contains about 60% or more by weight of the (-)- enantiomer of the compound and about 40% or less by weight of (+)-enantiomer of the compound. In certain embodiments, a compound as disclosed herein contains about 70% or more by weight of the (-)-enantiomer of the compound and about 30% or less by weight of (+)-enantiomer of the compound. In certain embodiments, a compound as disclosed herein con

(III) tains about 80% or more by weight of the (-)-enantiomer of the compound and about 20% or less by weight of (+)-enan tiomer of the compound. In certain embodiments, a com pound as disclosed herein contains about 90% or more by weight of the (-)-enantiomer of the compound and about 10% or less by weight of the (+)-enantiomer of the compound. In certain embodiments, a compound as disclosed herein con tains about 95% or more by weight of the (-)-enantiomer of the compound and about 5% or less by weight of (+)-enanti omer of the compound. In certain embodiments, a compound as disclosed herein contains about 99% or more by weight of the (-)-enantiomer of the compound and about 1% or less by weight of (+)-enantiomer of the compound. 0179 The deuterated compounds as disclosed herein may also contain less prevalent isotopes for other elements, (I) including, but not limited to, 'Cor'C for carbon, S, S. 0176 Compounds having structural formula III can be or S for sulfur, 'N for nitrogen, and ''O or 'O for oxygen. prepared by methods known to one of skill in the art or 0180. In certain embodiments, without being bound by following procedures similar to those described in the any theory, a compound disclosed herein may expose a Example section herein and routine modifications thereof. patient to a maximum of about 0.000005% DO or about Compound III is contacted with formic acid ord-formic acid 0.00001% DHO, assuming that all of the C-D bonds in the and an additive at an elevated temperature. Additives contem compound as disclosed hereinare metabolized and released as plated for use in the practice of this particular disclosure DO or DHO. This quantity is a small fraction of the naturally US 2008/02342.57 A1 Sep. 25, 2008 22 occurring background levels of DO or DHO in circulation. In incorporation rates are determined by equilibrium conditions, certain embodiments, the levels of DO shown to cause tox and may be highly variable depending on the reaction condi icity in animals is much greater than even the maximum limit tions. Synthetic techniques, where tritium or deuterium is of exposure because of the deuterium enriched compound as directly and specifically inserted by tritiated or deuterated disclosed herein. Thus, in certain embodiments, the deute reagents of known isotopic content, may yield high tritium or rium-enriched compound disclosed herein should not cause deuterium abundance, but can be limited by the chemistry any additional toxicity because of the use of deuterium. required. Exchange techniques, on the other hand, may yield 0181. In one embodiment, the deuterated compounds dis lower tritium or deuterium incorporation, often with the iso closed herein maintain the beneficial aspects of the corre tope being distributed over many sites on the molecule. sponding non-isotopically enriched molecules while Substan 0183 Compounds having the structural formulae below tially increasing the maximum tolerated dose, decreasing can be prepared by methods known to one of skill in the art or toxicity, increasing the half-life (T), lowering the maxi following procedures similar to those described in the mum plasma concentration (C) of the minimum effica Example section herein and routine modifications thereof. In cious dose (MED), lowering the efficacious dose and thus the Schemes below, deuterated intermediates are either com decreasing the non-mechanism-related toxicity, and/or low mercially available or can be prepared by methods known to ering the probability of drug-drug interactions. one of skill in the art or following procedures similar to those 0182 Isotopic hydrogen can be introduced into a com described in the Example section herein and routine modifi pound as disclosed herein by synthetic techniques that cations thereof. employ deuterated reagents, whereby incorporation rates are 0.184 For example, a compound having structural formula pre-determined; and/or by exchange techniques, wherein I can be prepared as shown in Scheme 1.

Scheme 1

US 2008/02342.57 A1 Sep. 25, 2008

0185. Phenol 4 reacts with methyl iodide and a deproto 0189 Deuterium can be incorporated to different posi nating agent, such as potassium carbonate, to give ether 5, tions synthetically, according to the synthetic procedures as which reacts with cyclohexanone 6 in the presence of a depro shown in Scheme 1, by using appropriate deuterated interme tonating agent, such as Sodium hydroxide, and a phase trans diates. For example, to introduce deuterium at one or more fer catalyst, Such tetra-n-butyl ammonium hydrogen Sulfate, positions selected from R2s, R29. Rao R49, Rso Rs1, Rs.2, Rss. to give nitrile 7. Compound 7 is reduced to aminoalcohol 8 Rs. Rss, Rs, and Rs.7 methyl iodide with the corresponding under a hydrogen atmosphere in the presence of a catalyst, deuterium Substitutions can be used. Such as rhodium on alumina. Alternatively, alcohol 7 is dis 0190. By way of another example, a compound having Solved in ammonia in methanol and reduced to aminoalcohol structural formula III or structural formula I can be prepared 8 using a continuous flow hydrogenation reactor equipped as shown in Scheme 3. with a Raney Ni catalyst cartridge. Compound 8 reacts with excess methyl iodide to give the corresponding quaternary salt II (similar to the reaction step shown in scheme 2) which is demethylated with a nucleophile, Such as 2-aminoethanol or 3-aminopropanol, at an elevated temperature to produce the compound of formula I as the free base. The hydrochlo ride salt of the compound of Formula I can be prepared by methods known in the art.

0186 Deuterium can be incorporated to different posi tions synthetically, according to the synthetic procedures as shown in Scheme 1, by using appropriate deuterated interme diates. For example, to introduce deuterium at one or more positions selected from R, R2, R. R. R. R. R. Rs. and R, methyl iodide with the corresponding deuterium Substitutions can be used. 0187. By way of another example, a compound having structural formula II can be prepared as shown in Scheme 2.

II 0191 Compound 10 is prepared as in Scheme 1 and reacts with formic acid and formaldehyde at an elevated tempera 0188 Compound 9 is prepared as in Scheme 1 and reacts ture to produce the compound of formula III. The compound with excess methyl iodide to produce the compound of for of formula III reacts with formic acid and a deprotonating mula II as the iodide salt. agent, such as sodium hydroxide or sodium formate, to pro US 2008/02342.57 A1 Sep. 25, 2008 24 duce the compound of formula I. The hydrochloride salt of the York, 1994, pp. 1119-1190. Such chiral centers, chiral axes, compound of formula I can be prepared by methods known in and chiral planes may be of either the (R) or (S) configuration, the art. or may be a mixture thereof. 0.192 Deuterium can be incorporated to different posi 0.197 Another method for characterizing a composition tions synthetically, according to the synthetic procedures as containing a compound having at least one chiral center is by the effect of the composition on a beam of polarized light. shown in Scheme 3, by using appropriate deuterated interme When a beam of plane polarized light is passed through a diates. For example, to introduce deuterium at one or more Solution of a chiral compound, the plane of polarization of the positions selected from Rs. Roo, Rso Rs, and Rs formic light that emerges is rotated relative to the original plane. This acid and formaldehyde with the corresponding deuterium phenomenon is known as optical activity, and compounds that Substitutions can be used. To introduce deuterium at one or rotate the plane of polarized light are said to be optically more positions selected from Rss, Rs, and Ro, methyl iodide active. One enantiomer of a compound will rotate the beam of with the corresponding deuterium Substitutions can be used. polarized light in one direction, and the other enantiomer will 0193 By way of example, a compound having structural rotate the beam of light in the opposite direction. The enan formula IV or structural formula can be prepared as shown in tiomer that rotates the polarized light in the clockwise direc Scheme 4. tion is the (+) enantiomer and the enantiomer that rotates the polarized light in the counterclockwise direction is the (-)

enantiomer. Included within the scope of the compositions described herein are compositions containing between 0 and 100% of the (+) and/or (-) enantiomer of compounds dis closed herein. 0198 Where a compound as disclosed herein contains an alkenyl or alkenylene group, the compound may exist as one or mixture of geometric cis/trans (or Z/E) isomers. Where structural isomers are interconvertible via a low energy bar rier, the compound as disclosed herein may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in the compound as disclosed hereinthat contains for example, an imino, keto, or oxime group; or so-called Valence tautomerism in the compound that contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. 0199 The compounds disclosed herein may be enantio merically pure. Such as a single enantiomer or a single dias tereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers, a racemic mixture, or a diastereomeric mixture. As such, one of skill in the art will recognize that administra tion of a compound in its (R) form is equivalent, for com pounds that undergo epimerization in Vivo, to administration of the compound in its (S) form. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a Suitable optically pure precursor or resolution of the racemate using, for example, chiral chroma tography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts fol lowed by separation. 0200 When the compound as disclosed herein contains an acidic or basic moiety, it may also disclosed as a pharmaceu tically acceptable salt (See, Berge et al., J. Pharm. Sci. 1977, 66, 1-19; and “Handbook of Pharmaceutical Salts, Properties, IV and Use.” Stah and Wermuth, Ed.; Wiley-VCH and VHCA, Zurich, 2002). 0201 Suitable acids for use in the preparation of pharma 0194 Compound II is prepared as in Scheme 1-3 and ceutically acceptable acid addition salts include, but are not reacts with a demethylating agent to produce the compound limited to, acetic acid, 2,2-dichloroacetic acid, acylated of formula IV. amino acids, adipic acid, alginic acid, ascorbic acid, L-aspar 0.195 Deuterium can be incorporated to different posi tic acid, benzenesulfonic acid, benzoic acid, 4-acetamidoben tions synthetically, according to the synthetic procedures as Zoic acid, boric acid, (+)-camphoric acid, camphorsulfonic shown in Scheme 4, by using appropriate deuterated interme acid, (+)-(1S)-camphor-10-Sulfonic acid, capric acid, caproic diates as described in Schemes 1-3. acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, 0196. It is to be understood that the compounds disclosed cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2- herein may contain one or more chiral centers, chiral axes, disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethane and/or chiral planes, as described in "Stereochemistry of Car Sulfonic acid, formic acid, fumaric acid, galactaric acid, gen bon Compounds' Eliel and Wilen, John Wiley & Sons, New tisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic US 2008/02342.57 A1 Sep. 25, 2008 acid, L-glutamic acid, C.-OXO-glutaric acid, glycolic acid, hip Pharm. Sci. 1996, 4, 49-59; Gangwar et al., Des. Biopharm. puric acid, hydrobromic acid, hydrochloric acid, hydroiodic Prop. Prodrugs Analogs, 1977, 409–421; Nathwani and acid, (t)-L-lactic acid, (t)-DL-lactic acid, lactobionic acid, Wood, Drugs 1993, 45,866-94: Sinhababu and Thakker, Adv. lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (+)- Drug Delivery Rev. 1996, 19, 241-273; Stella et al., Drugs DL-mandelic acid, methanesulfonic acid, naphthalene-2-sul 1985, 29, 455-73; Tan et al., Adv. Drug Delivery Rev. 1999, fonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2- 39, 117-151; Taylor, Adv. Drug Delivery Rev. 1996, 19, 131 naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic 148; Valentino and Borchardt, Drug Discovery Today 1997.2, acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, phosphoric acid, L-pyroglutamic acid, Saccharic acid, sali 39, 63-80; Waller et al., Br. J. Clin. Pharmac. 1989, 28, cylic acid, 4-amino-salicylic acid, sebacic acid, Stearic acid, 497-507. Succinic acid, Sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, Pharmaceutical Compositions and Valeric acid. 0204 Disclosed herein are pharmaceutical compositions 0202 Suitable bases for use in the preparation of pharma comprising a compound as disclosed herein as an active ceutically acceptable basic addition salts, including, but not ingredient, or a pharmaceutically acceptable salt, Solvate, or limited to, inorganic bases, such as magnesium hydroxide, prodrug thereof, in combination with one or more pharma calcium hydroxide, potassium hydroxide, Zinc hydroxide, or ceutically acceptable excipients or carriers. Sodium hydroxide; and organic bases, such as primary, sec 0205 Disclosed herein are pharmaceutical compositions ondary, tertiary, and quaternary, aliphatic and aromatic in modified release dosage forms, which comprise a com amines, including L-arginine, benethamine, benzathine, cho pound as disclosed herein and one or more release controlling line, deanol, diethanolamine, diethylamine, dimethylamine, excipients or carriers as described herein. Suitable modified dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, release dosage vehicles include, but are not limited to, hydro ethanolamine, ethylamine, ethylenediamine, isopropy philic or hydrophobic matrix devices, water-soluble separat lamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, ing layer coatings, enteric coatings, osmotic devices, multi L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, particulate devices, and combinations thereof. The methylamine, piperidine, piperazine, propylamine, pyrroli pharmaceutical compositions may also comprise non-release dine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, controlling excipients or carriers. quinoline, isoquinoline, secondary amines, triethanolamine, 0206. Further disclosed herein are pharmaceutical compo trimethylamine, triethylamine, N-methyl-D-glucamine, sitions in enteric coated dosage forms, which comprise a 2-amino-2-(hydroxymethyl)-1,3-propanediol. and compound as disclosed herein and one or more release con tromethamine. trolling excipients or carriers for use in an enteric coated 0203 The compound as disclosed herein may also be dosage form. The pharmaceutical compositions may also designed as a prodrug, which is a functional derivative of the comprise non-release controlling excipients or carriers. compound as disclosed herein and is readily convertible into 0207. Further disclosed herein are pharmaceutical compo the parent compound in vivo. Prodrugs are often useful sitions in effervescent dosage forms, which comprise a com because, in Some situations, they may be easier to administer pound as disclosed herein and one or more release controlling than the parent compound. They may, for instance, be bio excipients or carriers for use in an effervescent dosage form. available by oral administration whereas the parent com The pharmaceutical compositions may also comprise non pound is not. The prodrug may also have enhanced solubility release controlling excipients or carriers. in pharmaceutical compositions over the parent compound. A 0208. Additionally disclosed are pharmaceutical compo prodrug may be converted into the parent drug by various sitions in a dosage form that has an instant releasing compo mechanisms, including enzymatic processes and metabolic nent and at least one delayed releasing component, and is hydrolysis. See Harper, Progress in Drug Research 1962, 4, capable of giving a discontinuous release of the compound in 221-294; Morozowich etal. in “Design of Biopharmaceutical the form of at least two consecutive pulses separated in time Properties through Prodrugs and Analogs. Roche Ed., from 0.1 up to 24 hours. The pharmaceutical compositions APHA Acad. Pharm. Sci. 1977: “Bioreversible Carriers in comprise a compound as disclosed herein and one or more Drug in Drug Design, Theory and Application. Roche Ed., release controlling and non-release controlling excipients or APHA Acad. Pharm. Sci. 1987: “Design of Prodrugs.” Bund carriers, such as those excipients or carriers suitable for a gaard, Elsevier, 1985; Wang et al., Curr: Pharm. Design 1999, disruptable semi-permeable membrane and as swellable sub 5,265-287: Pauletti et al., Adv. Drug. Delivery Rev. 1997,27, StanceS. 235-256; Mizen et al., Pharm. Biotech. 1998, 11, 345-365; 0209 Disclosed herein also are pharmaceutical composi Gaignault et al., Pract. Med. Chem. 1996, 671-696; tions in a dosage form for oral administration to a Subject, Asgharnejad in “Transport Processes in Pharmaceutical Sys which comprise a compound as disclosed herein and one or tems. Amidon et al., Ed., Marcell Dekker, 185-218, 2000; more pharmaceutically acceptable excipients or carriers, Balant et al., Eur: J. Drug Metab. Pharmacokinet. 1990, 15, enclosed in an intermediate reactive layer comprising a gas 143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, tric juice-resistant polymeric layered material partially neu 39, 183-209; Browne, Clin. Neuropharmacol. 1997, 20, 1-12; tralized with alkali and having cation exchange capacity and Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39: Bundgaard, a gastric juice-resistant outer layer. Controlled Drug Delivery 1987, 17, 179–96: Bundgaard, Adv. 0210 Pharmaceutical compositions are provided herein Drug Delivery Rev. 1992, 8, 1-38; Fleisher et al., Adv. Drug which comprise about 0.1 to about 1000 mg, about 1 to about Delivery Rev. 1996, 19, 115-130; Fleisher et al., Methods 500 mg, about 2 to about 100 mg, about 1 mg, about 2 mg, Enzymol. 1985, 112,360-381: Farquhar et al., J. Pharm. Sci. about 3 mg, about 5 mg, about 10 mg, about 20 mg, about 30 1983, 72, 324-325; Freeman et al., J. Chem. Soc., Chem. mg, about 40 mg, about 50 mg, about 100 mg, about 500 mg Commun. 1991, 875-877: Friis and Bundgaard, Eur: J. of one or more compounds as disclosed herein. US 2008/02342.57 A1 Sep. 25, 2008 26

0211. In certain embodiments, the pharmaceutical com 0219. Once improvement of the patient's conditions has positions are in the form of immediate-release capsules for occurred, a maintenance dose is administered if necessary. oral administration, and may further comprise cellulose, iron Subsequently, the dosage or the frequency of administration, oxides, lactose, magnesium Stearate, and sodium starch gly or both, can be reduced, as a function of the symptoms, to a colate. level at which the improved disorder is retained. Patients can, 0212. In certain embodiments, the pharmaceutical com however, require intermittent treatment on a long-term basis positions are in the form of delayed-release capsules for oral upon any recurrence of symptoms. administration, and may further comprise cellulose, ethylcel 0220 Any of the pharmaceutical formulations described lulose, gelatin, hypromellose, iron oxide, and titanium diox herein can comprise (as the active component) at least one of the hydrochloride salt Forms A-F of formula I, or further ide. contain (as the active component) Substantially only one or 0213. In certain embodiments, the pharmaceutical com positions are in the form of enteric coated delayed-release more of the hydrochloride salt Forms A-F of formula I. tablets for oral administration, and may further comprise A. Oral Administration carnauba wax, crospovidone, diacetylated monoglycerides, ethylcellulose, hydroxypropyl cellulose, hypromellose 0221) The pharmaceutical compositions disclosed herein phthalate, magnesium Stearate, mannitol, Sodium hydroxide, may be provided in Solid, semisolid, or liquid dosage forms Sodium Stearyl fumarate, talc, titanium dioxide, and yellow for oral administration. As used herein, oral administration ferric oxide. also include buccal, lingual, and Sublingual administration. 0214. In certain embodiments, the pharmaceutical com Suitable oral dosage forms include, but are not limited to, positions are in the form of enteric coated delayed-release tablets, capsules, pills, troches, lozenges, pastilles, cachets, tablets for oral administration, and may further comprise pellets, medicated chewing gum, granules, bulk powders, calcium Stearate, crospovidone, hydroxypropyl methylcellu effervescent or non-effervescent powders or granules, solu lose, iron oxide, mannitol, methacrylic acid copolymer, tions, emulsions, Suspensions, Solutions, wafers, sprinkles, polysorbate 80, povidone, propylene glycol, Sodium carbon elixirs, and syrups. In addition to the active ingredient(s), the ate, sodium lauryl Sulfate, titanium dioxide, and triethyl cit pharmaceutical compositions may contain one or more phar rate. maceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting 0215. The compound as disclosed herein may be admin agents, lubricants, glidants, coloring agents, dye-migration istered alone or in combination with one or more other active inhibitors, Sweetening agents, and flavoring agents. ingredients. Pharmaceutical compositions comprising a com 0222 Binders or granulators impart cohesiveness to a tab pound disclosed herein may be formulated in various dosage let to ensure the tablet remaining intact after compression. forms for oral, parenteral, and topical administration. The Suitable binders or granulators include, but are not limited to, pharmaceutical compositions may also be formulated as a starches, such as corn Starch, potato starch, and pre-gelati modified release dosage form, including delayed-, extended-, nized starch (e.g., STARCH 1500); gelatin: sugars, such as prolonged-, Sustained-, pulsatile-, controlled-, accelerated Sucrose, glucose, dextrose, molasses, and lactose; natural and fast-, targeted-, programmed-release, and gastric retention Synthetic gums, such as acacia, alginic acid, alginates, extract dosage forms. These dosage forms can be prepared according of Irish moss, Panwar gum, ghatti gum, mucilage of isabgol to conventional methods and techniques known to those husks, carboxymethylcellulose, methylcellulose, polyvi skilled in the art (see, Remington. The Science and Practice of nylpyrrolidone (PVP), Veegum, larch arabogalactan, pow Pharmacy, supra; Modified-Release Drug Delivery Technol dered tragacanth, and guar gum, celluloses, such as ethyl ogy, Rathbone et al., Eds. Drugs and the Pharmaceutical cellulose, cellulose acetate, carboxymethyl cellulose cal Science, Marcel Dekker, Inc.: New York, N.Y., 2002; Vol. cium, Sodium carboxymethyl cellulose, methyl cellulose, 126). hydroxyethylcellulose (HEC), hydroxypropylcellulose 0216. The pharmaceutical compositions disclosed herein (HPC), hydroxypropyl methylcellulose (HPMC); microcrys may be administered at once, or multiple times at intervals of talline celluloses, such as AVICEL-PH-101, AVICEL-PH time. It is understood that the precise dosage and duration of 103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Mar treatment may vary with the age, weight, and condition of the cus Hook, Pa.); and mixtures thereof. Suitable fillers include, patient being treated, and may be determined empirically but are not limited to, talc, calcium carbonate, microcrystal using known testing protocols or by extrapolation from in line cellulose, powdered cellulose, dextrates, kaolin, manni vivo or in vitro test or diagnostic data. It is further understood tol, silicic acid, Sorbitol, Starch, pre-gelatinized starch, and that for any particular individual, specific dosage regimens mixtures thereof. The binder or filler may be present from should be adjusted over time according to the individual need about 50 to about 99% by weight in the pharmaceutical com and the professional judgment of the person administering or positions disclosed herein. Supervising the administration of the formulations. 0223 Suitable diluents include, but are not limited to, 0217. In the case wherein the patient's condition does not dicalcium phosphate, calcium sulfate, lactose, Sorbitol, improve, upon the doctor's discretion the compounds may be Sucrose, inositol, cellulose, kaolin, mannitol, Sodium chlo administered chronically, that is, for an extended period of ride, dry starch, and powdered Sugar. Certain diluents, such as time, including throughout the duration of the patient’s life in mannitol, lactose, Sorbitol. Sucrose, and inositol, when order to ameliorate or otherwise control or limit the symp present in Sufficient quantity, can impart properties to some toms of the patient's disease or condition. compressed tablets that permit disintegration in the mouth by 0218. In the case wherein the patient's status does chewing. Such compressed tablets can be used as chewable improve, upon the doctor's discretion the compounds may be tablets. given continuously or temporarily Suspended for a certain 0224 Suitable disintegrants include, but are not limited to, length of time (i.e., a "drug holiday'). agar, bentonite; celluloses. Such as methylcellulose and car US 2008/02342.57 A1 Sep. 25, 2008 27 boxymethylcellulose; wood products; natural sponge; cation film-coated tablets. Enteric-coated tablets are compressed exchange resins; alginic acid: gums, such as guar gum and tablets coated with substances that resist the action of stom Veegum HV. citrus pulp, cross-linked celluloses, such as ach acid but dissolve or disintegrate in the intestine, thus croScarmellose; cross-linked polymers, such as crospovi protecting the active ingredients from the acidic environment done; cross-linked Starches; calcium carbonate; microcrys of the stomach. Enteric-coatings include, but are not limited talline cellulose, Such as sodium starch glycolate; polacrilin to, fatty acids, fats, phenylsalicylate, waxes, shellac, ammo potassium; Starches, such as corn starch, potato starch, tapi niated shellac, and cellulose acetate phthalates. Sugar-coated oca starch, and pre-gelatinized starch; clays; aligns; and mix tablets are compressed tablets Surrounded by a Sugar coating, tures thereof. The amount of disintegrant in the pharmaceu which may be beneficial in covering up objectionable tastes tical compositions disclosed herein varies upon the type of or odors and in protecting the tablets from oxidation. Film formulation, and is readily discernible to those of ordinary coated tablets are compressed tablets that are covered with a skill in the art. The pharmaceutical compositions disclosed thin layer or film of a water-soluble material. Film coatings herein may contain from about 0.5 to about 15% or from include, but are not limited to, hydroxyethylcellulose, sodium about 1 to about 5% by weight of a disintegrant. carboxymethylcellulose, polyethylene glycol 4000, and cel 0225 Suitable lubricants include, but are not limited to, lulose acetate phthalate. Film coating imparts the same gen calcium Stearate; magnesium Stearate; mineral oil; light min eral characteristics as Sugar coating. Multiple compressed eral oil; glycerin; Sorbitol; mannitol; glycols, such as glycerol tablets are compressed tablets made by more than one com behenate and polyethylene glycol (PEG); stearic acid; pression cycle, including layered tablets, and press-coated or Sodium lauryl Sulfate; talc, hydrogenated vegetable oil, dry-coated tablets. including peanut oil, cottonseed oil, Sunflower oil, Sesame oil, 0229. The tablet dosage forms may be prepared from the olive oil, corn oil, and soybean oil; Zinc Stearate; ethyl oleate; active ingredient in powdered, crystalline, or granular forms, ethyl laureate; agar, starch, lycopodium; silica or silica gels, alone or in combination with one or more carriers or excipi such as AEROSIL(R) 200 (W.R. Grace Co., Baltimore, Md.) ents described herein, including binders, disintegrants, con and CAB-O-SILR) (Cabot Co. of Boston, Mass.); and mix trolled-release polymers, lubricants, diluents, and/or colo tures thereof. The pharmaceutical compositions disclosed rants. Flavoring and Sweetening agents are especially useful herein may contain about 0.1 to about 5% by weight of a in the formation of chewable tablets and lozenges. lubricant. 0230. The pharmaceutical compositions disclosed herein 0226 Suitable glidants include colloidal silicon dioxide, may be disclosed as Soft or hard capsules, which can be made CAB-O-SIL(R) (Cabot Co. of Boston, Mass.), and asbestos from gelatin, methylcellulose, starch, or calcium alginate. free talc. Coloring agents include any of the approved, certi The hard gelatin capsule, also known as the dry-filled capsule fied, water soluble FD&C dyes, and water insoluble FD&C (DFC), consists of two sections, one slipping over the other, dyes Suspended on alumina hydrate, and color lakes and thus completely enclosing the active ingredient. The Soft elas mixtures thereof. A color lake is the combination by adsorp tic capsule (SEC) is a soft, globular shell. Such as a gelatin tion of a water-soluble dye to a hydrous oxide of a heavy shell, which is plasticized by the addition of glycerin, sorbi metal, resulting in an insoluble form of the dye. Flavoring tol, or a similar polyol. The soft gelatin shells may contain a agents include natural flavors extracted from plants, such as preservative to prevent the growth of microorganisms. Suit fruits, and synthetic blends of compounds which produce a able preservatives are those as described herein, including pleasant taste sensation, Such as peppermint and methyl sali methyl- and propyl-parabens, and Sorbic acid. The liquid, cylate. Sweetening agents include Sucrose, lactose, mannitol, semisolid, and Solid dosage forms disclosed herein may be syrups, glycerin, and artificial Sweeteners, such as saccharin encapsulated in a capsule. Suitable liquid and semisolid dos and aspartame. Suitable emulsifying agents include gelatin, age forms include solutions and Suspensions in propylene acacia, tragacanth, bentonite, and Surfactants, such as poly carbonate, vegetable oils, or triglycerides. Capsules contain oxyethylene sorbitan monooleate (TWEENR 20), polyoxy ing Such solutions can be prepared as described in U.S. Pat. ethylene sorbitan monooleate 80 (TWEENR 80), and trietha Nos. 4.328,245; 4,409.239; and 4.410,545. The capsules may nolamine oleate. Suspending and dispersing agents include also be coated as known by those of skill in the art in order to Sodium carboxymethylcellulose, pectin, tragacanth, Veegum, modify or Sustain dissolution of the active ingredient. acacia, Sodium carbomethylcellulose, hydroxypropyl meth 0231. The pharmaceutical compositions disclosed herein ylcellulose, and polyvinylpyrolidone. Preservatives include may be disclosed in liquid and semisolid dosage forms, glycerin, methyl and propylparaben, benzoic add, sodium including emulsions, Solutions, Suspensions, elixirs, and Syr benzoate and alcohol. Wetting agents include propylene gly ups. An emulsion is a two-phase system, in which one liquid col monostearate, Sorbitan monooleate, diethylene glycol is dispersed in the form of small globules throughout another monolaurate, and polyoxyethylene lauryl ether. Solvents liquid, which can be oil-in-water or water-in-oil. Emulsions include glycerin, Sorbitol, ethyl alcohol, and syrup. Examples may include a pharmaceutically acceptable non-aqueous liq of non-aqueous liquids utilized in emulsions include mineral uids or solvent, emulsifying agent, and preservative. Suspen oil and cottonseed oil. Organic acids include citric and tartaric sions may include a pharmaceutically acceptable Suspending acid. Sources of carbon dioxide include sodium bicarbonate agent and preservative. Aqueous alcoholic Solutions may and sodium carbonate. include a pharmaceutically acceptable acetal. Such as a 0227. It should be understood that many carriers and di(lower alkyl)acetal of a lower alkyl aldehyde (the term excipients may serve several functions, even within the same “lower” means an alkyl having between 1 and 6 carbon formulation. atoms), e.g., acetaldehyde diethyl acetal; and a water-mis 0228. The pharmaceutical compositions disclosed herein cible solvent having one or more hydroxyl groups, such as may be disclosed as compressed tablets, tablet triturates, propylene glycol and ethanol. Elixirs are clear, Sweetened, chewable lozenges, rapidly dissolving tablets, multiple com and hydroalcoholic Solutions. Syrups are concentrated aque pressed tablets, or enteric-coating tablets, Sugar-coated, or ous solutions of a Sugar, for example, Sucrose, and may also US 2008/02342.57 A1 Sep. 25, 2008 28 contain a preservative. For a liquid dosage form, for example, against the growth of microorganisms, stabilizers, Solubility a solution in a polyethylene glycol may be diluted with a enhancers, isotonic agents, buffering agents, antioxidants, Sufficient quantity of a pharmaceutically acceptable liquid local anesthetics, Suspending and dispersing agents, wetting carrier, e.g., water, to be measured conveniently for adminis or emulsifying agents, complexing agents, sequestering or tration. chelating agents, cryoprotectants, lyoprotectants, thickening 0232 Other useful liquid and semisolid dosage forms agents, pH adjusting agents, and inert gases. include, but are not limited to, those containing the active ingredient(s) disclosed herein, and a dialkylated mono- or 0240 Suitable aqueous vehicles include, but are not lim poly-alkylene glycol, including, 1,2-dimethoxymethane, dig ited to, water, Saline, physiological Saline or phosphate buff lyme, triglyme, tetraglyme, polyethylene glycol-350-dim ered saline (PBS), sodium chloride injection, Ringers injec ethyl ether, polyethylene glycol-550-dimethyl ether, polyeth tion, isotonic dextrose injection, sterile water injection, ylene glycol-750-dimethyl ether, wherein 350, 550, and 750 dextrose and lactated Ringers injection. Non-aqueous refer to the approximate average molecular weight of the vehicles include, but are not limited to, fixed oils of vegetable polyethylene glycol. These formulations may further com origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, prise one or more antioxidants, such as butylated hydroxy peppermint oil, Safflower oil, Sesame oil, soybean oil, hydro toluene (BHT), butylated hydroxyanisole (BHA), propyl gal genated vegetable oils, hydrogenated Soybean oil, and late, vitamin E, hydroquinone, hydroxycoumarins, medium-chain triglycerides of coconut oil, and palm seed oil. ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, Water-miscible vehicles include, but are not limited to, etha sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, nol. 1,3-butanediol, liquid polyethylene glycol (e.g., polyeth thiodipropionic acid and its esters, and dithiocarbamates. ylene glycol 300 and polyethylene glycol 400), propylene 0233. The pharmaceutical compositions disclosed herein glycol, glycerin, N-methyl-2-pyrrolidone, dimethylaceta for oral administration may be also disclosed in the forms of mide, and dimethylsulfoxide. liposomes, micelles, microspheres, or nanosystems. Micellar 0241 Suitable antimicrobial agents or preservatives dosage forms can be prepared as described in U.S. Pat. No. include, but are not limited to, phenols, cresols, mercurials, 6,350,458. benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxy 0234. The pharmaceutical compositions disclosed herein benzates, thimerosal, benzalkonium chloride, benzethonium may be disclosed as non-effervescent or effervescent, gran chloride, methyl- and propyl-parabens, and Sorbic acid. Suit ules and powders, to be reconstituted into a liquid dosage able isotonic agents include, but are not limited to, Sodium form. Pharmaceutically acceptable carriers and excipients chloride, glycerin, and dextrose. Suitable buffering agents used in the non-effervescent granules or powders may include include, but are not limited to, phosphate and citrate. Suitable diluents, Sweeteners, and wetting agents. Pharmaceutically antioxidants are those as described herein, including bisulfite acceptable carriers and excipients used in the effervescent and sodium metabisulfite. Suitable local anesthetics include, granules or powders may include organic acids and a source but are not limited to, procaine hydrochloride. Suitable sus of carbon dioxide. pending and dispersing agents are those as described herein, 0235 Coloring and flavoring agents can be used in all of including Sodium carboxymethylcellulose, hydroxypropyl the above dosage forms. methylcellulose, and polyvinylpyrrolidone. Suitable emulsi 0236. The pharmaceutical compositions disclosed herein fying agents include those described herein, including poly may be co-formulated with other active ingredients which do oxyethylene Sorbitan monolaurate, polyoxyethylene Sorbitan not impair the desired therapeutic action, or with Substances monooleate 80, and triethanolamine oleate. Suitable seques that Supplement the desired action, Such as drotrecogin-C. tering or chelating agents include, but are not limited to and hydrocortisone. EDTA. Suitable pH adjusting agents include, but are not limited to, Sodium hydroxide, hydrochloric acid, citric acid, B. Parenteral Administration and lactic acid. Suitable complexing agents include, but are 0237. The pharmaceutical compositions disclosed herein not limited to, cyclodextrins, including C-cyclodextrin, B-cy may be administered parenterally by injection, infusion, or clodextrin, hydroxypropyl-f-cyclodextrin, sulfobutylether implantation, for local or systemic administration. Parenteral B-cyclodextrin, and sulfobutylether 7-B-cyclodextrin (CAP administration, as used herein, include intravenous, intraar TISOL(R), CyDex, Lenexa, Kans.). terial, intraperitoneal, intrathecal, intraventricular, intraure 0242. The pharmaceutical compositions disclosed herein thral, intrasternal, intracranial, intramuscular, intrasynovial, may be formulated for single or multiple dosage administra and Subcutaneous administration. tion. The single dosage formulations are packaged in an 0238. The pharmaceutical compositions disclosed herein ampule, a vial, or a syringe. The multiple dosage parenteral may be formulated in any dosage forms that are suitable for formulations must contain an antimicrobial agent at bacterio parenteral administration, including solutions, Suspensions, static or fungistatic concentrations. All parenteral formula emulsions, micelles, liposomes, microspheres, nanosystems, tions must be sterile, as known and practiced in the art. and Solid forms suitable for solutions or Suspensions in liquid 0243 In one embodiment, the pharmaceutical composi prior to injection. Such dosage forms can be prepared accord tions are disclosed as ready-to-use Sterile solutions. In ing to conventional methods known to those skilled in the art another embodiment, the pharmaceutical compositions are of pharmaceutical Science (see, Remington. The Science and disclosed as Sterile dry soluble products, including lyo Practice of Pharmacy, Supra). philized powders and hypodermic tablets, to be reconstituted 0239. The pharmaceutical compositions intended for with a vehicle prior to use. In yet another embodiment, the parenteral administration may include one or more pharma pharmaceutical compositions are disclosed as ready-to-use ceutically acceptable carriers and excipients, including, but sterile Suspensions. In yet another embodiment, the pharma not limited to, aqueous vehicles, water-miscible vehicles, ceutical compositions are disclosed as sterile dry insoluble non-aqueous vehicles, antimicrobial agents or preservatives products to be reconstituted with a vehicle prior to use. In still US 2008/02342.57 A1 Sep. 25, 2008 29 another embodiment, the pharmaceutical compositions are Emeryville, Calif.), and BIOJECTTM (Bioject Medical Tech disclosed as ready-to-use sterile emulsions. nologies Inc., Tualatin, Oreg.). 0244. The pharmaceutical compositions may be formu 0251. The pharmaceutical compositions disclosed herein lated as a Suspension, Solid, semi-solid, or thixotropic liquid, may be disclosed in the forms of ointments, creams, and gels. for administration as an implanted depot. In one embodiment, Suitable ointment vehicles include oleaginous or hydrocar the pharmaceutical compositions disclosed herein are dis bon vehicles, including such as lard, benzoinated lard, olive persed in a solidinner matrix, which is Surrounded by an outer oil, cottonseed oil, and other oils, white petrolatum; emulsi polymeric membrane that is insoluble in body fluids but fiable or absorption vehicles, such as hydrophilic petrolatum, allows the active ingredient in the pharmaceutical composi hydroxyStearin Sulfate, and anhydrous lanolin; water-remov tions diffuse through. able vehicles, such as hydrophilic ointment; water-soluble 0245 Suitable inner matrixes include polymethyl ointment vehicles, including polyethylene glycols of varying methacrylate, polybutylmethacrylate, plasticized or unplasti molecular weight; emulsion vehicles, either water-in-oil cized polyvinylchloride, plasticized nylon, plasticized poly (W/O) emulsions or oil-in-water (O/W) emulsions, including ethyleneterephthalate, natural rubber, polyisoprene, cetyl alcohol, glyceryl monostearate, lanolin, and Stearic acid polyisobutylene, polybutadiene, polyethylene, ethylene-vi (see, Remington. The Science and Practice of Pharmacy, nylacetate copolymers, silicone rubbers, polydimethylsilox Supra). These vehicles are emollient but generally require anes, silicone carbonate copolymers, hydrophilic polymers, addition of antioxidants and preservatives. Such as hydrogels of esters of acrylic and methacrylic acid, 0252 Suitable cream base can be oil-in-water or water-in collagen, cross-linked polyvinylalcohol, and cross-linked oil. Cream vehicles may be water-washable, and contain an partially hydrolyzed polyvinyl acetate. oil phase, an emulsifier, and an aqueous phase. The oil phase 0246 Suitable outer polymeric membranes include poly is also called the “internal' phase, which is generally com ethylene, polypropylene, ethylene/propylene copolymers, prised of petrolatum and a fatty alcohol Such as cetyl or ethylene/ethyl acrylate copolymers, ethylene/vinylacetate Stearyl alcohol. The aqueous phase usually, although not nec copolymers, silicone rubbers, polydimethyl siloxanes, neo essarily, exceeds the oil phase in Volume, and generally con prene rubber, chlorinated polyethylene, polyvinylchloride, tains a humectant. The emulsifier in a cream formulation may vinylchloride copolymers with vinyl acetate, vinylidene chlo be a nonionic, anionic, cationic, or amphoteric Surfactant. ride, ethylene and propylene, ionomer polyethylene tereph 0253) Gels are semisolid, suspension-type systems. thalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl Single-phase gels contain organic macromolecules distrib alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol ter uted Substantially uniformly throughout the liquid carrier. polymer, and ethylene/vinyloxyethanol copolymer. Suitable gelling agents include crosslinked acrylic acid poly mers, such as carbomers, carboxypolyalkylenes, Carbopol R; C. Topical Administration hydrophilic polymers, such as polyethylene oxides, polyoxy ethylene-polyoxypropylene copolymers, and polyvinylalco 0247 The pharmaceutical compositions disclosed herein hol; cellulosic polymers, such as hydroxypropyl cellulose, may be administered topically to the skin, orifices, or mucosa. hydroxyethyl cellulose, hydroxypropyl methylcellulose, Topical administration, as described herein, includes (intra) hydroxypropyl methylcellulose phthalate, and methylcellu dermal, conjuctival, intracorneal, intraocular, ophthalmic, lose; gums, such as tragacanth and Xanthan gum, Sodium auricular, transdermal, nasal, vaginal, uretheral, respiratory, alginate; and gelatin. In order to prepare a uniform gel, dis and rectal administration. persing agents such as alcohol or glycerin can be added, or the 0248. The pharmaceutical compositions disclosed herein gelling agent can be dispersed by trituration, mechanical mix may be formulated in any dosage forms that are suitable for ing, and/or stirring. topical administration for local or systemic effect, including 0254 The pharmaceutical compositions disclosed herein emulsions, Solutions, Suspensions, creams, gels, hydrogels, may be administered rectally, urethrally, vaginally, or ointments, dusting powders, dressings, elixirs, lotions, Sus perivaginally in the forms of Suppositories, pessaries, bou pensions, tinctures, pastes, foams, films, aerosols, irrigations, gies, poultices or cataplasm, pastes, powders, dressings, sprays, Suppositories, bandages, dermal patches. The topical creams, plasters, contraceptives, ointments, solutions, emul formulation of the pharmaceutical compositions disclosed Sions, Suspensions, tampons, gels, foams, sprays, or enemas. herein may also comprise liposomes, micelles, microspheres, These dosage forms can be manufactured using conventional nanosystems, and mixtures thereof. processes as described in Remington. The Science and Prac 0249 Pharmaceutically acceptable carriers and excipients tice of Pharmacy, Supra. suitable for use in the topical formulations disclosed herein 0255 Rectal, urethral, and vaginal suppositories are solid include, but are not limited to, aqueous vehicles, water-mis bodies for insertion into body orifices, which are solid at cible vehicles, non-aqueous vehicles, antimicrobial agents or ordinary temperatures but melt or soften at body temperature preservatives against the growth of microorganisms, stabiliz to release the active ingredient(s) inside the orifices. Pharma ers, solubility enhancers, isotonic agents, buffering agents, ceutically acceptable carriers utilized in rectal and vaginal antioxidants, local anesthetics, Suspending and dispersing Suppositories include bases or vehicles, such as stiffening agents, wetting or emulsifying agents, complexing agents, agents, which produce a melting point in the proximity of sequestering or chelating agents, penetration enhancers, body temperature, when formulated with the pharmaceutical cryopretectants, lyoprotectants, thickening agents, and inert compositions disclosed herein; and antioxidants as described gases. herein, including bisulfite and sodium metabisulfite. Suitable 0250. The pharmaceutical compositions may also be vehicles include, but are not limited to, cocoa butter (theo administered topically by electroporation, iontophoresis, broma oil), glycerin-gelatin, carbowax (polyoxyethylene gly phonophoresis, Sonophoresis and microneedle or needle-free col), spermaceti, paraffin, white and yellow wax, and appro injection, such as POWDERJECTTM (Chiron Corp., priate mixtures of mono-, di- and triglycerides of fatty acids, US 2008/02342.57 A1 Sep. 25, 2008 30 hydrogels, such as polyvinyl alcohol, hydroxyethyl meth compositions in modified release dosage forms can be pre acrylate, polyacrylic acid; glycerinated gelatin. Combina pared using a variety of modified release devices and methods tions of the various vehicles may be used. Rectal and vaginal known to those skilled in the art, including, but not limited to, Suppositories may be prepared by the compressed method or matrix controlled release devices, osmotic controlled release molding. The typical weight of a rectal and vaginal Supposi devices, multiparticulate controlled release devices, ion-ex tory is about 2 to about 3 g. change resins, enteric coatings, multilayered coatings, micro 0256 The pharmaceutical compositions disclosed herein spheres, liposomes, and combinations thereof. The release may be administered ophthalmically in the forms of solu rate of the active ingredient(s) can also be modified by vary tions, Suspensions, ointments, emulsions, gel-forming solu ing the particle sizes and polymorphism of the active ingre tions, powders for Solutions, gels, ocular inserts, and dient(s). implants. 0263. Examples of modified release include, but are not 0257 The pharmaceutical compositions disclosed herein limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916, may be administered intranasally or by inhalation to the res 899; 3,536,809;3,598,123; 4,008,719:5,674,533; 5,059,595; piratory tract. The pharmaceutical compositions may be dis 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; closed in the form of an aerosol or solution for delivery using 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; a pressurized container, pump, spray, atomizer, Such as an 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; atomizer using electrohydrodynamics to produce a fine mist, 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; or nebulizer, alone or in combination with a suitable propel 6,376.461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500. lant, such as 1,1,1,2-tetrafluoroethane or 1.1.1.2.3,3,3-hep tafluoropropane. The pharmaceutical compositions may also 1. Matrix Controlled Release Devices be disclosed as a dry powder for insufflation, alone or in combination with an inert carrier Such as lactose orphospho 0264. The pharmaceutical compositions disclosed herein lipids; and nasal drops. For intranasal use, the powder may in a modified release dosage form may be fabricated using a comprise a bioadhesive agent, including chitosan or cyclo matrix controlled release device known to those skilled in the dextrin. art (see, Takada et al in “Encyclopedia of Controlled Drug 0258 Solutions or suspensions for use in a pressurized Delivery.” Vol. 2, Mathiowitz ed., Wiley, 1999). container, pump, spray, atomizer, or nebulizer may beformu 0265. In one embodiment, the pharmaceutical composi lated to contain ethanol, aqueous ethanol, or a Suitable alter tions disclosed herein in a modified release dosage form is native agent for dispersing, Solubilizing, or extending release formulated using an erodible matrix device, which is water of the active ingredient disclosed herein, a propellant as Sol Swellable, erodible, or soluble polymers, including synthetic vent; and/or an Surfactant, Such as Sorbitan trioleate, oleic polymers, and naturally occurring polymers and derivatives, acid, or an oligolactic acid. Such as polysaccharides and proteins. 0259. The pharmaceutical compositions disclosed herein 0266 Materials useful in forming an erodible matrix may be micronized to a size suitable for delivery by inhala include, but are not limited to, chitin, chitosan, dextran, and tion, such as about 50 micrometers or less, or about 10 pullulan, gum agar, gum arabic, gum karaya, locust bean micrometers or less. Particles of such sizes may be prepared gum, gum tragacanth, carrageenans, gum ghatti, guar gum, using a comminuting method known to those skilled in the art, Xanthan gum, and Scleroglucan: Starches, such as dextrin and Such as spiral jet milling, fluid bed jet milling, Supercritical maltodextrin; hydrophilic colloids, such aspectin; phosphati fluid processing to form nanoparticles, high pressure homog des, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; and cellulosics, such as ethyl cellulose enization, or spray drying. (EC), methylethyl cellulose (MEC), carboxymethyl cellulose 0260 Capsules, blisters and cartridges for use in an inhaler (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypro or insufflator may be formulated to contain a powder mix of pyl cellulose (HPC), cellulose acetate (CA), cellulose propi the pharmaceutical compositions disclosed herein; a suitable onate (CP), cellulose butyrate (CB), cellulose acetate butyrate powder base. Such as lactose or starch; and a performance (CAB), CAP CAT, hydroxypropyl methyl cellulose modifier, Such as 1-leucine, mannitol, or magnesium Stearate. (HPMC), HPMCP HPMCAS, hydroxypropyl methyl cellu The lactose may be anhydrous or in the form of the monohy lose acetate trimelitate (HPMCAT), and ethylhydroxyethyl drate. Other suitable excipients or carriers include dextran, cellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol: glucose, maltose, Sorbitol. Xylitol, fructose. Sucrose, and tre polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; halose. The pharmaceutical compositions disclosed herein polyacrylic acid; copolymers of ethacrylic acid or meth for inhaled/intranasal administration may further comprise a acrylic acid (EUDRAGITR), Rohm America, Inc., Piscat suitable flavor, such as menthol and levomenthol, or Sweet away, N.J.), poly(2-hydroxyethyl-methacrylate); polylac eners, such as saccharin or saccharin Sodium. tides; copolymers of L-glutamic acid and ethyl-L-glutamate; 0261 The pharmaceutical compositions disclosed herein degradable lactic acid-glycolic acid copolymers; poly-D-(-)- for topical administration may beformulated to be immediate 3-hydroxybutyric acid; and other acrylic acid derivatives, release or modified release, including delayed-, Sustained Such as homopolymers and copolymers ofbutylmethacrylate, pulsed-, controlled-, targeted, and programmed release. methylmethacrylate, ethylmethacrylate, ethylacrylate, (2-dimethylaminoethyl)methacrylate, and (trimethylamino D. Modified Release ethyl)methacrylate chloride. 0262 The pharmaceutical compositions disclosed herein 0267 In further embodiments, the pharmaceutical com may be formulated as a modified release dosage form. As positions are formulated with a non-erodible matrix device. used herein, the term “modified release' refers to a dosage The active ingredient(s) is dissolved or dispersed in an inert form in which the rate or place of release of the active ingre matrix and is released primarily by diffusion through the inert dient(s) is different from that of an immediate dosage form matrix once administered. Materials suitable for use as a when administered by the same route. The pharmaceutical non-erodible matrix device included, but are not limited to, US 2008/02342.57 A1 Sep. 25, 2008 insoluble plastics. Such as polyethylene, polypropylene, pressure gradient across the barrier of the Surrounding coat polyisoprene, polyisobutylene, polybutadiene, polymethyl ing. Suitable osmogens include, but are not limited to, inor methacrylate, polybutylmethacrylate, chlorinated polyethyl ganic salts, such as magnesium sulfate, magnesium chloride, ene, polyvinylchloride, methyl acrylate-methyl methacrylate calcium chloride, sodium chloride, lithium chloride, potas copolymers, ethylene-vinylacetate copolymers, ethylene? sium Sulfate, potassium phosphates, sodium carbonate, propylene copolymers, ethylene/ethyl acrylate copolymers, Sodium sulfite, lithium sulfate, potassium chloride, and vinylchloride copolymers with vinyl acetate, vinylidene chlo Sodium sulfate; Sugars, such as dextrose, fructose, glucose, ride, ethylene and propylene, ionomer polyethylene tereph inositol, lactose, maltose, mannitol, raffinose, Sorbitol, thalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl Sucrose, trehalose, and Xylitol, organic acids, such as ascorbic alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol ter acid, benzoic acid, fumaric acid, citric acid, maleic acid, polymer, and ethylene/vinyloxyethanol copolymer, polyvi sebacic acid, Sorbic acid, adipic acid, edetic acid, glutamic nyl chloride, plasticized nylon, plasticized polyethylene acid, p-toluenesulfonic acid, Succinic acid, and tartaric acid; terephthalate, natural rubber, silicone rubbers, urea; and mixtures thereof. polydimethylsiloxanes, silicone carbonate copolymers, and; 0273) Osmotic agents of different dissolution rates may be hydrophilic polymers, such as ethyl cellulose, cellulose employed to influence how rapidly the active ingredient(s) is acetate, crospovidone, and cross-linked partially hydrolyzed initially delivered from the dosage form. For example, amor polyvinyl acetate, and fatty compounds, such as carnauba phous Sugars, such as Mannogeme EZ (SPI Pharma, Lewes, wax, microcrystalline wax, and triglycerides. Del.) can be used to provide faster delivery during the first 0268. In a matrix controlled release system, the desired couple of hours to promptly produce the desired therapeutic release kinetics can be controlled, for example, via the poly effect, and gradually and continually release of the remaining mer type employed, the polymer viscosity, the particle sizes amount to maintain the desired level of therapeutic or pro of the polymer and/or the active ingredient(s), the ratio of the phylactic effect over an extended period of time. In this case, active ingredient(s) versus the polymer, and other excipients the active ingredient(s) is released at Such a rate to replace the or carriers in the compositions. amount of the active ingredient metabolized and excreted. 0269. The pharmaceutical compositions disclosed herein 0274 The core may also include a wide variety of other in a modified release dosage form may be prepared by meth excipients and carriers as described herein to enhance the ods known to those skilled in the art, including direct com performance of the dosage form or to promote stability or pression, dry or wet granulation followed by compression, processing. melt-granulation followed by compression. (0275 Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, 2. Osmotic Controlled Release Devices polyamides, polyesters, and cellulosic derivatives that are 0270. The pharmaceutical compositions disclosed herein water-permeable and water-insoluble at physiologically rel in a modified release dosage form may be fabricated using an evant pHs, or are susceptible to being rendered water-in osmotic controlled release device, including one-chamber soluble by chemical alteration, Such as crosslinking. system, two-chamber system, asymmetric membrane tech Examples of suitable polymers useful informing the coating, nology (AMT), and extruding core system (ECS). In general, include plasticized, unplasticized, and reinforced cellulose Such devices have at least two components: (a) the core which acetate (CA), cellulose diacetate, cellulose triacetate, CA contains the active ingredient(s); and (b) a semipermeable propionate, cellulose nitrate, cellulose acetate butyrate membrane with at least one delivery port, which encapsulates (CAB), CAethyl carbamate, CAP, CA methylcarbamate, CA the core. The semipermeable membrane controls the influx of succinate, cellulose acetate trimellitate (CAT), CA diethy water to the core from an aqueous environment of use so as to laminoacetate, CA ethyl carbonate, CA chloroacetate, CA cause drug release by extrusion through the delivery port(s). ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA 0271 In addition to the active ingredient(s), the core of the p-toluene Sulfonate, agar acetate, amylose triacetate, beta osmotic device optionally includes an osmotic agent, which glucan acetate, beta glucan triacetate, acetaldehyde dimethyl creates a driving force for transport of water from the envi acetate, triacetate of locust bean gum, hydroxlated ethylene ronment of use into the core of the device. One class of vinylacetate, EC, PEG, PPG, PEG/PPG copolymers, PVP. osmotic agents water-swellable hydrophilic polymers, which HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, are also referred to as “osmopolymers' and “hydrogels.” HPMCAT, poly(acrylic) acids and esters and poly-(meth including, but not limited to, hydrophilic vinyl and acrylic acrylic) acids and esters and copolymers thereof, starch, dex polymers, polysaccharides such as calcium alginate, polyeth tran, dextrin, chitosan, collagen, gelatin, polyalkenes, poly ylene oxide (PEO), polyethylene glycol (PEG), polypropy ethers, polysulfones, polyetherSulfones, polystyrenes, lene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly polyvinyl halides, polyvinyl esters and ethers, natural waxes, (acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone and synthetic waxes. (PVP), crosslinked PVP polyvinyl alcohol (PVA). PVA/PVP 0276 Semipermeable membrane may also be a hydropho copolymers, PVA/PVP copolymers with hydrophobic mono bic microporous membrane, wherein the pores are substan merS Such as methyl methacrylate and vinyl acetate, hydro tially filled with a gas and are not wetted by the aqueous philic polyurethanes containing large PEO blocks, sodium medium but are permeable to water vapor, as disclosed in U.S. croScarmellose, carrageenan, hydroxyethyl cellulose (HEC), Pat. No. 5,798,119. Such hydrophobic but water-vapor per hydroxypropyl cellulose (HPC), hydroxypropyl methyl cel meable membrane are typically composed of hydrophobic lulose (HPMC), carboxymethyl cellulose (CMC) and car polymers such as polyalkenes, polyethylene, polypropylene, boxyethyl, cellulose (CEC), sodium alginate, polycarbophil. polytetrafluoroethylene, polyacrylic acid derivatives, poly gelatin, Xanthan gum, and sodium starch glycolate. ethers, polysulfones, polyetherSulfones, polystyrenes, poly 0272. The other class of osmotic agents are osmogens, vinyl halides, polyvinylidene fluoride, polyvinyl esters and which are capable of imbibing water to affect an osmotic ethers, natural waxes, and synthetic waxes. US 2008/02342.57 A1 Sep. 25, 2008 32

0277. The delivery port(s) on the semipermeable mem Such as enteric polymers, water-swellable, and water-soluble brane may be formed post-coating by mechanical or laser polymers. The multiparticulates can be further processed as a drilling. Delivery port(s) may also be formed in situ by ero capsule or a tablet. sion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the 4. Targeted Delivery core. In addition, delivery ports may be formed during coat 0285. The pharmaceutical compositions disclosed herein ing process, as in the case of asymmetric membrane coatings may also be formulated to be targeted to a particular tissue, of the type disclosed in U.S. Pat. Nos. 5,612,059 and 5,698, receptor, or other area of the body of the subject to be treated, 220. including liposome-, resealed erythrocyte-, and antibody 0278. The total amount of the active ingredient(s) released based delivery systems. Examples include, but are not limited and the release rate can substantially by modulated via the to, U.S. Pat. Nos. 6,316,652; 6,274,552; 6,271,359; 6,253, thickness and porosity of the semipermeable membrane, the 872: 6,139,865; 6,131.570; 6,120,751; 6,071,495; 6,060,082: composition of the core, and the number, size, and position of 6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; the delivery ports. 5,900,252; 5,840,674; 5,759,542; and 5,709,874. 0279. The pharmaceutical compositions in an osmotic Polymorphs of Compounds of Formula I controlled-release dosage form may further comprise addi tional conventional excipients or carriers as described herein 0286 The hydrochloride salt Forms A-F of the compound to promote performance or processing of the formulation. of formula I have been characterized using X-ray powder diffractometry. The hydrochloride salt Forms A-F of the com 0280. The osmotic controlled-release dosage forms can be pound of Formula I provide X-ray powder diffraction patterns prepared according to conventional methods and techniques substantially the same as shown in FIGS. 1-6. known to those skilled in the art (see, Remington. The Science (0287. The hydrochloride salt Form A of d-1-(2-dimethy and Practice of Pharmacy, Supra; Santus and Baker, J. Con lamino-1-(4-methoxyphenyl)-ethylcyclohexanol (do-Ven trolled Release 1995, 35, 1-21; Verma et al., Drug Develop lafaxine) of the present disclosure is characterized in that the ment and Industrial Pharmacy 2000, 26, 695-708; Verma et crystal provides high-intensity diffraction peaks at diffraction al., J. Controlled Release 2002, 79, 7-27). angles of 2-theta (20) in a X-ray powder diffraction spectrum 0281. In certain embodiments, the pharmaceutical com of about 6.703, 8.321, 12.681, 13.5, 15.54, 18.918, 20.359, positions disclosed herein are formulated as AMT controlled 21.161, 21.762, 25.04, and 28.518. release dosage form, which comprises an asymmetric 0288 The hydrochloride salt Form B of d-1-2-dimethy osmotic membrane that coats a core comprising the active lamino-1-(4-methoxyphenyl)-ethylcyclohexanol (do-Ven ingredient(s) and other pharmaceutically acceptable excipi lafaxine) of the present disclosure is characterized in that the ents or carriers. See, U.S. Pat. No. 5,612,059 and WO 2002/ crystal provides high-intensity diffraction peaks at diffraction 17918. The AMT controlled-release dosage forms can be angles of 2-theta (20) in a X-ray powder diffraction spectrum prepared according to conventional methods and techniques of about 6.683, 10.201, 13.441, 15.517, 18.198, 19.719, known to those skilled in the art, including direct compres 20.258, 21.68, 22.658, 25.543, 28.022, and 35.02. Sion, dry granulation, wet granulation, and a dip-coating 0289. The hydrochloride salt Form C of d-1-2-dimethy method. lamino-1-(4-methoxyphenyl)-ethylcyclohexanol (d-ven 0282. In certain embodiments, the pharmaceutical com lafaxine) of the present disclosure is characterized in that the positions disclosed herein are formulated as ESC controlled crystal provides high-intensity diffraction peaks at diffraction release dosage form, which comprises an osmotic membrane angles of 2-theta (20) in a X-ray powder diffraction spectrum that coats a core comprising the active ingredient(s), a of about 6.718, 8.335, 12.68, 13.5, 15.539, 16.282, 18.902, hydroxylethyl cellulose, and other pharmaceutically accept 19.737, 20.34, 21.161, 21.758, 25.02, 25.601, 26.261, able excipients or carriers. 28.518, 31.54, 33.198, 33.937, and 35.159. 0290 The hydrochloride salt Form D of d-1-2-dimethy 3. Multiparticulate Controlled Release Devices lamino-1-(4-methoxyphenyl)-ethylcyclohexanol (do-Ven lafaxine) of the present disclosure is characterized in that the 0283. The pharmaceutical compositions disclosed herein crystal provides high-intensity diffraction peaks at diffraction in a modified release dosage form may be fabricated a mul angles of 2-theta (20) in a X-ray powder diffraction spectrum tiparticulate controlled release device, which comprises a of about 6.74, 7.421, 8.341, 10.219, 12.7, 13.502, 17.9, multiplicity of particles, granules, or pellets, ranging from 15.541, 20.36, 21.221, 21.761, 25.078, 31.04, 34.018, and about 10 um to about 3 mm, about 50 um to about 2.5 mm, or 35.139. from about 100 um to about 1 mm in diameter. Such multi 0291. The hydrochloride salt Form E of d-1-(2-dimethy particulates may be made by the processes know to those lamino-1-(4-methoxyphenyl)-ethylcyclohexanol (do-Ven skilled in the art, including wet- and dry-granulation, extru lafaxine) of the present disclosure is characterized in that the sion/spheronization, roller-compaction, melt-congealing, crystal provides high-intensity diffraction peaks at diffraction and by spray-coating seed cores. See, for example, Multipar angles of 2-theta (20) in a X-ray powder diffraction spectrum ticulate Oral Drug Delivery; Marcel Dekker: 1994; and Phar of about 5.597, 7.182, 9.078, 9.557, 11.201, 14.46, 14.76, maceutical Pelletization Technology; Marcel Dekker: 1989. 16.86, 17.497, 19.201, 19.619, 20.241, 20.66, 21.76, 22.596, 0284. Other excipients or carriers as described herein may 23.06, 24.4, 25.02, 26.519, 26.842, 31.52, and 35.438. be blended with the pharmaceutical compositions to aid in 0292. The hydrochloride salt Form F of d-1-2-dimethy processing and forming the multiparticulates. The resulting lamino-1-(4-methoxyphenyl)-ethylcyclohexanol (do-Ven particles may themselves constitute the multiparticulate lafaxine) of the present disclosure is characterized in that the device or may be coated by various film-forming materials, crystal provides high-intensity diffraction peaks at diffraction US 2008/02342.57 A1 Sep. 25, 2008 angles of 2-theta (20) in a X-ray powder diffraction spectrum of about 5.581, 7.186, 11.22, 14.499, 14.802, 16.882, 19.242, TABLE 1-continued 20.317, 21.798, 22.637, and 35.445. 0293. In the infrared absorption spectra FIGS. 7-12 the 2-theta RI horizontal axis shows the wavenumber in cm and the ver 16.299 11.4 tical axis shows the transmittance in percent (%). 16.762 8.1 0294 The hydrochloride salt of do-1-(2-dimethylamino 17.318 4.6 18.5 4.2 1-(4-methoxyphenyl)-ethyl-cyclohexanol (do-Venlafaxine) 18.918 24.4 has been characterized by X-ray powder diffractometry. 19.757 6.1 0295 The hydrochloride crystals of do-1-(2-dimethy 20.359 1OO lamino-1-(4-methoxyphenyl)-ethyl-cyclohexanol (d-ven 21.161 38.3 21.762 26.1 lafaxine, Forms A-F) provide powder X-ray diffraction spec 22.196 2 trums substantially the same as the powder X-ray diffraction 22.92 2.8 spectrums shown in FIGS. 1-6, respectively. However, it is 24.084 1.7 25.04 27.8 known that a powder X-ray diffraction spectrum may be 25.34 5.3 obtained with a measurement error depending on measure 25.641 8 ment conditions. In particular, it is generally known that 26.261 6.4 intensities in a powder X-ray diffraction spectrum may fluc 26.481 4.9 26.866 1.6 tuate depending on measurement conditions. Therefore, it 27.265 6.7 should be understood that the salts of the present disclosure 28.518 18.2 are not limited to the crystals that provide X-ray powder 28.822 6.2 diffraction spectrum completely identical to the X-ray pow 3O419 2.5 31.001 7.9 der diffraction spectrums shown in FIGS. 1-6, and that any 31.539 1O.S crystals providing X-ray powder diffraction spectrums Sub 32.456 2.1 stantially the same as the aforementioned X-ray powder dif 32.758 3.3 fraction spectrums fall within the scope of the present disclo 33.162 7.3 33.957 10.4 sure. Those skilled in the field of X-ray powder 35.181 15.5 diffractometry can readily judge the substantial identity of 36.024 1.8 X-ray powder diffraction spectrums. 36.399 1.6 0296 Generally, a measurement error of diffraction angle 36.814 2 37.76 3 for a usual X-ray powder diffractometry is about 5% or less, 38.68 S.1 and Such degree of a measurement error should be taken into 39.159 2.2 account as to diffraction angles. Furthermore, it should be understood that intensities may fluctuate depending on experimental conditions. 0299. The hydrochloride salt Form B of the compound of 0297. The hydrochloride salt Form A of the compound of formula I is characterized in that the crystal provides high formula I is characterized in that the crystal provides high intensity diffraction peaks at diffraction angles of about intensity diffraction peaks at diffraction angles of about 2-theta, 9% relative intensity: 6.683 (15.5., 10.201 (93.6). 2-theta, 9% relative intensity: 6.703 (29.3), 8.321 (19), 13.441 (27.8, 15.517 (66.2, 18.198 (41, 19.719 (34.1), 12.681 (77.5, 13.5 (47.9, 15.54 17.7, 18.918 24.4, 20.258 100, 21.68 71.2, 22.658 (24.8), 25.543. 22.4), 20.359 100, 21.161 38.3), 21.76226.1, 25.0427.8), and 28.02220.9), and 35.02 (33.4. The hydrochloride salt Form 28.51818.2. The hydrochloride salt Form A of the present B of the present disclosure provides a X-ray powder diffrac disclosure provides a X-ray powder diffraction spectrum sub tion spectrum Substantially the same as the X-ray diffraction stantially the same as the X-ray diffraction spectrum shown in spectrum shown in FIG. 2. FIG 1. 0300. The characteristic 2-theta (20) values and relative 0298. The characteristic 2-theta (20) values and relative intensity (RI) in percentage for the diffraction spectrum of the intensity (RI) in percentage for the diffraction spectrum of the hydrochloride salt Form B of the compound of formula I is hydrochloride salt Form A of the compound of Formula I is shown in Table 2. Thus, described herein is a polymorph of shown in Table 1. Thus, described herein is a polymorph of the hydrochloride salt of formula I having at least four of the the hydrochloride salt of Formula I having at least four of the most intense peaks presented in Table 2. most intense peaks presented in Table 1. TABLE 2 TABLE 1. 2-theta RI 2-theta RI 6.683 15.5 6.703 29.3 10.2O1 93.6 7.399 9 13.441 27.8 8.321 19 15.014 7.6 8.52 2.7 15.517 66.2 10.195 3.6 16.458 1.5 12681 77.5 16.84 10.3 13.5 47.9 17.2O6 2.7 14.863 9.3 18.198. 41 15.54 17.7 19.719 34.1 15.92 3.8 20.258 1OO US 2008/02342.57 A1 Sep. 25, 2008 34

TABLE 2-continued TABLE 3-continued

2-theta RI 2-theta RI

21.68 71.2 22.151 3.6 22.658 24.8 22.659 2.1 23.923 2.7 22.955 2.4 25.322 9.6 24.073 1.7 25.543 22.4 25.02 31.5 26.5O2 6.7 25.36 11.1 27.122 9.5 25.6O1 18.9 27.557 5.5 26.261 15.2 28.022 20.9 26.856 3.2 28.64 4.4 27.258 8.8 29.241 10.6 28.518 30.2 29.659 7.1 28.839 11.6 31.079 11.9 30.42 2.4 31.379 8.2 30.962 11.7 31.978 9.1 31.54 18.7 32.28 1O.S 32.478 4.6 32.701 6.5 32.775 3.9 32.981 2.3 33.198 14.2 34:12 9.1 33.937 16.5 35.02 33.4 35.159 21.3 36.024 3.1 36.076 3.1 36.842 2.6 36.438 2.7 37.5 6.7 36.765 3.9 38.341 3.9 37.66 S.6 38.753 1.2 38.2O7 2.2 38.658 6.7 39.2 3.6 0301 The hydrochloride salt Form C of the compound of formula I is characterized in that the crystal provides high intensity diffraction peaks at diffraction angles of about (0303. The hydrochloride salt Form D of the compound of 2-theta, 9% relative intensity: 6.718 (21.4), 8.335 (20.6), formula I is characterized in that the crystal provides high 12.68 (80), 13.5 (40.7, 15.539 (20.2, 16.282 24.3, 18.902 intensity diffraction peaks at diffraction angles of about 48.9, 19.737 (17.4, 20.34 100, 21.161 (79.4, 21.758 2-theta, 96 relative intensity: 6.7421.2, 7.421 14, 8.341 30.5), 25.02 31.5, 25.601 18.9, 26.261 (15.2), 28.518 35.5, 10.21923, 12.7 99.5, 13.502 (40.7, 17.917.5), 30.2, 31.5418.7), 33.19814.2, 33.93716.5, and 35.159 15.541 (37.3, 20.36 (100), 21.221 23.7), 21.761 (41), 21.3. The hydrochloride salt Form C of the present disclo 25.07826.3.31.0417.7), 34.01814.8, and 35.13922.7. Sure provides a X-ray powder diffraction spectrum Substan The hydrochloride salt Form D of the present disclosure tially the same as the X-ray diffraction spectrum shown in provides a X-ray powder diffraction spectrum substantially FIG. 3. the same as the X-ray diffraction spectrum shown in FIG. 4. 0302) The characteristic 2-theta (20) values and relative 0304. The characteristic 2-theta (20) values and relative intensity (RI) in percentage for the diffraction spectrum of the intensity (RI) in percentage for the diffraction spectrum of the hydrochloride salt Form C of the compound of formula I is hydrochloride salt Form D of the compound of formula I is shown in Table 3. Thus, described herein is a polymorph of shown in Table 4. Thus, described herein is a polymorph of the hydrochloride salt of formula I having at least four of the the hydrochloride salt of formula I having at least four of the most intense peaks presented in Table 3. most intense peaks presented in Table 4.

TABLE 3 TABLE 4

2-theta RI 2-theta RI

6.718 21.4 6.74 21.2 8.335 20.6 7.421 14 10.18 9.1 8.341 35.5 12.68 8O 10.219 23 13.5 40.7 12.7 99.5 15.539 2O2 13.5O2 40.7 15.68 11.5 17.9 17.5 15.938 9.4 15.541 37.3 16.282 24.3 16.361 9.9 16.778 9.9 16.764 13 16.916 9.5 17.424 3 17.302 8.2 18.276 102 18.182 4.2 18.54 7.2 18.4 3 18.96 12.1 18.902 48.9 19.741 12 19.737 17.4 20.36 1OO 20.34 100 21.221 23.7 21.161 79.4 21.761 41 21.758 3O.S 22.279 2.2 US 2008/02342.57 A1 Sep. 25, 2008 35

TABLE 4-continued TABLE 5-continued

2-theta RI 2-theta RI

22.719 4.9 17.866 3 23.039 3 18.398 2.8 24.024 3.2 19.2O1 66.5 25.078 26.3 19.619 9.6 25.383 5.9 2O.241 35.2 25.604 9.7 20.66 9.6 26.303 6 20.879 1.2 26.483 8.9 21.76 22.5 26.959 6.9 22.596 26.4 27.258 7.1 23.06 3.2 28.223 7.3 23.994 2 28.518 11.9 24.4 5.3 28.919 4.8 25.02 2.1 29.322 3.2 25.643 3.9 3O419 3.2 25.861 6.7 31.04 17.7 26.519 3.5 3166 10.6 26.842 8.7 32.742 4 27.5O2 S.1 33.239 5.4 28.422 6.1 34.018 14.8 28.859 7.2 35.139 22.7 29.937 3.1 36.1 2.5 30.98 7.7 36.388 1.8 31.52 12.6 36.839 2.2 32.362 6.4 37.719 3.5 32.721 6 38.681 5.5 33.162 2.1 39.198 3.8 34.461 9.6 35.438 17.9 35.899 S.6 0305. The hydrochloride salt Form E of the compound of 36.779 4.7 37.4 4.5 formula I is characterized in that the crystal provides high 37.984 2 intensity diffraction peaks at diffraction angles of about 38.962 3.6 2-theta, 9% relative intensity: 5.597 (28), 7.18236.2), 9.078 24.1, 9.557 (14.9, 11.201 100, 14.46.40.2, 14.7640.4. 16.86 (71.7, 17.497 15.7, 19.201 (66.5, 19.619 19.6, (0307. The hydrochloride salt Form F of the compound of 20.241 35.2, 20.66 (19.6, 21.76 22.5), 22.596 (26.4), formula I is characterized in that the crystal provides high 23.0613.2, 24.415.3), 25.02 12.1, 26.51913.5, 26.842 intensity diffraction peaks at diffraction angles of about 18.7), 31.52 (12.6), and 35.438 17.9. The hydrochloride 2-theta, 9% relative intensity: 5.581 (26.1, 7.186 18.3), salt Form E of the present disclosure provides an X-ray pow 11.22 100, 14.499 (18.8, 14.802 (20.5, 16.882 (63.9, der diffraction spectrum substantially the same as the X-ray 19.242 (38.4, 20.317 (51.6, 21.798 17.5), 22.637 (26.3), diffraction spectrum shown in FIG. 5. and 35.445 16.2). The hydrochloride salt Form F of the 0306 The characteristic 2-theta (20) values and relative present disclosure provides a X-ray powder diffraction spec intensity (RI) in percentage for the diffraction spectrum of the trum Substantially the same as the X-ray diffraction spectrum hydrochloride salt Form E of the compound of formula I is shown in FIG. 6. shown in Table 5. Thus, described herein is a polymorph of 0308 The characteristic 2-theta (20) values and relative the hydrochloride salt of formula I having at least four of the intensity (RI) in percentage for the diffraction spectrum of the most intense peaks presented in Table 5. hydrochloride salt Form F of the compound of formula I is shown in Table 6. Thus, described herein is a polymorph of TABLE 5 the hydrochloride salt of formula I having at least 4 of the 2-theta RI most intense peaks presented in Table 6. 5.597 28 TABLE 6 7.182 36.2 9.078 24.1 2-theta RI 9.557 14.9 10.663 9 5.581 26.1 11.2O1 100 6.688 6.4 12.104 2.4 7.186 18.3 12.361 1.2 9.079 7.7 13.422 2.1 9.576 9.1 13.921 4.4 10.2O6 2.4 14.46 40.2 10.735 4.4 14.76 40.4 1122 1OO 15.366 3.2 12.133 3 15.721 11.2 13.447 9 16.041 8.4 13.963 2.2 16.86 71.7 14499 18.8 17497 15.7 14.8O2 2O.S US 2008/02342.57 A1 Sep. 25, 2008 36

ride salt Forms A-F of the compound of formula I are more TABLE 6-continued stable in air and can be used without deliquescence. 2-theta RI Methods of Use 15.559 S.1 15.796 6.1 0312 Disclosed are methods for treating a monoamine 16.087 3.6 related disorder, comprising administering to a Subject hav 16.882 63.9 ing or being Suspected to have Such a disorder, a therapeuti 17.519 10.6 cally effective amount compound as disclosed herein or a 18.407 S.6 pharmaceutically acceptable salt, Solvate, or prodrug thereof. 19.242 38.4 1968 11.8 0313 Monoamine-mediated disorders include, but are not 20.317 S1.6 limited to, psychotropic disorders, anxiety disorder, general 20.72 8.8 ized anxiety disorder, depression, post-traumatic stress dis 20.923 6.3 order, obsessive-compulsive disorder, panic disorder, hot 21.798 17.5 22.637 26.3 flashes, senile dementia, migraine, hepatopulmonary Syn 23.101 9 drome, chronic pain, nociceptive pain, neuropathic pain, 24.425 11.9 painful diabetic retinopathy, bipolar depression, obstructive 25.042 7.1 sleep apnea, psychiatric disorders, premenstrual dysphoric 25.921 7.7 26.587 5.4 disorder, Social phobia, Social anxiety disorder, urinary 26.939 10.1 incontinence, anorexia, bulimia nervosa, obesity, ischemia, 27.194 5.3 head injury, calcium overload in brain cells, drug depen 27.579 2.5 dence, Gilles de la Tourette syndrome, Shy Drager syndrome, 28.435 3.9 28.921 3.5 vasomotor flushing, chronic fatigue syndrome, cognition 29.4 1.6 enhancement, attention deficit hyperactivity disorder, fibro 29.808 2.6 myalgia, irritable bowel syndrome, and/or premature ejacu 31.064 3.7 lation. 31.597 9.1 32.374 1.6 0314. Also disclosed are methods of treating, preventing, 33.32 1.3 or ameliorating one or more symptoms of a disorder associ 34.524 6.3 ated with serotonin and/or norepinephrine receptors and/or 35.112 4.7 transporters, by administering to a subject having or being 35.445 16.2 35.88 1.3 suspected to have such a disorder a therapeutically effective 36.727 2.3 amount of a compound as disclosed herein or a pharmaceu 36.981 3.2 tically acceptable salt, Solvate, or prodrug thereof. 37.464 2.9 0315. Furthermore, disclosed herein are methods of 39.023 1.9 modulating the activity of Serotonin and/or norepinephrine 38.962 3.6 receptors and/or transporters, comprising contacting the receptors with at least one compound as disclosed herein or a 0309 X-ray powder diffraction pattern is only one of pharmaceutically acceptable salt, Solvate, or prodrug thereof. many ways to characterize the arrangement of atoms com In one embodiment, the serotonin and/or norepinephrine prising the hydrochloride salt of d-1-2-dimethylamino-1- receptor and/or transporter is expressed by a cell. (4-methoxyphenyl)-ethyl-cyclohexanol (do-Venlafaxine, 0316. In certain embodiments, the inter-individual varia Forms A-F). Other methods are well known in the art, such as, tion in plasma levels of the compounds as disclosed herein, or single X-ray crystal diffraction, may be used to identify afore metabolites thereof, is decreased as defined herein. 0317 Disclosed herein are methods for treating a subject, mentioned salt forms of compounds of formula I. including a human, having or Suspected of having a disorder 0310. The hydrochloride salt Forms A-F of the compound comprising administering to the Subject a therapeutically of formula I have high crystallinity, i.e., substantially free of effective amount of a compound as disclosed herein or a amorphous material. Such salts provide more reproducible pharmaceutically acceptable salt, Solvate, or prodrug thereof. dosing results. The hydrochloride salt Forms A-F of the com So as to affect increased average plasma levels of the com pound of formula I are substantially hygroscopically stable, pound or decreased average plasma levels of at least one which alleviates potential problems associated with weight metabolite of the compound per dosage unit as compared to changes of the active ingredient during the manufacture of the corresponding non-isotopically enriched compound. capsules or tablets. The hydrochloride Forms A-F of the com 0318. In certain embodiments, the average plasma levels pound of formula I also have a low tendency for concentrated of the compounds as disclosed herein are increased as defined aqueous Solution to form viscous mixtures upon standing. herein. The hydrochloride salt Forms A-F of the compound of for 0319. In certain embodiments, the average plasma levels mula I have rapid kinetic aqueous solubility which simplifies of a metabolite of the compounds as disclosed herein are aqueous dosing and make them Suitable for injectable dosage decreased as defined herein. forms. Furthermore, the hydrochloride salt Forms A-F of the 0320 Plasma levels of the compounds as disclosed herein, compound of formula I with enhanced solubility characteris or metabolites thereof, are measured using the methods tics facilitate the dissolution of solid dosage forms in a timely described by Li et al. (Rapid Communications in Mass Spec a. trometry 2005, 19, 1943-1950). 0311. The hydrochloride salt Forms A-F of the compound 0321 Disclosed herein are methods for treating a subject, of formula I have greater kinetic solubility than the free base including a human, having or Suspected of having a disorder of the compound of formula I. Additionally, the hydrochlo comprising administering to the Subject a therapeutically US 2008/02342.57 A1 Sep. 25, 2008 37 effective amount of a compound as disclosed herein or a So as to affect at least one statistically-significantly improved pharmaceutically acceptable salt, Solvate, or prodrug thereof; disorder-control and/or disorder-eradication endpoint as so as to affect a decreased inhibition of, and/or metabolism by compared to the corresponding non-isotopically enriched at least one cytochrome P450 or monoamine oxidase isoform compound. Examples of improved disorder-control and/or in the Subject during the treatment of the disease as compared disorder-eradication endpoints include, but are not limited to, to the corresponding non-isotopically enriched compound. statistically-significant improvement of pain indices, depres 0322 Examples of cytochrome Paso isoforms in a mam sion indices, and/or diminution of hepatotoxicity, as com malian subject include, but are not limited to, CYP1A1, pared to the corresponding non-isotopically enriched com CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, pound. CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, 0331 Disclosed herein are methods for treating a subject, CYP2E1, CYP2G1 CYP2J2, CYP2R1, CYP2S1, CYP3A4, including a human, having or Suspected of having a disorder CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, comprising administering to the Subject a therapeutically effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt, Solvate, or prodrug thereof. So as to affect an improved clinical effect as compared to the CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, corresponding non-isotopically enriched compound. CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and Examples of improved clinical effects include, but are not CYP51. limited to, statistically-significant improvement of pain indi 0323 Examples of monoamine oxidase isoforms in a ces, perfusion of ischemic tissues with oxygen, prevention of mammalian Subject include, but are not limited to, MAO ischemia, entheogenic effects sufficient to facilitate psycho and MAO. therapy, cataleptic effects sufficient to enable medical treat 0324. In certain embodiments, the decrease in inhibition ment of a non-compliant trauma victim, neuroprotection dur of the cytochrome Paso or monoamine oxidase isoform by a ing an ischemic event, and/or diminution of hepatotoxicity, as compound as disclosed herein is greater than about 5%, compared to the corresponding non-isotopically enriched greater than about 10%, greater than about 20%, greater than compound. about 30%, greater than about 40%, or greater than about 50% 0332 Disclosed herein are methods for treating a subject, as compared to the corresponding non-isotopically enriched including a human, having or Suspected of having a disorder compounds. comprising administering to the Subject a therapeutically 0325 The inhibition of the cytochrome Paso isoform is effective amount of a compound as disclosed herein or a measured by the method of Ko et al. (British Journal of pharmaceutically acceptable salt, Solvate, or prodrug thereof. Clinical Pharmacology, 2000, 49, 343-351). The inhibition so as to affect prevention of recurrence, or delay of decline or of the MAO isoform is measured by the method of Weyler et appearance, of abnormal alimentary or hepatic parameters as al. (J. Biol. Chem. 1985,260, 13199-13207). The inhibition of the primary clinical benefit, as compared to the corresponding the MAO isoform is measured by the method of Uebelhack non-isotopically enriched compound. et al. (Pharmacopsychiatry, 1998, 31, 187-192). 0333 Disclosed herein are methods for treating a subject, 0326 Disclosed herein are methods for treating a subject, including a human, having or Suspected of having a disorder including a human, having or Suspected of having a disorder comprising administering to the Subject a therapeutically comprising administering to the Subject a therapeutically effective amount of a compound as disclosed herein or a effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt, Solvate, or prodrug thereof. pharmaceutically acceptable salt, Solvate, or prodrug thereof; So as to allow the treatment while reducing or eliminating So as to affect a decreased metabolism via at least one poly deleterious changes in any diagnostic hepatobiliary function morphically-expressed cytochrome P450 isoform in the sub endpoints as compared to the corresponding nonisotopically ject during the treatment of the disease as compared to the enriched compound. corresponding non-isotopically enriched compound. 0334 Examples of diagnostic hepatobiliary function end 0327 Examples of polymorphically-expressed cyto points include, but are not limited to, alanine aminotrans chrome Paso isoforms in a mammalian Subject include, but are ferase (ALT), serum glutamic-pyruvic transaminase not limited to, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. (“SGPT), aspartate aminotransferase (“AST' or “SGOT), 0328. In certain embodiments, the decrease in metabolism ALT/AST ratios, serum aldolase, alkaline phosphatase of the compound as disclosed hereinby at least one polymor (ALP), ammonia levels, bilirubin, gamma-glutamyl phically-expressed cytochrome Paso isoforms cytochrome transpeptidase (“GGTP” “Y-GTP or “GGT), leucine ami Pisoform is greater than about 5%, greater than about 10%, nopeptidase (“LAP), liver biopsy, liver ultrasonography, greater than about 20%, greater than about 30%, greater than liver nuclear Scan, 5'-nucleotidase, and blood protein. Hepa about 40%, or greater than about 50% as compared to the tobiliary endpoints are compared to the stated normal levels corresponding non-isotopically enriched compound. as given in “Diagnostic and Laboratory Test Reference', 4' 0329. The metabolic activities of liver microsomes and the edition, Mosby, 1999. These assays are run by accredited cytochrome Paso isoforms are measured by the methods laboratories according to standard protocol. described in Examples 41 and 42. The metabolic activities of 0335 Depending on the disease to be treated and the sub the monoamine oxidase isoforms are measured by the meth ject's condition, the compound of Formula I provided herein ods described in Examples 42 and 43. may be administered by oral, parenteral (e.g., intramuscular, 0330 Disclosed herein are methods for treating a subject, intraperitoneal, intravenous, ICV, intracistemal injection or including a human, having or Suspected of having a disorder infusion, Subcutaneous injection, or implant), inhalation, comprising administering to the Subject a therapeutically nasal, vaginal, rectal, Sublingual, or topical (e.g., transdermal effective amount of a compound as disclosed herein or a or local) routes of administration, and may be formulated, pharmaceutically acceptable salt, Solvate, or prodrug thereof; alone or together, in Suitable dosage unit with pharmaceuti US 2008/02342.57 A1 Sep. 25, 2008

cally acceptable carriers, adjuvants and vehicles appropriate 0342. In certain embodiments, the compounds disclosed for each route of administration. herein can be combined with one or more opioid antagonists 0336. The dose may be in the form of one, two, three, four, known in the art, including, but not limited to, nalmefene, five, six, or more Sub-doses that are administered at appro maltrexone, and naloxone. priate intervals per day. The dose or sub-doses can be admin 0343. In certain embodiments, the compounds disclosed istered in the form of dosage units containing from about 0.1 herein can be combined with one or more local and/or general to about 1000 milligram, from about 0.1 to about 500 milli anesthetics and sedatives known in the art, including, but not grams, or from 0.5 about to about 100 milligrams of active limited to, propofol, procaine, lidocaine, prilocaine, bupiv ingredient(s) per dosage unit, and if the condition of the acaine, levobupivicaine, nitrous oxide, halothane, enflurane, patient requires, the dose can, by way of alternative, be isoflurane, sevoflurane, desflurane, thiopental, methohexital, administered as a continuous infusion. etomidate, diazepam, midazolam, lorazepam, Succinylcho 0337. In certain embodiments, an appropriate dosage level is about 0.01 to about 100 mg per kg patient body weight per line, Vecuroniurn, rocuronium, pipecuronium, rapacuronium, day (mg/kg per day), about 0.01 to about 50 mg/kg per day, tubocurarine, and gallamine. about 0.01 to about 25 mg/kg per day, or about 0.05 to about 0344) The compounds disclosed herein can also be admin 10 mg/kg per day, which may be administered in single or istered in combination with other classes of compounds, multiple doses. A suitable dosage level may be about 0.01 to including, but not limited to, endothelin converting enzyme about 100 mg/kg per day, about 0.05 to about 50 mg/kg per (ECE) inhibitors, such as phosphoramidon; thromboxane day, or about 0.1 to about 10 mg/kg per day. Within this range receptor antagonists, such as ifetroban; potassium channel the dosage may be about 0.01 to about 0.1, about 0.1 to about openers; thrombin inhibitors, such as hirudin; growth factor 1.0, about 1.0 to about 10, or about 10 to about 50 mg/kg per inhibitors, such as modulators of PDGF activity; platelet acti day. Vating factor (PAF) antagonists; anti-platelet agents, such as GPIb/IIIa blockers (e.g., abdximab, eptifibatide, and Combination Therapy tirofiban), P2Y (AC) antagonists (e.g., clopidogrel, ticlopi dine and CS-747), and aspirin; anticoagulants, such as war 0338. The a compound as disclosed herein or pharmaceu farin; low molecular weight heparins, such as enoxaparin; tically acceptable salts, Solvates, or prodrugs thereofmay also Factor VIa Inhibitors and Factor Xa Inhibitors; renin inhibi be combined or used in combination with other agents useful tors; neutral endopeptidase (NEP) inhibitors; vasopepsidase in the treatment, prevention, or amelioration of one or more inhibitors (dual NEP-ACE inhibitors), such as omapatrilat symptoms of the disorders for which the compound provided and gemopatrilat; HMG CoA reductase inhibitors, such as herein are useful. Or, by way of example only, the therapeutic pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 effectiveness of one of the compounds described herein may (a.k.a. itavastatin, nis vastatin, or nisbastatin), and ZD-4522 be enhanced by administration of an adjuvant (i.e., by itself (also known as rosuvastatin, or atavastatin or visastatin); the adjuvant may only have minimal therapeutic benefit, but squalene synthetase inhibitors; fibrates; bile acid seques in combination with another therapeutic agent, the overall trants. Such as questran; niacin; anti-atherosclerotic agents, therapeutic benefit to the patient is enhanced). such as ACAT inhibitors; MTP Inhibitors; calcium channel 0339 Such other agents, adjuvants, or drugs, may be blockers, such as amlodipine besylate; potassium channel administered, by a route and in an amount commonly used activators; alpha-histamine H1 agents; beta-histamine H1 therefor, simultaneously or sequentially with a compound as agents, such as carvedilol and metoprolol, antiarrhythmic disclosed herein or a pharmaceutically acceptable salt, Sol agents: diuretics, such as chlorothlazide, hydrochlorothiaz Vate, or prodrug thereof. When a pharmaceutically acceptable ide, flumethiazide, hydroflumethiazide, bendroflumethiaz salt of a compound as disclosed herein is used contempora ide, methylchlorothiazide, trichloromethiazide, polythiazide, neously with one or more other drugs, a pharmaceutical com benzothlazide, ethacrynic acid, tricrynafen, chlorthalidone, position containing Such other drugs in addition to the com furosenilde, musolimine, bumetanide, triamterene, pound disclosed herein may be utilized, but is not required. amiloride, and spironolactone; thrombolytic agents, such as Accordingly, the pharmaceutical compositions disclosed tissue plasminogen activator (tPA), recombinant tRA, strep herein include those that also contain one or more other active tokinase, urokinase, prourokinase, and anisoylated plasmino ingredients ortherapeutic agents, in addition to the compound gen streptokinase activator complex (APSAC); anti-diabetic provided herein. agents, such as biguanides (e.g. metformin), glucosidase 0340. In certain embodiments, the compounds disclosed inhibitors (e.g., acarbose), insulins, meglitinides (e.g., repa herein can be combined with one or more modulators of glinide), Sulfonylureas (e.g., glimepiride, glyburide, and glip NMDA-receptors known in the art, including, but not limited izide), thioZolidinediones (e.g. troglitaZone, rosiglitaZone to, phencyclidine (PCP), amantadine, ibogaine, memantine, and pioglitaZone), and PPAR-gamma agonists; mineralocor dextrorphan, ketamine, nitrous oxide, and dextromethorphan. ticoid receptor antagonists, such as Spironolactone and 0341. In certain embodiments, the compounds provided eplerenone; growth hormone secretagogues; aP2 inhibitors; herein can be combined with one or more natural, semisyn phosphodiesterase inhibitors, such as PDE III inhibitors (e.g., thetic, or fully synthetic opioids known in the art, including, cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil. but not limited to, morphine, codeine, thebain, diacetylmor Vardenafil); protein tyrosine kinase inhibitors; antiinflamma phine, oxycodone, hydrocodone, hydromorphone, oxymor tories; antiproliferatives, such as methotrexate, FK506 (tac phone, nicomorphine, fentanyl, C.-methylfentanyl, alfentanil, rolimus, Prograf), mycophenolate mofetil: chemotherapeutic Sufentanil, remifentanyl, carfentanyl, ohmefentanyl, pethi agents; immunosuppressants; anticancer agents and cyto dine, ketobemidone, propoxyphene, dextropropoxyphene, toxic agents (e.g., alkylating agents, such as nitrogen mus methadone, loperamide, pentazocine, buprenorphine, etor tards, alkyl Sulfonates, nitrosoureas, ethylenimines, and tria phine, butorphanol, nalbufine, levorphanol, naloxone, naltr Zenes); antimetabolites, such as folate antagonists, purine exone, and tramadol. analogues, and pyridine analogues; antibiotics. Such as US 2008/02342.57 A1 Sep. 25, 2008 39 anthracyclines, bleomycins, mitomycin, dactinomycin, and trimethylsilyl, TBS refers to tert-butyldimethylsilyl. Ms plicamycin; enzymes, such as L-asparaginase; farnesyl-pro refers to methanesulfonyl (CHSO ), Ts refers to p-tolu tein transferase inhibitors; hormonal agents, such as gluco enesulfonyl (p-CHPhSO ), Tfrefers to trifluoromethane corticoids (e.g., cortisone), estrogens/antiestrogens, andro sulfonyl (CFSO ), TfG) refers to trifluoromethane gens/antiandrogens, progestins, and luteinizing hormone sulfonate (CFSO, ), DO refers to deuterium oxide, DMF releasing hormone anatagonists, and ocreotide acetate; refers to N,N-dimethylformamide, DCM refers to dichlo microtubule-disruptor agents, such as ecteinascidins; micro romethane (CHCl), THF refers to tetrahydrofuran, EtOAc tubule-stabilizing agents, such as paclitaxel, docetaxel, and refers to ethyl acetate, EtO refers to diethyl ether, MeCN epothilones A-F; plant-derived products, such as Vinca alka refers to acetonitrile (CHCN), NMP refers to 1-N-methyl loids, epipodophyllotoxins, and taxanes; and topoisomerase 2-pyrrolidinone, DMA refers to N,N-dimethylacetamide, inhibitors; prenyl-protein transferase inhibitors; and cyclosporins; steroids, such as prednisone and dexametha DMSO refers to dimethylsulfoxide, DCC refers to 1,3-dicy Sone; cytotoxic drugs, such as azathiprine and cyclophospha clohexyldicarbodiimide, EDCI refers to 1-(3-dimethylami mide; TNF-alpha inhibitors, such as tenidap; anti-TNF anti nopropyl)-3-ethylcarbodiimide, Boc refers to tert-butylcar bodies or soluble TNF receptor, such as etanercept, bonyl, Fmoc refers to 9-fluorenylmethoxycarbonyl, TBAF rapamycin, and leflunomide; and cyclooxygenase-2 (COX-2) refers to tetrabutylammonium fluoride, TBAI refers to tet inhibitors, such as celecoxib and rofecoxib; and miscella rabutylammonium iodide, TMEDA refers to N.N.N.N-tet neous agents such as, hydroxyurea, procarbazine, mitotane, ramethylethylene diamine. Dess-Martin periodinane or Dess hexamethylmelamine, gold compounds, platinum coordina Martin reagent refers to 1,1,1-triacetoxy-1,1-dihydro-1,2- tion complexes, such as cisplatin, satraplatin, and carbopl benziodoxol-3(1H)-one, DMAP refers to 4-N,N-dimethy laminopyridine, (i-Pr).NEtor DIEA or Hunig's base refers to atin. N,N-diethylisopropylamine, DBU refers to 1.8-Diazabicyclo Kits/Articles of Manufacture 5.4.0]undec-7-ene, (DHQ), AQN refers to dihydroquinine anthraquinone-1,4-diyl diether, (DHQ)PHAL refers to dihy 0345 For use in the therapeutic applications described droquinine phthalazine-1,4-diyl diether, (DHQ)PYR refers herein, kits and articles of manufacture are also described to dihydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether, herein. Such kits can comprise a carrier, package, or container (DHQD)AQN refers to dihydroquinidine anthraquinone-1, that is compartmentalized to receive one or more containers 4-diyl diether, (DHQD),PHAL refers to dihydroquinidine Such as vials, tubes, and the like, each of the container(s) phthalazine-1,4-diyl diether, (DHQD)PYR refers to dihyd comprising one of the separate elements to be used in a roquinidine 2,5-diphenyl-4,6-pyrimidinediyl diether. LDA method described herein. refers to lithium diisopropylamide, LiTMP refers to lithium 0346 For example, the container(s) can comprise one or 2.2.6,6-tetramethylpiperidinamide, n-Bulli refers to n-butyl more compounds described herein, optionally in a composi lithium, t-BuLi refers to tert-butyl lithium, IBA refers to tion or in combination with another agent as disclosed herein. 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide, OsO refers The container(s) optionally have a sterile access port (for to osmium tetroxide, m-CPBA refers to meta-chloroperben example the container can be an intravenous solution bag or a Zoic acid, DMD refers to dimethyl dioxirane, PDC refers to vial having a stopper pierceable by a hypodermic injection pyridinium dichromate, NMO refers to N-methyl morpho needle). Such kits optionally comprise a compound with an line-N-oxide, NaHMDS refers to sodium hexamethyldisi identifying description or label or instructions relating to its lazide, LiHMDS refers to lithium hexamethyldisilazide, use in the methods described herein. HMPA refers to hexamethylphosphoramide, TMSC1 refers to 0347 A kit will typically comprise one or more additional trimethylsilyl chloride, TMSCN refers to trimethylsilyl cya containers, each with one or more of various materials (such nide, TBSC1 refers to tert-butyldimethylsilyl chloride, TFA as reagents, optionally in concentrated form, and/or devices) refers to trifluoroacetic acid, TFAA refers to trifluoroacetic desirable from a commercial and user standpoint for use of a anhydride, AcOH refers to acetic acid, AcO refers to acetic compound described herein. Non-limiting examples of Such anhydride, AcCl refers to acetyl chloride, TsOH refers to materials include, but are not limited to, buffers, diluents, p-toluenesulfonic acid, TsCl refers to p-toluenesulfonyl chlo filters, needles, syringes; carrier, package, container, vial and/ ride, MBHA refers to 4-methylbenzhydrylamine. BHA refers or tube labels listing contents and/or instructions for use, and to benzhydrylamine, ZnCl2 refers to Zinc (II) dichloride, BF package inserts with instructions for use. A set of instructions refers to boron trifluoride, Y(OTf) refers to yttrium (III) will also typically be included. trifluoromethanesulfonate, Cu(BF) refers to copper(II) tet 0348 Alabel or package insert can be on, in, or associated rafluoroborate, LAH refers to lithium aluminum hydride (Li with the container. A label can be used to indicate that the AlH4), LAD refers to lithium aluminum deuteride, NaHCO contents are to be used for a specific therapeutic application. refers to Sodium bicarbonate, KCO refers to Potassium The label can also indicate directions for use of the contents, carbonate, NaOH refers to sodium hydroxide, KOH refers to such as in the methods described herein. These other thera potassium hydroxide, LiOH refers to lithium hydroxide, HCl peutic agents may be used, for example, in the amounts indi refers to hydrochloric acid, HSO refers to sulfuric acid, cated in the Physicians’ Desk Reference (PDR) or as other MgSO, refers to magnesium sulfate, and Na2SO, refers to wise determined by one of ordinary skill in the art. sodium sulfate. "H NMR refers to proton nuclear magnetic 0349. As used herein, and unless otherwise indicated, the resonance, 'C NMR refers to carbon-13 nuclear magnetic following abbreviations have the following meanings: Me resonance, NOE refers to nuclear overhauser effect, NOESY refers to methyl (CH ), Et refers to ethyl (CHCH ), i-Pr refers to nuclear overhauser and exchange spectroscopy, refers to isopropyl ((CH3)2CH ), t-Bu or tert-butyl refers to COSY refers to homonuclear correlation spectroscopy, tertiary butyl ((CH)-CH ), Ph refers to phenyl, Bn refers to HMOC refers to proton detected heteronuclear multiplet benzyl (PhCH ), BZ refers to benzoyl (PhCO ), MOM quantum coherence, HMBC refers to heteronuclear multiple refers to methoxymethyl, Ac refers to acetyl, TMS refers to bond connectivity, s refers to singlet, bris refers to broad US 2008/02342.57 A1 Sep. 25, 2008 40 singlet, drefers to doublet, brid refers to broad doublet, trefers to triplet, q refers to quartet, dd refers to double doublet, m -continued refers to multiplet, ppm refers to parts permillion, IR refers to D D D, CD3 infrared spectrometry, MS refers to mass spectrometry, D N HRMS refers to high resolution mass spectrometry, EI refers YCD, to electron impact, FAB refers to fast atom bombardment, CI refers to chemical ionization, HPLC refers to high pressure O liquid chromatography, TLC refer to thin layer chromatogra DCO D phy, R, refers to retention factor, R, refers to retention time, D GC refers to gas chromatography, min is minutes, his hours, 0354) The title compound is prepared according to the rt or RT is room or ambient temperature, g is grams, mg is procedure described in Yardley et al. Journal of Medicinal milligrams, kg is kilograms, L is liters, mL is milliliters, mol Chemistry 1990, 33(10), 2899-2905, which is hereby incor is moles and mmol is millimoles. porated by reference in its entirety. A solution of d-(4-meth 0350. The invention is further illustrated by the following oxyphenyl)-acetic acid (1 SS in methylene chloride is examples. treated with oxalyl chloride (1.22 equiv) and DMF (catalytic amount) and then stirred at room temperature until all acid is converted to the acid chloride. The solvent is removed under EXAMPLES reduced pressure and the residue is taken up in methylene chloride and treated with d-dimethylamine hydrochloride (1 Example 1 equiv, Cambridge Isotopes Laboratories), ethyl diisopropy lamine (2.1 equiv), and DMAP (0.2 equiv). The mixture is do-2-(4-Methoxyphenyl)-acetic Acid stirred overnight, the solvent is removed under reduced pres Sure and the crude residue is purified by silica gel column 0351 chromatography. Example 3 da-2-(1-Hydroxycyclohexyl)-2-(4-methoxyphenyl)- D D D O N,N-dimethylacetamide 0355 D CO2H DCO lsOCD,

K2CO3, 160° C. HO D

D P D D D CO2H

DCO D D

0352 d-(4-Methoxyphenyl)-acetic acid can be prepared according to known literature procedures Ouk et al., Green Chemistry, 2002, 4(5), 431-435, which is hereby incorporated by reference in its entirety, by reacting d-(4-hydroxyphe nyl)-acetic acid (1 equiv, Cambridge Isotopes Laboratories), KCO (0.04 equiv)andd-carbonic acid dimethyl ester (1.25 equiv. Cambridge Isotopes Laboratories) at 160° C. until completion. Example 2 dis-2-(4-Methoxyphenyl)-N,N-dimethyl-acetamide 0356. The title compound is prepared according to the 0353 procedure described in Yardley et al., Journal of Medicinal Chemistry 1990, 33(10), 2899-2905, which is hereby incor porated by reference in its entirety. A solution of dis-2-(4- P D D methoxyphenyl)-N,N-dimethyl-acetamide (1 equiv) in THF is treated with n-butyllithium (1 equiv) at -78°C. The mix D 1. Oxalyl Chloride, DMF ture is stirred for 90 minutes at -78° C.; a THF solution of CO2H 2. H do-cyclohexanone (1.2 equiv. Sigma-Aldrich) is added, and -NN stirring is maintained until completion. The reaction is DCO D DC * CD quenched by addition of DO (2 equiv), the mixture is DIEA, DMAP, CH2Cl2 warmed to room temperature and the Solvent is removed D under reduced pressure and the crude residue is purified by silica gel column chromatography. US 2008/02342.57 A1 Sep. 25, 2008

Example 4 ture, filtered, and concentrated to give the crude product, de-1-2-Dimethylamino-1-(4-methoxyphenyl)- which was purified by flash chromatography using hexanes ethyl acetate to afford the desired product, d-(4-methox ethyl-cyclohexanol yphenyl)-acetonitrile, as a light yellow oil. 0357 0361. Yield: 3.99 g (89%). 'H-NMR (CDC1) 8 ppm: 3.67 (s. 2H), 6.88 (d. 2H, J–8.7 Hz), 7.22 (d. 2H, J=8.7 Hz). Example 6 d-(1-Hydroxycyclohexyl)-(4-methoxyphenyl)-ac etonitrile 0362

CN --

DCO

DCO CN OH

DCO

0363 Tetra-n-butyl ammonium hydrogen sulfate (0.10 g, 0.29 mmol) and 2N NaOH (1.2 mL) were added sequentially to a vigorously stirred d-(4-methoxyphenyl)-acetonitrile (0.85g. 5.66 mmol) at 0°C., and stirring was maintained for 30 minutes. Cyclohexanone (0.67 g. 6.8 mmol) was added to this mixture at 0-5°C. over 10 minute. The reaction mixture 0358. The title compound is prepared according to the was allowed to warm to ambient temperature and vigorous procedure described in Yardley et al., Journal of Medicinal stirring was continued for an additional 1 hour. The white Chemistry 1990, 33(10), 2899-2905, which is hereby incor precipitate was filtered and washed with water and hexanes to porated by reference in its entirety. da-2-(1-Hydroxycyclo afford the desired product, d-(1-hydroxycyclohexyl)-(4- hexyl)-2-(4-methoxyphenyl)-N,N-dimethyl-acetamide (1 methoxyphenyl)-acetonitrile, as a white solid. equiv) in THF is added dropwise to a mixture of lithium 0364 Yield: 1.28 g (91%). "H-NMR (CDC1) 8 ppm. aluminum deuteride (1.6 equiv) at 0° C. and stirred until 105-1.80 (m. 10H), 3.73 (s, 1H), 6.90 (d. 2H, J=8.7 Hz), 7.27 completion. The reaction is quenched with DO, and worked (d. 2H, J=8.7 Hz). up under standard conditions known to one skilled in the art. The mixture is then filtered and the precipitate is washed Example 7 several times with THF. The combined filtrates are evapo rated, and the residue is recrystallized from a suitable solvent. d-1-2-Amino-1-(4-methoxyphenyl)-ethyl-cyclo hexanol Example 5 d-(4-Methoxyphenyl)-acetonitrile 0365

0359 CN OH

CN CN

DCO HN HO DCO OH 0360 d-Iodomethane (8.70 g. 60 mmol) was added to a stirred solution of (4-hydroxyphenyl)-acetonitrile (4.50 g., 30 mmol) in acetone (30 mL) containing potassium carbonate DCO (6.21 g, 45 mmol) at ambient temperature, and the mixture was heated at reflux overnight, cooled to ambient tempera US 2008/02342.57 A1 Sep. 25, 2008 42

0366 d-(1-Hydroxycyclohexyl)-(4-methoxyphenyl)-ac etonitrile (400.0 mg, 1.61 mmol) was reduced on an -continued H-CubeTM continuous-flow hydrogenation reactor (Thales Nanotechnology, Budapest, Hungary) equipped witha Raney Ni catalyst cartridge (eluent: 2.0M ammonia in methanol, flow rate: 1 mL/min, temperature: 80°C., pressure: 80 bar) to OH yield the desired product, d-1-2-amino-1-(4-methoxyphe nyl)-ethyl-cyclohexanol, as a clear colorless oil. 0367. Yield: 280 mg (69%). 'H-NMR (CDC1,) 8 ppm. 105-1.80 (m. 10H), 2.59 (brs, 2H), 2.68 (t, 1H, 6.9 Hz), 3.21 DCO (m. 2H), 6.83 (d. 2H, J=9.0 Hz), 7.17 (d. 2H, J=9.0 Hz). Example 8 0371. A solution of d-1-2-trimethylammonium-1-(4- d-1-2-Trimethylammonium-1-(4-methoxyphenyl)- methoxyphenyl)-ethyl-cyclohexanol iodide in 3-amino-1- ethyl-cyclohexanol Iodide propanol (1 mL) was heated at 170° C. for 4 hours, cooled to ambient temperature, diluted with water and extracted with 0368 ethyl acetate. The combined organic layers were washed with brine, dried and concentrated under reduced pressure. The resulting residue was dissolved in 6N hydrochloric acid (5 HN ml.), washed with ether. The aqueous layer was basified with OH 30% aqueous sodium hydroxide to pH=11-12 and extracted with ethyl acetate. The organic extract was washed with brine, Her dried, and concentrated to afford do-Venlafaxine (208 mg. 73%). "H-NMR (CDC1) 8 ppm: 0.78-1.80 (m, 10H), 2.33 DCO (dd. 1H, J=12.0, 3.3 Hz), 2.96 (dd. 1H, J=12.0, 3.3 Hz), 3.31 DC CD3 (t, 1H, J=12.0 Hz), 6.81 (d. 2H, J=9.0 Hz), 7.17 (d. 2H, J=9.0 \ I Hz). MS (m/z): 287 (M+1). DC1 OH Example 10 do-1-(2-Dimethylamino-1-(4-methoxyphenyl)- ethyl-cyclohexanol hydrochloride (d-venlafaxine DCO hydrochloride) 0372 0369 D-Iodomethane (0.4 mL, 6.34 mmol) and potas sium carbonate (424 mg., 3.0 mmol) were added at ambient temperature to a solution of d1-2-amino-1-(4-methoxyphe CD3 nyl)-ethyl-cyclohexanol (252 mg, 1.0 mmol) in anhydrous tetrahydrofuran (1.5 ml.), and stirred at ambient temperature DC1 N for 20 hours. The reaction mixture was diluted with tetrahy OH drofuran, filtered, and the filtrate was concentrated in vacuo to provide the product, d-1-2-trimethylammonium-1-(4- He methoxyphenyl)-ethyl-cyclohexanol iodide, as a beige Solid. 'H-NMR (CDOD) 8 ppm: 0.90-1.80 (m. 10H), 3.19 (m. 1H), DCO 4.00 (m, 2H), 6.93 (d. J=8.1 Hz, 2H), 7.43 (d. J=8.1 Hz, 2H). CD Hn C Example 9 1 N DC * do-1-(2-Dimethylamino-1-(4-methoxyphenyl)- OH ethyl-cyclohexanol (do-Venlafaxine) 0370 DCO

PvP I 0373) A solution of de-Venlafaxine (63 mg 0.22 mmol) in DC1. ether (10 mL) was treated with 2N hydrochloric acid in ether OH (0.2 mL) at 0°C. for 10 minutes. The white precipitate was collected by filtration, washed with ether, and dried in vacuo to provide d-venlafaxine hydrochloride salt (60 mg. 85%). H-NMR (CDOD) 8 ppm: 0.95-1.80 (m. 10H), 2.83 (s, 6H), DCO 3.04 (dd. 1H, J=9.9, 5.4 Hz), 3.68 (m, 2H), 6.96 (d. 2H, J–9.0 Hz), 7.30 (d. 1H, J=9.0 Hz). US 2008/02342.57 A1 Sep. 25, 2008 43

Example 11 Example 13 d-1-2-Dimethylamino-1-(4-methoxyphenyl)- d-1-2-Trimethylammonium-1-(4-methoxyphenyl)- ethyl-cyclohexanol hydrochloride (d-Venlafaxine ethyl-cyclohexanol Iodide hydrochloride) 0378 0374

HN 1. N OH OH

DCO DCO

H -Nn C 1N I OH OH

DCO

DCO 0379 Prepared according to Example 10. Example 14 0375 Prepared according to Example 8 by substituting d-1-2-Dimethylamino-1-(4-methoxyphenyl)- methyl iodide for d-methyl iodide. 'H-NMR (CDOD) Ö ethyl-cyclohexanol (d-Venlafaxine) ppm: 0.90-1.80 (m. 10H), 3.05 (s.9H), 3.12 (m, 1H), 3.96 (m, 2H), 6.94 (d. J=8.1 Hz, 2H), 7.39 (d. J=8.1 Hz, 2H). 0380

Example 12 HN d-1-2-Dimethylamino-1-(4-methoxyphenyl)- OH ethyl-cyclohexanol (d-Venlafaxine)

0376 DCO

1 N I 1N OH OH

DCO DCO 0381 d-1-(2-Amino-1-(4-methoxyphenyl)-ethyl-cy clohexanol (207 mg, 0.82 mmol), 37% aqueous formalde hyde (0.3 mL), formic acid (0.3 mL) and water (2 mL) were stirred at 80-90° C. for 12 hours, concentrated in vacuo to a -N volume of 1.5 mL, made basic by the dropwise addition of OH aqueous 20% sodium hydroxide, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (NaSO), filtered and concentrated in vacuo to give a crude residue which was purified by silica gel chroma DCO tography (ethyl acetate-methanol-ammonium hydroxide) to give the desired product, d-1-2-dimethylamino-1-(4-meth oxyphenyl)-ethyl-cyclohexanol. 0377 Prepared according to Example 9. 'H-NMR 0382. Yield: 24.4 mg (11%). "H-NMR (methanol-d) & (CDOD) 8 ppm: 0.84-1.54 (m, 10H), 2.42 (s, 6H), 2.84-2.92 ppm: 0.84-1.54 (m. 10H), 2.42 (s, 6H), 2.84-2.92 (m. 2H), (m. 2H), 3.26-3.36 (m. 1H), 6.87 (d. 2H), 7.18 (d. 2H). 3.26-3.36 (m. 1H), 6.87 (d. 2H), 7.18 (d. 2H). US 2008/02342.57 A1 Sep. 25, 2008 44

Example 15 0387. The title compound was prepared as in Example 6 do-1-(2-Dimethylamino-1-(4-methoxyphenyl)- by substituting do-cyclohexanone (Sigma-Aldrich) for cyclohexanone and 2N NaOD in DO for 2N NaOH in water. ethyl-cyclohexanol (do-Venlafaxine) The final product was purified by recrystallization from ethyl 0383 acetate-hexanes. 0388 Yield (60%). "H-NMR (CDC1) 8 ppm: 1.60 (brs, HN 1H), 6.90 (d. 2H, J=8.4 Hz), 7.26 (d. 2H, J=8.4 Hz). OH Example 17 da-1-2-Amino-1-(4-methoxyphenyl)-ethyl-cyclo hexanol DCO CD3 0389)

DC OH

DCO

0384. A solution of d-1-(2-amino-1-(4-methoxyphenyl)- ethyl-cyclohexanol (0.126g, 0.5 mmol), d-formic acid (0.3 mL), and d-formaldehyde (20 wt % in D.O, 0.25 mL) in DO (1.5 mL) was heated at 100° C. for 16 hours, cooled to ambient temperature, diluted with water (5 mL), neutralized with 35% aqueous ammonia, and extracted with ethylacetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to yield a crude residue which was purified by flash chromatography (ethyl DCO acetate-methanol-NHOH) to give the desired product, d-1- 2-methylamino-1-(4-methoxyphenyl)-ethyl-cyclohexanol, as a light yellow semi-solid. 0385) Yield: 0.024 g (20%). 'H-NMR (CDC1) 8 ppm: 0390 da-(1-Hydroxycyclohexyl)-(4-methoxyphenyl)- 0.78-1.80 (m. 10H), 2.33 (dd. 1H, J=12.0, 3.3 Hz), 2.96 (dd. acetonitrile (570.0 mg, 2.21 mmol) was reduced on an 1H, J=12.0, 3.3 Hz), 3.31 (t, 1H, J=12.0 Hz), 6.81 (d. 2H, H-CubeTM continuous-flow hydrogenation reactor (Thales J=9.0 Hz), 7.17 (d. 2H, J=9.0 Hz). MS (m/z): 287 (M+1). Nanotechnology, Budapest, Hungary) equipped with a Raney Ni catalyst cartridge (eluent: 2.0M ammonia in methanol, Example 16 flow rate: 1 mL/min, temperature: 80°C., pressure: 80 bar) to da-(1-Hydroxycyclohexyl)-(4-methoxyphenyl)- yield the desired product, da-1-2-amino-1-(4-methoxyphe acetonitrile nyl)-ethyl-cyclohexanol, as a clear colorless oil. 0391. Yield: 530 mg (92%). "H-NMR (CDC1) 8 ppm: 0386 2.62 (brs, 3H), 3.21 (dd, 2H), 6.83 (d. 2H), 7.17 (d. 2H).

O Example 18 CN da-1-2-Dimethylamino-1-(4-methoxyphenyl)- -- ethyl-cyclohexanol (da-Venlafaxine)

DCO 0392

DCO US 2008/02342.57 A1 Sep. 25, 2008

Example 20 -continued de-4-2-Dimethylamino-1-(1-hydroxycyclohexyl)- ethyl-phenol (d-O-desmethylvenlafaxine) 0398

CD3 DC1 N OH 0393 A solution of d-1-2-amino-1-(4-methoxyphe nyl)-ethyl-cyclohexanol (257.0 mg. 0.98 mmol), formic acid (0.334 mL), and formaldehyde (37% in water, 0.146 mL) in DCO water (2.32 mL) was stirred at room temperature for 45 min CD utes. Formaldehyde (37% in water, 0.146 mL) was added and N the mixture was heated to reflux for 17 hours, cooled to room DC1 temperature, washed with ethyl acetate, made basic with 20% OH aqueous Sodium hydroxide and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a HO crude residue which was purified by column chromatography (ethyl acetate-methanol-ammonium hydroxide) to give the desired product, da-1-2-dimethylamino-1-(4-methoxyphe 0399. A 1.0 M solution of borontribromide in methylene nyl)-ethyl-cyclohexanol, as a clear colorless oil. chloride (0.125 mL, 0.125 mol) was added at -40°C. to a 0394) Yield: 154.4 mg (54%), H-NMR (methanol-d) & stirred solution of d-venlafaxine (17 mg, 0.059 mmol) in ppm: 2.25 (s, 6H), 2.55 (d. 1H), 3.14 (d. 1H), 6.84 (d. 2H), methylene chloride (0.5 mL) over 5 minutes, and the mixture 7.13 (d. 2H). was allowed to warm to 0°C. over 30 minutes. After being stirred for additional 3 hours at 0° C., the reaction was Example 19 quenched at 0°C. with aqueous 2N NaOH (0.35 mL) and the mixture was slowly allowed to warm to ambient temperature do-1-(2-Dimethylamino-1-(4-methoxyphenyl)- overnight with stirring. The solvent was removed under ethyl-cyclohexanol (do-Venlafaxine) reduced pressure and the resulting residue was extracted with ethyl acetate. The combined organic layers were washed with 0395 brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a beige Solid.

(0400 Yield: 75%. 'H-NMR (CDC1,) 8: 0.75-1.80 (m, 10H), 2.52 (dd. 1H, J=12.3, 4.2 Hz), 2.99 (dd. 1H, J=10.2, 4.2 Hz), 3.39 (t, 1H, J=10.8 Hz), 6.75 (d. 2H, J=8.7 Hz), 6.99 (d. 1H, J=8.7 Hz). MS: m/z 270.1 (M"+1). Example 21 d-4-2-Dimethylamino-1-(1-hydroxycyclohexyl)- ethyl-phenol (d-O-desmethylvenlafaxine) 04.01

0396 The title compound was prepared as in Example 15. 0397) Yield (31%). 'H-NMR (CDC1,) oppm: 2.33 (d. 1H, J=12.6 Hz), 3.30 (d. 1H, J=12.6 Hz), 6.81 (d. 2H, J=9.0 Hz), 7.05 (d. 2H, J=9.0 Hz). MS (m/z): 298 (M+1). US 2008/02342.57 A1 Sep. 25, 2008 46

-continued -continued CD HCI

DC OH

DCO (S) 0402. The title compound is prepared from da-Venlafax 0406 A solution of (-)-di-p-toluoyl-L-tartaric acid (3.60 ine according to Example 20. mmol) in ethyl acetate (10 mL) was added at once at room temperature to a solution of do-Venlafaxine (7.22 mmol) in Example 22 ethyl acetate (20 mL), and the mixture was stirred at room temperature for 4 hours. The resulting precipitate was col d-4-2-Dimethylamino-1-(1-hydroxycyclohexyl)- lected by filtration, dried and recrystallized from a mixture of ethyl-phenol (d-O-desmethylvenlafaxine) methanol and ethyl acetate to afford d-(S)-Venlafaxine di-p- toluoyl-L tartarate salt as white crystals (optical purity >99. 0403 5% by a chiral HPLC). The filtrate was used to provide d-(R)-venlafaxine (see Example 18). Chiral separation was preformed at ambient temperature on an Agilent 1100 HPLC equipped with a Chirobiotic V chiral column (Astec), 250x 4.6 mm column. Isocratic gradient: 5 mMammonium acetate in water (60%) and tetrahydrofuran (40%); Flowrate: 1 mL/min: Run time: 30 minutes; Injection volume: 10 LIL injection (1 mg/mL). UV wavelength: 229 nm. All samples were dissolved in acetonitrile-water (1:1). 0407 d-(S)-Venlafaxine di-p-toluoyl-L tartarate salt was DCO suspended in dichloromethane (25 mL) and treated with 2N NaOHuntil pH 13. The layers were separated and the aqueous

layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium Sulfate, filtered, and concentrated to give d-(S)-Venlafaxine as a white solid Yield: 0.71 g. 'H-NMR (CDC1) 8: 0.75-1.80 (m. 10H), 2.37 (s, 6H), 2.40 (m, 1H), 3.01 (dd. 1H, J=11.1.3.3 Hz), 3.39 (t, 1H, J=12.0 Hz), 6.81 (d. 2H, J=8.7 Hz), 7.05 (d. 1H, J=8.7 Hz). MS: m/z 281.3 (M"+1). 04.08 d-(S)-Venlafaxine (0.69 g, 2.46 mol) was dissolved in ether (30 mL) and treated with a solution of 2N HCl in ether (1.7 mL) at 0-5° C. for 10 minutes. The precipitate was filtered, washed with ether, and recrystallized from a mixture of ether and methanol to give d-(S)-Venlafaxine HCl salt as a white solid (optical purity >99.5% by chiral HPLC). 04.04 The title compound is prepared from de-Venlafax (0409 Yield: 0.55g. 'H-NMR (CDOD) 8: 0.95-1.80 (m, ine according to Example 20. 10H), 2.83 (s, 6H), 3.04 (dd. 1H, J=9.9, 5.4 Hz), 3.68 (m, 2H), 6.96 (d. 2H, J=9.0 Hz), 7.30 (d. 1H, J=9.0 Hz). Chiral HPLC: Example 2 RT=23.45 min. 3-(S)-do-1-(2-Dimethylamino-1-(4-methoxyphenyl)- Example 24—(R)-d-1-2-Dimethylamino-1-(4- ethyl-cyclohexanol Hydrochloride Salt ((S)-di-ven methoxyphenyl)-ethyl-cyclohexanol Hydrochloride lafaxine HCl) Salt ((R)-di-venlafaxine HCl) 0405 0410

OH OH

DCO DCO US 2008/02342.57 A1 Sep. 25, 2008 47

Example 26 -continued (R)-d-1-2-Dimethylamino-1-(4-methoxyphenyl)- ethyl-cyclohexanol hydrochloride ((R)-di-venlafax ine HCl) P 0414 DC1 N N. HCI pH

1. N OH DCO (R) DCO 0411. The filtrate obtained in Example 23 was concen H n C trated under reduced pressure, and the resulting residue (1.80 -n. g) was dissolved in dichloromethane and treated with 2N pH aqueous Sodium hydroxide as in Example 23, washed with brine, and concentrated to give a white Solid (1.01 g), which was dissolved in ethyl acetate (15 mL) and treated with (+)- di-p-toluoyl-D-tartaric acid in ethyl acetate (10 mL). The DCO mixture was stirred at room temperature for 4 hours. The resulting white precipitate was collected by filtration and 0415 Prepared according to Example 23. recystallized from a mixture of ethyl acetate and methanol to Example 27 provide d-(R)-Venlafaxine di-p-toluoyl-D tartarate salt (op ds-5-(4-Methoxy-phenyl)-3-methyl-1-Oxa-3-aza tical purity >99.5% by chiral HPLC). The corresponding free spiro5.5undecane base of d-(R)-venlafaxine (optical purity >99.5% by chiral HPLC) were prepared as in Example 23. 0416

Example 25 HN (S)-d-1-2-Dimethylamino-1-(4-methoxyphenyl)- OH ethyl-cyclohexanol hydrochloride (S)-di-venlafax ine HCl) DCO 0412

NP D Sk D 1. N O OH

DCO

DCO 0417. A solution of d-1-(2-amino-1-(4-methoxyphenyl)- ethyl-cyclohexanol (0.126 g., 0.5 mmol), d formic acid (0.3 mL), and d-formaldehyde (20 wt % in deuterium oxide, 0.25 H mL) in deuterium oxide (1.5 mL) was heated at 100° C. for 16 n C hours, cooled to ambient temperature, diluted with water (5 1N mL), neutralized with 35% aqueous ammonia, and extracted OH with ethyl acetate. The combined organic layers were dried over sodium Sulfate and concentrated under reduced pressure to yield a crude residue which was purified by flash chroma tography (ethyl acetate-methanol-ammonium hydroxide) to DCO give the desired product, ds-5-(4-methoxyphenyl)-3-methyl 1-Oxa-3-aza-spiro[5.5undecane. 'H-NMR (CDC1) 8: 0.75 1.80 (m, 9H), 2.28 (brid, 1H), 2.70 (dd. 1H, J=12.3, 3.6 Hz), 3.03 (dd. 1H, J=12.3, 3.6Hz), 3.21 (t, 1H, J=12.3 Hz), 6.81 (d. 0413 Prepared according to Example 23. 2H, J=8.7 Hz), 7.05 (d. 2H, J=8.7 Hz). MS: m/z 284 (M+1). US 2008/02342.57 A1 Sep. 25, 2008 48

Example 28 cooled to ambient temperature, diluted with water, basified to do-1-(2-Dimethylamino-1-(4-methoxyphenyl)- pH-11 with 2N aqueous sodium hydroxide, and extracted ethyl-cyclohexanol (do-Venlafaxine) with ethyl acetate. The combined organic extracts were dried 0418 and concentrated under reduced pressure to give a crude residue, which was purified by flash column chromatography to afford dis-Venlafaxine (68 mg, 55%) as a white solid. 'H-NMR (CDC1) 8: 0.75-1.80 (m, 10H), 2.28 (s, 1H), 2.32 p (dd. 1H, J=12.3, 3.3 Hz), 2.96 (dd. 1H, J=12.3, 3.3 Hz), 3.31 N D (t, 1H, J=12.3 Hz), 6.81 (d. 2H, J=8.7 Hz), 7.05 (d. 2H, J=8.7 SK, He Hz). MS: m/z 286.4 (M+1). O Example 30 d-1-2-Dimethylamino-1-(4-methoxyphenyl)- DCO ethyl-cyclohexanol hydrochloride (ds-Venlafaxine CD3 hydrochloride) DC1 N 0422 OH CDH DC1 N DCO OH

0419. A stirred emulsion of ds-5-(4-methoxyphenyl)-3- methyl-1-oxa-3-aza-spiro5.5undecane (1.93 g. 6.82 mmol) in deuterium oxide (25 mL) was treated with d-formic acid DCO (1.96 g. 40.92 mmol), and 30% sodium deuteroxide in deu CDH terium oxide (2.8 mL. 20.46 mmol) at ambient temperature. The resulting clear solution was heated at 100° C. for 20 HS C hours, cooled to ambient temperature, diluted with water, DC1 N. basified to pH=11 with 2N aqueous sodium hydroxide, and pH extracted with ethyl acetate. The combined organic extracts were dried and concentrated under reduced pressure to give a crude residue, which was purified by flash column chroma tography to afford do-Venlafaxine (1.21 g, 62%) as a white DCO solid. Example 29 ds-1-2-Dimethylamino-1-(4-methoxyphenyl)- 0423 Prepared according to Example 23. "H-NMR ethyl-cyclohexanol (dis-Venlafaxine) (CDOD) 8: 0.85-1.80 (m, 10H), 2.80 (s, 1H), 3.04 (dd. 1H, J=9.9, 5.4 Hz), 3.59-3.75 (m, 2H), 6.96 (d. 2H, J=8.4 Hz), 0420 7.30 (d. 2H, J=8.4 Hz). Example 31 p ds-1-2-Amino-1-(4-methoxyphenyl)-ethyl-cyclo N SK,D hexanol O 0424

NC DCO CDH D.C1 N HO --- OH DCO NC D

D DCO HO 0421) A stirred emulsion of ds-5-(4-methoxyphenyl)-3- methyl-1-oxa-3-aza-spiro5.5undecane (123 mg, 0.434 DCO mmol) in water (1 mL) was treated with formic acid (100 mg. 2.17 mmol), and sodium formate at 100° C. for 18 hours, US 2008/02342.57 A1 Sep. 25, 2008 49

0425 The title compound can be prepared according to the 0429. The title compound was prepared from (S)-d-ven procedure of Example 7, by substituting the water reservoir lafaxine according to Example 20. with a deuterium oxide reservoir for the generation of deute rium gas. Example 34 do-1-(2-Dimethylamino-1-(4-methoxyphenyl)- Example 32 ethyl-cyclohexanol hydrochloride Form A (R)-de-4-2-Dimethylamino-1-(1-hydroxycyclo hexyl)-ethyl-phenol ((R)-di-O-desmethylvenlafax d-venlafaxine hydrochloride Form A ine) 0430 de-Venlafaxine hydrochloride (500 mg) was dis solved in isopropanol (8 mL) at about 60° C., and subse 0426 quently cooled to 0-5°C. in ice-water bath and kept at that temperature for about 3 hours. The solid was filtered, washed with cold isopropanol and dried under high Vacuum to give P do-Venlafaxine hydrochloride Form A (248 mg). Character N istic X-ray powder diffraction peaks (2-theta, 96 relative DC1 N. intensity): 6.703 (29.3), 8.321 19, 12.681 (77.5, 13.547. pH 9, 15.5417.7, 18.918 24.4, 20.359 100, 21.161 38.3), 21.76226.1, 25.0427.8, 28.51818.2), and 35.18115.5. A sample of do-Venlafaxine hydrochloride Form A was ana lyzed by infrared spectroscopy. The results are shown in FIG. DCO 7. (R) P Example 35 DC1 N N. do-1-(2-Dimethylamino-1-(4-methoxyphenyl)- pH ethyl-cyclohexanol hydrochloride Form B d-venlafaxine hydrochloride Form B 0431 de-Venlafaxine hydrochloride (150 mg) was tritu rated in a vial with acetone at about 60° C. for about 1 hour HO and cooled to 0-5°C. for about 1 hour. The solid was filtered, (R) washed with cold acetone and dried at 50° C. on rotary evapo rator to a constant weight to give ds-Venlafaxine hydrochlo 0427. The title compound was prepared from (R)-di-ven ride Form B (102 mg). Characteristic X-ray powder diffrac lafaxine according to Example 20. tion peaks (2-theta, 96 relative intensity)): 6.683 15.5, 10.201 (93.6, 13.441 (27.8), 15.517 66.2, 18.198 (41), Example 33 19.719 (34.1, 20.258 100, 21.68 71.2, 22.658 (24.8), 25.543 (22.4, 28.02220.9, and 35.02 (33.4. A sample of (S)-de-4-2-Dimethylamino-1-(1-hydroxycyclo d-Venlafaxine hydrochloride Form B was analyzed by infra hexyl)-ethyl-phenol ((S)-di-O-desmethylvenlafax red spectroscopy. The results are shown in FIG.8. A sample ine) of de-Venlafaxine hydrochloride Form B was heated at 10° C./min from ambient to approximately 700° C. and then in 0428 regular mode to 1000° C., in a nitrogen atmosphere (25 cc/min). The results are shown in FIG. 13. CD3 Example 36 DC do-1-(2-Dimethylamino-1-(4-methoxyphenyl)- OH ethyl-cyclohexanol hydrochloride Form C d-Venlafaxine hydrochloride Form C 0432 A slurry of d-venlafaxine hydrochloride Form A DCO (70 mg) in isopropanol (0.56 mL) was stirred in a vial at (S) ambient temperature for 3 days. The solid was filtered, washed with cold isopropanol and dried under high vacuum to give d-venlafaxine hydrochloride Form C (30 mg). Char acteristic X-ray powder diffraction peaks (2-theta, '% relative OH intensity): 6.71821.4), 8.335 (20.6), 12.6880), 13.540.7. 15.539 (20.2, 16.282 24.3, 18.902 (48.9, 19.737 (17.4), 20.34 100, 21.161 (79.4, 21.758 (30.5, 25.601 18.9, 26.261 (15.2), 28.51830.2, 31.5418.7), 33.93716.5, and HO 35.159 (21.3. A sample of d-venlafaxine hydrochloride (S) Form C was analyzed by infrared spectroscopy. The results are shown in FIG. 9. A sample of d-venlafaxine hydrochlo ride Form C was heated at 10° C./min from ambient to US 2008/02342.57 A1 Sep. 25, 2008 50 approximately 700° C. and then in regular mode to 1000°C., and 35.445 16.2. A sample of do-Venlafaxine hydrochloride in a nitrogen atmosphere (25 cc/min). The results are shown Form F was analyzed by infrared spectroscopy. The results in FIG. 14. are shown in FIG. 12.

Example 37 Example 40 In Vitro Liver Microsomal Stability Assay do-1-(2-Dimethylamino-1-(4-methoxyphenyl)- ethyl-cyclohexanol hydrochloride Form D 0436 Liver microsomal stability assays were conducted at 1 mg per mL liver microsome protein with an NADPH generating system in 2% NaHCO, (2.2 mM NADPH, 25.6 do-Venlafaxine hydrochloride Form D mM glucose 6-phosphate, 6 units per mL glucose 6-phos 0433) A suspension of d-venlafaxine hydrochloride (1.45 phate dehydrogenase and 3.3 mM MgCl). Test compounds were prepared as solutions in 20% acetonitrile-water and g) in ether (40 mL) was heated under reflux at 65° C. Metha added to the assay mixture (final assay concentration 5 micro nol was added dropwise to the mixture until it became homo gram per mL) and incubated at 37°C. Final concentration of geneous and the Solution was cooled to ambient temperature, acetonitrile in the assay were <1%. Aliquots (50 uL) were and kept at that temperature for 1 hour and at 0-5°C. for an taken out at times 0, 15, 30, 45, and 60 minutes, and diluted additional 3 hours. The solid was filtered and dried under high with ice cold acetonitrile (200 uL) to stop the reactions. vacuum to provide d-venlafaxine hydrochloride Form D Samples were centrifuged at 12000 RPM for 10 minutes to (1.08 g). Characteristic X-ray powder diffraction peaks precipitate proteins. Supernatants were transferred to micro (2-theta, 96 relative intensity): 6.7421.2.7.42114,8.341 centrifuge tubes and stored for LC/MS/MS analysis of the 35.5, 10.21923, 12.7 99.5, 13.502 (40.7, 17.917.5), degradation half-life of the test compounds. It has thus been 15.541 (37.3, 20.36 (100), 21.221 23.7), 21.761 (41), found that the compounds as disclosed herein that have been 25.078 (26.3, 31.04 17.7), and 35.139 22.7. A sample of tested in this assay showed an increase of 10% or more in the do-Venlafaxine hydrochloride Form D was analyzed by infra degradation half-life, as compared to the non-isotopically red spectroscopy. The results are shown in FIG. 10. enriched drug. For example, the degradation half-life of (+)- d-Venlafaxine, (R)-di-Venlafaxine, (S)-di-Venlafaxine, (+)- Example 38 ds-Venlafaxine, (+)-de-Venlafaxine, (R)-do-Venlafaxine, (S)- do-Venlafaxine, da-Venlafaxine, and do-Venlafaxine were do-1-(2-Dimethylamino-1-(4-methoxyphenyl)- increased by 50-300% as compared to non-isotopically ethyl-cyclohexanol hydrochloride Form E enriched Venlafaxine. d-Venlafaxine hydrochloride Form E Example 41 0434 d-Venlafaxine hydrochloride Form D (98 mg) was In Vitro Metabolism. Using Human Cytochrome Pso heated in a sealed tube for 1.5 hours at 200-200° C. and cooled Enzymes to ambient temperature. Characteristic X-ray powder diffrac tion peaks (2-theta, '% relative intensity): 5.597 28, 7.182 0437. The cytochrome Paso enzymes are expressed from 36.2), 9.07824.1), 9.557 (14.9, 11.201 100, 14.46.40.2, the corresponding human cDNA using a baculovirus expres 14.76 4.0.4, 16.86 (71.7, 17.497 15.7, 19.201 66.5, sion system (BDBiosciences). A 0.25 milliliter reaction mix 19.619 19.6, 20.241 35.2, 20.66 (19.6, 21.76 22.5), ture containing 0.8 milligrams per milliliter protein, 1.3 mil 22.596 (26.4), 23.0613.2, 24.415.3), 26.84218.7), 31.52 limolar NADP, 3.3 millimolar glucose-6-phosphate, 0.4 12.6, and 35.438 17.9. A sample of d-venlafaxine hydro U/mL glucose-6-phosphate dehydrogenase, 3.3 millimolar chloride Form E was analyzed by infrared spectroscopy. The magnesium chloride and 0.2 millimolar of a compound of results are shown in FIG. 11. A sample of d-venlafaxine Formula I, the corresponding non-isotopically enriched com hydrochloride Form E was heated at 110°C/min from ambi pound or standard or control in 100 millimolar potassium ent to approximately 700° C. and then in regular mode to phosphate (pH 7.4) is incubated at 37° C. for 20 min. After 1000°C., in a nitrogen atmosphere (25 cc/min). The results incubation, the reaction is stopped by the addition of an are shown in FIG. 15. appropriate solvent (e.g. acetonitrile, 20% trichloroacetic acid, 94% acetonitrile/6% glacial acetic acid, 70% perchloric acid, 94% acetonitrile/6% glacial acetic acid) and centrifuged Example 39 (10,000 g) for 3 minutes. The Supernatant is analyzed by HPLC/MS/MS. do-1-(2-Dimethylamino-1-(4-methoxyphenyl)- ethyl-cyclohexanol hydrochloride Form F do-Venlafaxine hydrochloride Form F Cytochrome P4so Standard CYP1A2 Phenacetin 0435 d-Venlafaxine hydrochloride Form A (68 mg) was CYP2A6 Coumarin heated at 205°C. for 2 hours and cooled to ambient tempera CYP2B6 'C-(S)-mephenytoin CYP2C8 Paclitaxel ture. The crystals that formed at the top of the flask were CYP2C9 Diclofenac collected. Characteristic X-ray powder diffraction peaks CYP2C19 'C-(S)-mephenytoin (2-theta, 9% relative intensity): 5.581 (26.1, 7.186 18.3), CYP2D6 (+/-)-Bufuralol 11.22 100, 14.499 (18.8, 14.802 (20.5, 16.882 (63.9, CYP2E1 ChlorZoxazone 19.242 (38.4, 20.317 (51.6, 21.798 17.5), 22.637 (26.3), US 2008/02342.57 A1 Sep. 25, 2008 51

0443 Human Norepinephrine transporter: GenBank -continued M65105. Pacholczyk et al, Nature 1991, 350, 350-354, which is hereby incorporated by reference in its entirety. Cytochrome P4so Standard 0444 Human Serotonin transporter: GenBank L05568. CYP3A4 Testosterone Ramamoorthy et al. Proceedings of the National Academy CYP4A 'C-Lauric acid of Sciences of the USA 1993, 90, 2542-2546, which is hereby incorporated by reference in its entirety. Example 42 Example 45 Monoamine Oxidase A Inhibition and Oxidative Turnover In Vitro SPA Binding Assay for the Norepinephrine 0438. The procedure is carried out as described in Weyler, Transporter Journal of Biological Chemistry 1985, 260, 13199-13207. Monoamine oxidase A activity is measured spectrophoto 0445. The assay is preformed according to the procedure metrically by monitoring the increase in absorbance at 314 described in Gobel et al., Journal of Pharmacological and nm on oxidation of kynuramine with formation of 4-hydrox Toxicological Methods 1999, 42(4), 237-244, which is hereby ycuinoline. The measurements are carried out, at 30°C., in 50 incorporated by reference in its entirety. Compound of For mM NaP, buffer, pH 7.2, containing 0.2% Triton X-100 mula I or the corresponding non-isotopically enriched com (monoamine oxidase assay buffer), plus 1 mM kynuramine, pounds are serotonin/norepinephrine reuptake inhibitors; and the desired amount of enzyme in 1 mL total Volume. H-nisoxetine binding to norepinephrine re-uptake sites in a cell line transfected with DNA encoding human norepineph Example 43 rine transporter binding protein has been used to determine Monoamine Oxidase B Inhibition and Oxidative the affinity of ligands at the norepinephrine transporter. Turnover 0439. The procedure is carried out as described in Uebel Membrane Preparation hack, Pharmacopsychiatry 1998, 31, 187-192. 0446 Cell pastes from large scale production of HEK-293 cells expressing cloned human norepinephrine transporters Pharmacology are homogenized in 4 volumes of 50 millimolar Tris-HCl 0440 The pharmacological profile of compounds of For containing 300 millimolar NaCl and 5 millimolar KC1, pH mula I or the corresponding non-isotopically enriched com 7.4. The homogenate is centrifuged twice (40,000 g, 10 min pounds or standards or controls can be demonstrated as fol utes. 4°C.) with pellet re-suspension in 4 volumes of Tris lows. The preferred exemplified compounds exhibit a K, HCl buffer containing the above reagents after the first spin, value less than 1 micromolar, more preferably less than 500 and 8 Volumes after the second spin. The Suspended homo nanomolar at the Serotonin transporter as determined using genate is centrifuged (10g, 10 minutes. 4°C.), the Superna the scintillation proximity assay (SPA) described below. See tant is kept and re-centrifuged (40,000 g, 20 minutes. 4°C.). WO 2005/060949. Furthermore, the preferred exemplified The pellet is re-suspended in Tris-HCl buffer containing the compounds selectively inhibit the Serotonin transporter rela above reagents along with 10% w/v sucrose and 0.1 millimo tive to the Norepinephrine and dopamine transporters by a lar phenylmethylsulfonyl fluoride (PMSF). The membrane factor of at least five using such SPAs. preparation is stored in aliquots (1.0 milliliter) at -80°C. until required. The protein concentration of the membrane prepa Example 44 ration is determined using a Bicinchoninic acid (BCA) pro Generation of Stable Cell Lines Expressing the tein assay reagent kit (available from Pierce). Human Dopamine, Norepinephrine and Serotonin Transporters HI-Nisoxetine Binding Assay 0441 Standard molecular cloning techniques are used to 0447. Each well of a 96 well microtiter plate is set up to generate stable cell-lines expressing the human dopamine, contain 50 microliters of 2 nanomolar N-methyl-3H-Nisox norepinephrine and serotonin transporters. The polymerase etine hydrochloride (70-87 Ci/millimole, from NEN Life Sci chain reaction (PCR) is used in order to isolate and amplify ence Products), 75 microliters Assay buffer (50 millimolar each of the three full-length cDNAs from an appropriate Tris-HCl pH 7.4 containing 300 millimolar NaCl and 5 mil cDNA library. PCR Primers for the following neurotransmit limolar KCl), 25 microliter of diluted compounds of Formula ter transporters are designed using published sequence data. I or the corresponding non-isotopically enriched compounds, The PCR products are cloned into a mammalian expression assay buffer (total binding) or 10 micromolar Desipramine vector, Such as for example pcDNA3.1 (Invitrogen), using HCl (non-specific binding), 50 microliter wheat germ agglu standard ligation techniques, followed by co-transfection of tinin coated poly(vinyltoluene) (WGA PVT) SPA Beads HEK293 cells using a commercially available lipofection (Amersham Biosciences RPNO0001) (10 milligram/millili reagent (LipofectamineTM Invitrogen) following the manu ter), 50 microliter membrane (0.2 milligram protein per mil facturer's protocol. liliter). The microtiter plates are incubated at room tempera 0442 Human Dopamine transporter: GenBank M95167. ture for 10 hours prior to reading in a Trilux scintillation Vandenbergh et al. Molecular Brain Research 1992, 15, counter. The results are analyzed using an automatic spline 161-166, which is hereby incorporated by reference in its fitting program (Multicalc, Packard, Milton Keynes, UK) to entirety. provide K values for each of the test compounds. US 2008/02342.57 A1 Sep. 25, 2008 52

Example 46 150 millimolar NaCl and 5 millimolar KCl), 25 microliters of diluted compounds of Formula I or the corresponding non In Vitro SPA Binding Assay for the Serotonin Trans isotopically enriched compounds, assay buffer (total binding) porter or 100 micromolar nomifensine (non-specific binding), 50 0448. The assay is preformed according to the procedure microliters WGA PVT SPA Beads (10 milligram/milliliter), described in Ramamoorthy etal, J. Biol. Chem. 1998, 273(4), 50 microliters membrane preparation (0.2 milligram protein 2458-2466, which is hereby incorporated by reference in its per milliliter). The microtiter plates are incubated at room entirety. The ability of a compound of Formula I or the cor temperature for 120 minutes prior to reading in a Trilux responding non-isotopically enriched compound to compete Scintilation counter. The results are analyzed using an auto with HI-Citalopram for its binding sites on cloned human matic spline-fitting program (Multicalc, Packard, Milton Serotonin transporter containing membranes has been used as Keynes, UK) to provide K values for each of the test com a measure of test compound ability to block Serotonin uptake pounds. via its specific transporter. Example 48 Membrane Preparation In Vivo Assay for Behavioral Despair in Rats 0449 Membrane preparation is essentially similar to that for the norepinephrine transporter containing membranes as 0454. The assay is performed according to the procedure described above. The membrane preparation is stored in ali described in Porsolt et al, Archives Internationales de Phar quots (1 milliliter) at -70° C. until required. The protein macodynamie et de Therapie, 1977. 229(2), 327-336. which concentration of the membrane preparation is determined is hereby incorporated by reference in its entirety. After intra using a BCA protein assay reagent kit. peritoneal administration of test compound in rats, animals are put in a cylinder containing water for 6 minutes. Immo HI-Citalopram Binding Assay bility time is measured during the last 4 minutes. Diminished 0450 Each well of a 96 well microtiter plate is set up to time of immobility is indicative of increased efficacy. contain 50 microliters of 2 nanomolar H-citalopram (60 0455 The examples set forth above are disclosed to give a 86Ci/millimole, Amersham Biosciences), 75 microliters complete disclosure and description of how to make and use Assay buffer (50 millimolar Tris-HCl pH 7.4 containing 150 the claimed embodiments, and are not intended to limit the millimolar NaCl and 5 millimolar KCl), 25 microliters of scope of what is disclosed herein. Modifications that are diluted compounds of Formula I or the corresponding non obvious, are intended to be within the scope of the following isotopically enriched compounds, assay buffer (total binding) claims. All publications, patents, and patent applications or 100 micromolar fluoxetine (non-specific binding), 50 cited in this specification are incorporated herein by reference microliters WGA PVT SPA Beads (40 milligram/milliliter), as if each Such publication, patent or patent application were 50 microliters membrane preparation (0.4 milligram protein specifically and individually indicated to be incorporated per milliliter). The microtiter plates are incubated at room herein by reference. However, with respect to any similar or temperature for 10 hours prior to reading in a Trilux scintil identical terms found in both the incorporated publications, lation counter. The results are analyzed using an automatic references, patent or patent applications and those explicitly spline-fitting program (Multicalc, Packard, Milton Keynes, put forth or defined in this document, then those terms defi UK) to provide K, (nanomolar) values for each of the test nitions or meanings explicitly put forth in this document shall compounds. control in all respects. Example 47 REFERENCES CITED In Vitro SPA Binding Assay for the Dopamine Trans 0456. The disclosures of each of the following references porter are incorporated by reference herein in their entireties. 0451. The assay is preformed according to the procedure described in Ramamoorthy etal, J. Biol. Chem. 1998, 273(4), Patent Documents 2458-2466, which is hereby incorporated by reference in its entirety. The ability of a test compound to compete with 0457 U.S. Pat. No. 4,069,346 Feb. 14, 1977 McCarty H-WIN35,428 for its binding sites on human cell mem 04:58 U.S. Pat. No. 5,386,032 Jan. 31, 1995 Brandstrom branes containing cloned human dopamine transporter has 0459 EP0654264 May 24, 1995 Thor been used as a measure of the ability of Such test compounds 0460 U.S. Pat. No. 5,846,514 Dec. 8, 1998 Foster to block dopamine uptake via its specific transporter. 0461 U.S. Pat. No. 6,221,335 Apr. 24, 2001 Foster 0462 U.S. Pat. No. 6,333,342 Dec. 25, 2001 Foster Membrane Preparation 0463 U.S. Pat. No. 6,334,997 Jan. 1, 2002 Foster 0452 Membrane preparation is performed in the same 0464 U.S. Pat. No. 6,342.507 Jan. 29, 2002 Foster manner as membranes containing cloned human Serotonin 0465 U.S. Pat. No. 6,476,058 Nov. 5, 2002 Foster transporter as described above. 0466 U.S. Pat. No. 6,503,921 Jan. 7, 2003 Naicker 0467 U.S. Pat. No. 6,605,593 Aug. 12, 2003 Naicker H-WIN35,428 Binding Assay 0468 U.S. Pat. No. 6,613,739 Sep. 2, 2003 Naicker 0453 Each well of a 96 well microtiter plate is set up to 0469 U.S. Pat. No. 6,710,053 Mar. 23, 2004 Naicker contain 50 microliters of 4 nanomolar H-WIN35,428 (84 0470 U.S. Pat. No. 6,818,200 Nov. 16, 2004 Foster 87 Ci/millimole, from NEN Life Science Products), 5 micro 0471 U.S. Pat. No. 6,884,429 Apr. 26, 2005 Koziak liters Assay buffer (50 millimolar Tris-HCl pH 7.4 containing 0472 WO 2002064543 Aug. 22, 2002 Hadfield US 2008/02342.57 A1 Sep. 25, 2008

Other References (0505 Pacher, Current Medicinal Chemistry 2004, 11(7), 925-943. 0473 Alternatt, Cancer 1988, 62(3), 462-466. (0506 Pacher et al. Current Pharmaceutical Design 2004, 0474 Alternatt, International Journal of Cancer 1990, 10(20), 2463-2475. 45(3), 475-480. 0507 Pacholczyketal, Nature 1991, 350, 350-354. 0475 Baldwin, International Journal of Neuropsychop (0508 Phelps et al. Annals of Pharmacotherapy 2005, harmacology 2005, 8(2), 293-302. 39(1), 136-140. 0476 Baselt, Disposition of Toxic Drugs and Chemicals in (0509 Physicians Desk Reference, 2003. Man, 2004, 7th Edition. 0510 Porsolt et al. Archives Internationales de Pharma 0477 Bassapa et al. Bioorganic & Medicinal Chemistry codynamie et de Therapie, 1977, 229(2), 327-336. Letters 2004, 14, 3279-3281. 0511 Pohl, Drug Metabolism Reviews 1985 (Volume 0478 Browne, Synthesis and Applications of Isotopically Date 1984), 15(7), 1335-1351. Labelled Compounds, Proceedings of the International 0512 Preskorn et al. Handbook of Experimental Pharma Symposium, 7th, Dresden, Germany, Jun. 18-22, 2000, cology. Antidepressants. Past, Present and Future, 2004, 519-532. Volume 157. 0479 Browne, Pharmacochemistry Library, 1997, 26. 0513 Raggi, Current Topics in Medicinal Chemistry 0480 Browne, Pharmacochemistry Library, 1997, 26, 2003, 3, 203-220. 13-18. 0514 Ramamoorthy et al., J. Biol. Chem. 1998, 273(4), 2458-2466. 0481 Browne, Clinical Pharmacology & Therapeutics, 0515 Ramamoorthy et al. Proceedings of the National 1981, 29(4), 511-515. Academy of Sciences of the USA 1993, 90, 2542-2546. 0482 Browne, Journal of Clinical Pharmacology 1982, 0516 Reis et al. Therapeutic Drug Monitoring 2002, 24, 22(7), 309-315. 545-553. 0483 Browne, Synth. Appl. Isot. Labeled Compa., Proc. 0517 Roecker, J. Am. Chem. Soc. 1987, 109, 746. Int. Symp. 1983, Meeting Date 1982, 343-348. 0518 Schroeter, European Journal of Cell Biology 1992, 0484 Browne. Therapeutic Drug Monitoring 1984, 6(1), 58(2), 365-370. 3-9. 0519 Sicat et al., Pharmacotherapy 2004, 24(1), 79-93. 0485 Chavan et al, Tetrahedron Letters 2004, 45, 7291 0520 Silverstone, Journal of Clinical Psychiatry 2004, 65 7295. (Suppl. 17), 19-28. 0486 Davies et al., Journal of the Chemical Society, 0521 Tolonen, European Journal offbharmaceutical Sci Abstracts 1945, 352-354. ences 2005, 25, 155-162. 0487. Ding et al Journal of Neurochemistry 1995, 65(2), 0522 Thomson, International Series of Monographs on 682-690. Pure and Applied Biology, Modern trends in Physiological 0488 Eap et al. Pharmacogenetics 2002, 13, 39-47. Sciences, 1963, “Biological Effects of Deuterium”. 0489 Foster, Trends in Pharmacological Sciences 1984, 0523. Urey, Phys. Rev. 1932, 39, 164“A Hydrogen Isotope 5(12),524-527. of Mass 2. 0490 Garland, Synth. Appl. Isot. Labeled Compa. Proc. 0524 Vandenbergh etal, Molecular Brain Research 1992, Int. Symp. 2', 1986, Meeting Date 1985, 283-284. 15, 161-166. 0491 Gobel et al., Journal of Pharmacological and Toxi 0525 Yardley etal, Journal of Medicinal Chemistry 1990, cological Methods 1999, 42(4), 237-244 33(10), 2899-2905. 0492 Goeringer, Journal of Forensic Sciences 2000, What is claimed is: 45(3), 633-648. 1. A pharmaceutically acceptable acid addition salt of a 0493 Katzman, Expert Review of Neurotherapeutics, compound having structural formula I: 2005, 5(1), 129-139.

0494 Kaufman, Phys. Rev. 1954, 93, 1337-1344. (I) 0495 Ko et al British Journal of Clinical Pharmacology 2000, 49(4), 343-351. 0496 Kritchevsky, Annals of the New York Academy of Science 1960, vol. 84, article 16. 0497. Kushner, Can. J. Physiol. Pharmacol. 1999, 77, 79-88. 0498 Lamprect, European Journal of Cell Biology 1990, 51(2), 303-312. 0499 Lessard et al. Pharmacogenetics 1999, 9(4), 435 443. 0500 Lewis, J. Am. Chem. Soc. 1968, 90,4337. 0501 Li et al Rapid Communications in Mass Spectrom etry 2005, 19(14), 1943-1950 0502 March, Advanced Organic Chemistry 1992, 4th edi tion, 226-230. 0503 Morton et al. Annals of Pharmacotherapy 1995, wherein R-R-7 are independently selected from the group 29(4), 387-395. consisting of hydrogen and deuterium; and 0504 Ouketal Green Chemistry, 2002, 4(5), 431-435. at least one of R-R-7 is deuterium. US 2008/02342.57 A1 Sep. 25, 2008 54

2. The pharmaceutically acceptable salt as recited in claim 1, wherein said pharmaceutically acceptable salt is Substan- -continued tially a single enantiomer, a mixture of about 90% or more by C H weight of the (-)-enantiomerand about 10% or less by weight 1. N1 D of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomerand about 10% or less by weight of the (-)-enantiomer, Substantially an individual diastere omer, or a mixture of about 90% or more by weight of an HO individual diastereomer and about 10% or less by weight of any other diastereomer. DCO s 3. The pharmaceutically acceptable salt as recited in claim 1, wherein at least one of R-R-7 independently has deuterium enrichment of no less than about 1%. C H 4. The pharmaceutically acceptable salt as recited in claim 1. N D 1, wherein at least one of R-R-7 independently has deuterium D enrichment of no less than about 5%. 5. The pharmaceutically acceptable salt as recited in claim 1, wherein at least one of R-R-7 independently has deuterium enrichment of no less than about 10%. DCO 6. The pharmaceutically acceptable salt as recited in claim 1, wherein at least one of R-R-7 independently has deuterium enrichment of no less than about 20%. H 7. The pharmaceutically acceptable salt as recited in claim 1. 1, wherein at least one of R-R-7 independently has deuterium 1. l enrichment of no less than about 50%. SC 8. The pharmaceutically acceptable salt as recited in claim 1, wherein at least one of R-R-7 independently has deuterium enrichment of no less than about 90%. DCO 9. The pharmaceutically acceptable salt as recited in claim 1, wherein at least one of R-R-7 independently has deuterium C -H enrichment of no less than about 98%. D -N 10. The pharmaceutically acceptable salt as recited in 3 claim 1, wherein said pharmaceutically acceptable salt is a hydrochloride salt. HO 11. The hydrochloride salt as recited in claim 10, having a structural formula selected from the group consisting of H3CO s CD3 C -NC H C N -H DC1 1.

HO H3CO s CD3 DCO s CI HQ -N C N -H D.C. Y 1.

HO HCO s

DCO s H CD3 C Y C H 1. N > N D E DC -- s D

HO HO

DCO s H3CO

US 2008/02342.57 A1 Sep. 25, 2008 56

12. The hydrochloride salt as recited in claim 11, wherein said compound is Substantially a single enantiomer, a mixture of about 90% or more by weight of the (-)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture 2-theta RI of about 90% or more by weight of the (+)-enantiomer and 6.703 29.3 about 10% or less by weight of the (-)-enantiomer, substan 7.399 9 8.321 19 tially an individual diastereomer, or a mixture of about 90% 8.52 2.7 or more by weight of an individual diastereomer and about 10.195 3.6 10% or less by weight of any other diastereomer. 12681 77.5 13. The hydrochloride salt as recited in claim 11, wherein 13.5 47.9 14.863 9.3 each of said positions represented as D have deuterium 15.54 17.7 enrichment of at least 1%. 15.92 3.8 14. The hydrochloride salt as recited in claim 11, wherein 16.299 11.4 each of said positions represented as D have deuterium 16.762 8.1 enrichment of at least 5%. 17.318 4.6 18.5 4.2 15. The hydrochloride salt as recited in claim 11, wherein 18.918 24.4 each of said positions represented as D have deuterium 19.757 6.1 enrichment of at least 10%. 20.359 1OO 21.161 38.3 16. The hydrochloride salt as recited in claim 11, wherein 21.762 26.1 each of said positions represented as D have deuterium 22.196 2 enrichment of at least 20%. 22.92 2.8 24.084 1.7 17. The hydrochloride salt as recited in claim 11, wherein 25.04 27.8 each of said positions represented as D have deuterium 25.34 5.3 enrichment of at least 50%. 25.641 8 26.261 6.4 18. The hydrochloride salt as recited in claim 11, wherein 26.481 4.9 each of said positions represented as D have deuterium 26.866 1.6 enrichment of at least 90%. 27.265 6.7 28.518 18.2 19. The hydrochloride salt as recited in claim 11, wherein 28.822 6.2 each of said positions represented as D have deuterium 3O419 2.5 enrichment of at least 98%. 31.001 7.9 20. The hydrochloride salt as recited in claim 11, wherein 31.539 1O.S 32.456 2.1 said hydrochloride salt is do-1-(2-dimethylamino-1-(4-meth 32.758 3.3 oxyphenyl)-ethyl-cyclohexanol hydrochloride (do-ven 33.162 7.3 lafaxine) having the structural formula: 33.957 10.4 35.181 15.5 36.024 1.8 36.399 1.6 C H 36.814 2 37.76 3 38.68 S.1 39.160 2.3

24. A polymorph of the hydrochloride salt of d-1-2- HO dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclohexanol hydrochloride (d-venlafaxine) as recited in claim 20, DCO wherein said polymorph has an X-ray powder diffraction spectrum Substantially the same as shown in FIG. 2. 21. A polymorph of the hydrochloride salt of d-1-2- 25. A polymorph of the hydrochloride salt of d-1-2- dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclohexanol dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclohexanol hydrochloride (d-venlafaxine) as recited in claim 20, hydrochloride (d-venlafaxine) as recited in claim 20, wherein said polymorph exhibits high-intensity diffraction wherein said polymorph has an X-ray powder diffraction peaks at diffraction angles (20) of 6.683, 10.201. 13.441. spectrum substantially the same as shown in FIG. 1. 15.517, 18.198, 19.719, 20.258, 21.68, 22.658, 25.543, 22. A polymorph of the hydrochloride salt of d-1-2- 28.022, and 35.02 in X-ray powder diffraction analysis. dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclohexanol 26. A polymorph of the hydrochloride salt of d-1-2- hydrochloride (d-venlafaxine) as recited in claim 20, dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclohexanol wherein said polymorph exhibits high-intensity diffraction hydrochloride (d-venlafaxine) as recited in claim 20, peaks at diffraction angles (20) of 6.703, 8.321, 12.681, 13.5. wherein said polymorph exhibits an X-ray powder diffraction 15.54, 18.918, 20.359, 21.161, 21.762, 25.04, and 28.518 in spectrum having characteristic peaks expressed in degrees X-ray powder diffraction analysis. (20) at approximately: 23. A polymorph of the hydrochloride salt of d-1-2- dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclohexanol hydrochloride (d-venlafaxine) as recited in claim 20, 2-theta RI wherein said polymorph exhibits an X-ray powder diffraction 6.683 15.5 spectrum having characteristic peaks expressed in degrees 10.2O1 93.6 (20) at approximately: US 2008/02342.57 A1 Sep. 25, 2008 57

-continued -continued

2-theta RI 2-theta RI

13.441 27.8 16.778 9.9 15.014 7.6 16.916 9.5 15.517 66.2 17.3O2 8.2 16.458 1.5 18.182 4.2 16.84 10.3 18.4 3 17.2O6 2.7 18.902 48.9 18.198 41 19.737 17.4 19.719 34.1 20.34 1OO 20.258 100 21.161 79.4 21.68 71.2 21.758 3O.S 22.658 24.8 22.151 3.6 23.923 2.7 22.659 2.1 25.322 9.6 22.955 2.4 25.543 22.4 24.073 1.7 26.5O2 6.7 25.02 31.5 27.122 9.5 25.36 11.1 27.557 5.5 25.6O1 18.9 28.022 20.9 26.261 15.2 28.64 4.4 26.856 3.2 29.241 10.6 27.258 8.8 29.659 7.1 28.518 30.2 31.079 11.9 28.839 11.6 31.379 8.2 30.42 2.4 31.978 9.1 30.962 11.7 32.28 1O.S 31.54 18.7 32.701 6.5 32.478 4.6 32.981 2.3 32.775 3.9 34:12 9.1 33.198 14.2 35.02 33.4 33.937 16.5 36.024 3.1 35.159 21.3 36.842 2.6 36.076 3.1 37.5 6.7 36.438 2.7 38.341 3.9 36.765 3.9 38.754 1.3 37.66 S.6 38.2O7 2.2 38.658 6.7 27. A polymorph of the hydrochloride salt of d-1-2- 39.2 3.6 dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclohexanol hydrochloride (d-venlafaxine) as recited in claim 20, 30. A polymorph of the hydrochloride salt of d-1-2- wherein said polymorph has an X-ray powder diffraction dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclohexanol spectrum substantially the same as shown in FIG. 3. hydrochloride (d-venlafaxine) as recited in claim 20, 28. A polymorph of the hydrochloride salt of d-1-2- wherein said polymorph has an X-ray powder diffraction dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclohexanol spectrum Substantially the same as shown in FIG. 4. hydrochloride (d-venlafaxine) as recited in claim 20, 31. A polymorph of the hydrochloride salt of d-1-2- wherein said polymorph exhibits high-intensity diffraction dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclohexanol peaks at diffraction angles (20) of 6.718, 8.335, 12.68, 13.5, hydrochloride (d-venlafaxine) as recited in claim 20, 15.539, 16.282, 18.902, 19.737, 20.34, 21.161, 21.758, wherein said polymorph exhibits high-intensity diffraction 25.02, 25.601, 26.261, 28.518, 31.54, 33.198. 33.937, and peaks at diffraction angles (20) of 6.74, 7.421, 8.341, 10.219, 35.159 in X-ray powder diffraction analysis. 12.7, 13.502, 17.9, 15.541, 20.36, 21.221, 21.761, 25.078, 29. A polymorph of the hydrochloride salt of d-1-2- 31.04, 34.018, and 35.139 in X-ray powder diffraction analy dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclohexanol S1S. hydrochloride (d-venlafaxine) as recited in claim 20, 32. A polymorph of the hydrochloride salt of d-1-2- wherein said polymorph exhibits an X-ray powder diffraction dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclohexanol spectrum having characteristic peaks expressed in degrees hydrochloride (d-venlafaxine) as recited in claim 20, (20) at approximately: wherein said polymorph exhibits an X-ray powder diffraction spectrum having characteristic peaks expressed in degrees (20) at approximately: 2-theta RI

6.718 21.4 8.335 20.6 2-theta RI 10.18 9.1 12.68 8O 6.74 21.2 13.5 40.7 7.421 14 15.539 2O2 8.341 35.5 15.68 11.5 10.219 23 15.938 9.4 12.7 99.5 16.282 24.3 13.5O2 40.7 US 2008/02342.57 A1 Sep. 25, 2008 58

-continued -continued

2-theta RI 2-theta RI

17.9 17.5 9.557 14.9 15.541 37.3 O.663 9 16.361 9.9 1.2O1 1OO 16.764 13 2.104 2.4 17.424 3 2.361 1.2 18.276 10.2 3.422 2.1 18.54 7.2 3.921 4.4 18.96 12.1 4.46 40.2 19.741 12 4.76 40.4 20.36 100 5.366 3.2 21.221 23.7 5.721 1.2 21.761 41 6.041 8.4 22.279 2.2 6.86 71.7 22.719 4.9 7497 5.7 23.039 3 7.866 3 24.024 3.2 8.398 2.8 25.078 26.3 9.2O1 66.5 25.383 5.9 9.619 9.6 25.604 9.7 2O.241 35.2 26.303 6 20.66 9.6 26.483 8.9 20.879 1.2 26.959 6.9 21.76 22.5 27.258 7.1 22.596 26.4 28.223 7.3 23.06 3.2 28.518 11.9 23.994 2 28.919 4.8 24.4 5.3 29.322 3.2 25.02 2.1 3O419 3.2 25.643 3.9 31.04 17.7 25.861 6.7 3166 10.6 26.519 3.5 32.742 4 26.842 8.7 33.239 5.4 27.5O2 S.1 34.018 14.8 28.422 6.1 35.139 22.7 28.859 7.2 36.1 2.5 29.937 3.1 36.388 1.8 30.98 7.7 36.839 2.2 31.52 12.6 37.719 3.5 32.362 6.4 38.681 5.5 32.721 6 39.198 3.8 33.162 2.1 34.461 9.6 35.438 17.9 33. A polymorph of the hydrochloride salt of d-1-2- 35.899 S.6 dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclohexanol 36.779 4.7 37.4 4.5 hydrochloride (d-venlafaxine) as recited in claim 20, 37.984 2 wherein said polymorph has an X-ray powder diffraction 38.962 3.6 spectrum substantially the same as shown in FIG. 5. 34. A polymorph of the hydrochloride salt of d-1-2- dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclohexanol 36. A polymorph of the hydrochloride salt of d-1-2- hydrochloride (d-venlafaxine) as recited in claim 20, dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclohexanol wherein said polymorph exhibits high-intensity diffraction hydrochloride (d-venlafaxine) as recited in claim 20, peaks at diffraction angles (20) of 5.597, 7.182, 9.078, 9.557, wherein said polymorph has an X-ray powder diffraction 11.201, 14.46, 14.76, 16.86, 17.497, 19.201, 19.619, 20.241, 20.66, 21.76, 22.596, 23.06, 24.4, 25.02, 26.519, 26.842, spectrum substantially the same as shown in FIG. 6. 31.52, and 35.438 in X-ray powder diffraction analysis. 37. A polymorph of the hydrochloride salt of d-1-2- 35. A polymorph of the hydrochloride salt of d-1-2- dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclohexanol dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclohexanol hydrochloride (d-venlafaxine) as recited in claim 20, hydrochloride (d-venlafaxine) as recited in claim 20, wherein said polymorph exhibits an X-ray powder diffraction wherein said polymorph exhibits high-intensity diffraction spectrum having characteristic peaks expressed in degrees peaks at diffraction angles (20) of 5.581, 7.186, 11.22. (20) at approximately: 14.499, 14.802, 16.882, 19.242, 20.317, 21.798, 22.637, and 35.445 in X-ray powder diffraction analysis. 38. A polymorph of the hydrochloride salt of d-1-2- dimethylamino-1-(4-methoxyphenyl)-ethyl-cyclohexanol 2-theta RI hydrochloride (d-venlafaxine) as recited in claim 20, 5.597 28 7.182 36.2 wherein said polymorph exhibits an X-ray powder diffraction 9.078 24.1 spectrum having characteristic peaks expressed in degrees (20) at approximately: US 2008/02342.57 A1 Sep. 25, 2008 59

39. A compound having structural formula II:

2-theta RI (II)

5.581 26.1 6.688 6.4 7.186 18.3 9.079 7.7 9.576 9.1 O.2O6 2.4 0.735 4.4 122 100 2.133 3.447 3.963 2.2 4499 18.8 4.8O2 2O.S 5.559 S.1 5.796 6.1 wherein Ras-Rs, are independently selected from the 6.087 3.6 group consisting of hydrogen and deuterium; 6.882 63.9 at least one of Rs-Rs, is deuterium; and 7.519 10.6 X is a leaving group anion. 8.407 S.6 40. The compound as recited in claim 39, wherein said 9.242 38.4 compound is Substantially a single enantiomer, a mixture of 9.68 11.8 about 90% or more by weight of the (-)-enantiomerand about 20.317 51.6 10% or less by weight of the (+)-enantiomer, a mixture of 20.72 8.8 about 90% or more by weight of the (+)-enantiomerand about 20.923 6.3 10% or less by weight of the (-)-enantiomer, substantially an 21.798 17.5 individual diastereomer, or a mixture of about 90% or more 22.637 26.3 by weight of an individual diastereomer and about 10% or 23.101 less by weight of any other diastereomer. 24.425 11.9 41. The compound as recited in claim 39, wherein at least 25.042 7.1 one of Rs-Rs, independently has deuterium enrichment of 25.921 7.7 no less than about 1%. 26.587 5.4 42. The compound as recited in claim 39, wherein at least 26.939 10.1 one of Rs-Rs, independently has deuterium enrichment of 27.194 5.3 no less than about 5%. 27.579 2.5 43. The compound as recited in claim 39, wherein at least 28.435 3.9 one of Rs-Rs, independently has deuterium enrichment of 28.921 3.5 no less than about 10%. 29.4 1.6 44. The compound as recited in claim 39, wherein at least 29.808 2.6 one of Rs-Rs, independently has deuterium enrichment of 31.064 3.7 no less than about 20%. 31.597 9.1 45. The compound as recited in claim 39, wherein at least 32.374 1.6 one of Rs-Rs, independently has deuterium enrichment of 33.32 1.3 no less than about 50%. 34.524 6.3 46. The compound as recited in claim 39, wherein at least 35.112 4.7 one of Rs-Rs, independently has deuterium enrichment of no less than about 90%. 35.445 16.2 47. The compound as recited in claim 39, wherein at least 35.88 1.3 one of Rs-Rs, independently has deuterium enrichment of 36.727 2.3 no less than about 98%. 36.981 3.2 48. The compound as recited in claim 39, wherein X is 37.464 2.9 selected from the group consisting of halogen, alkylsulfonate, 39.023 1.9 arylsulfonate, perhaloalkanesulfonate, CHOSO, and 38.962 3.6 CDOSO,. 49. The compound as recited in claim 39, wherein X is iodide.- US 2008/02342.57 A1 Sep. 25, 2008 60

50. The compound as recited in claim 39, having a struc 53. The compound as recited in claim 50, wherein each of tural formula selected from the group consisting of said positions represented as Dhave deuterium enrichment of at least 5%. 54. The compound as recited in claim 50, wherein each of said positions represented as Dhave deuterium enrichment of at least 10%. 55. The compound as recited in claim 50, wherein each of said positions represented as Dhave deuterium enrichment of at least 20%. 56. The compound as recited in claim 50, wherein each of HO said positions represented as Dhave deuterium enrichment of at least 50%. DCO 57. The compound as recited in claim 50, wherein each of said positions represented as Dhave deuterium enrichment of at least 90%. 58. The compound as recited in claim 50, wherein each of said positions represented as Dhave deuterium enrichment of at least 98%. 59. A compound having structural formula III: HO DCO (III)

HO DCO

HO DCO wherein Riss-Rs are independently selected from the group consisting of hydrogen and deuterium; and at least one of Rss-Rs is deuterium. 60. The compound as recited in claim 59, wherein said compound is Substantially a single enantiomer, a mixture of about 90% or more by weight of the (-)-enantiomerand about 10% or less by weight of the (+)-enantiomer, a mixture of HO about 90% or more by weight of the (+)-enantiomerand about 10% or less by weight of the (-)-enantiomer, substantially an DCO individual diastereomer, or a mixture of about 90% or more by weight of an individual diastereomer and about 10% or less by weight of any other diastereomer. 61. The compound as recited in claim 59, wherein at least one of Rss-Rs independently has deuterium enrichment of no less than about 1%. 62. The compound as recited in claim 59, wherein at least HO one of Rss-Rs independently has deuterium enrichment of no less than about 5%. DCO 63. The compound as recited in claim 59, wherein at least one of Rss-Rs independently has deuterium enrichment of no less than about 10%. 51. The compound as recited in claim 50, wherein said 64. The compound as recited in claim 59, wherein at least compound is substantially a single enantiomer, a mixture of one of Rss-Rs independently has deuterium enrichment of about 90% or more by weight of the (-)-enantiomerandabout no less than about 20%. 10% or less by weight of the (+)-enantiomer, a mixture of 65. The compound as recited in claim 59, wherein at least about 90% or more by weight of the (+)-enantiomerandabout one of Rss-Rs independently has deuterium enrichment of 10% or less by weight of the (-)-enantiomer, substantially an no less than about 50%. individual diastereomer, or a mixture of about 90% or more 66. The compound as recited in claim 59, wherein at least by weight of an individual diastereomer and about 10% or one of Rss-Rs independently has deuterium enrichment of less by weight of any other diastereomer. no less than about 90%. 52. The compound as recited in claim 50, wherein each of 67. The compound as recited in claim 59, wherein at least said positions represented as Dhave deuterium enrichment of one of Rss Rss-Rs independently has deuterium enrichment at least 1%. of no less than about 98%. US 2008/02342.57 A1 Sep. 25, 2008

68. The compound as recited in claim 59, having a struc 70. The compound as recited in claim 68, wherein each of tural formula selected from the group consisting of said positions represented as Dhave deuterium enrichment of at least 1%. 71. The compound as recited in claim 68, wherein each of said positions represented as Dhave deuterium enrichment of t at least 5%. 72. The compound as recited in claim 68, wherein each of N said positions represented as Dhave deuterium enrichment of O, at least 10%. 73. The compound as recited in claim 68, wherein each of said positions represented as Dhave deuterium enrichment of DCO at least 20%. 74. The compound as recited in claim 68, wherein each of t said positions represented as Dhave deuterium enrichment of D N at least 50%. 75. The compound as recited in claim 68, wherein each of Dr.O, said positions represented as Dhave deuterium enrichment of at least 90%. 76. The compound as recited in claim 68, wherein each of DCO said positions represented as Dhave deuterium enrichment of at least 98%. p 77. A process for preparing a compound having structural N D formula I comprising reacting a compound having structural formula II under Suitable conditions to form a compound K, having structural formula I: O

D3CO

p DDr N Sk,D O

DCO p N D K, and O (II)

H3CO p D N D D Sk, O

HCO 69. The compound as recited in claim 68, wherein said compound is substantially a single enantiomer, a mixture of about 90% or more by weight of the (-)-enantiomerandabout 10% or less by weight of the (+)-enantiomer, a mixture of (I) about 90% or more by weight of the (+)-enantiomerandabout 10% or less by weight of the (-)-enantiomer, substantially an individual diastereomer, or a mixture of about 90% or more wherein R-R-7 and Riss-Rs are independently selected by weight of an individual diastereomer and about 10% or from the group consisting of hydrogen and deuterium; less by weight of any other diastereomer. at least one of R-R-7 and Rss-Rs is deuterium; US 2008/02342.57 A1 Sep. 25, 2008 62

X is selected from the group consisting of halogen, alkyl said compound having structural formula III is reacted Sulfonate, arylsulfonate, perhaloalkanesulfonate, with a reagent selected from the group consisting of CHOSO, and CDOSO: formic acid and d-formic acid; the reaction is carried out in the absence of Solvent, in a Solvent selected from the group consisting of water, in the presence of an optional additive selected from the deuterium oxide, an alcohol, 1,4-dioxane, acetone, group consisting of lithium deuteroxide, lithium acetonitrile, dimethyl formamide, dimethyl acetamide, hydroxide, Sodium deuteroxide, Sodium hydroxide, N-methylpyrrolidone, and dimethylsulfoxide, or a mix potassium deuteroxide, potassium hydroxide, lithium ture thereof; formate, potassium formate, and sodium formate; in the presence of a nucleophile selected from the group in the presence of a solvent selected from the group con consisting of 2-aminoethanol, 3-aminopropanol, 1,8-di sisting of water, deuterium oxide, methanol, da-metha azabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2 nol, formic acid, d-formic acid, 1,4-dioxane, acetone, octane, trialkylamine, sodium borohydride, lithium acetonitrile, dimethylformamide, dimethylacetamide, borohydride, lithium trialkylborohydride, lithium hydride, potassium hydride, and sodium hydride; N-methylpyrrolidone, dimethyl sulfoxide, or a mixture at a temperature from about 0°C. to about 500° C.; thereof; for a period from 0.01 to 240 hours; at a temperature from about 0°C. to about 500° C.; at a pH from about 1 to about 14; and for about 0.01 to about 240 hours; at a pressure from about 1 mBar to about 350 Bar. at a pH from about 1 to about 14; and 78. The process as recited in claim 77, wherein the reaction at a pressure from about 1 mBar to about 350 Bar. is carried out in the presence of focused microwave radiation 80. The process as recited in claim 79, wherein the reaction using a quartz reactor at a pressure from about 1 Bar to about is carried out in the presence of focused microwave radiation 25 Bar, a power setting from about 1 W per liter of solvent to using a quartz reactor at a pressure from about 1 Bar to about about 900 W per liter of solvent, at a temperature from about 0° C. to about 500° C., for 0.01 to 5 hours, and at a pH from 25 Bar, a power setting from about 1 W per liter of solvent to about 1 to about 14. about 900 W per liter of solvent, at a temperature from about 79. A process for preparing a compound having structural 0° C. to about 500° C., for 0.01 to 5 hours, and at a pH from formula I comprising reacting a compound having structural about 1 to about 14. formula III under suitable conditions to form a compound 81. The use of a compound as recited in claim 39 for the having structural formula I: manufacture of a pharmaceutically acceptable acid addition salt as recited in claim 1. 82. The use of a compound as recited in claim 59 for the manufacture of a pharmaceutically acceptable acid addition salt as recited in claim 1. 83. A compound having structural formula IV:

(IV)

(III)

or a pharmaceutically acceptable salt, Solvate, or prodrug thereof, wherein Rs-Ro, are independently selected from the group consisting of hydrogen and deuterium; and at least one of Rs-Ro, is deuterium. 84. The compound as recited in claim 83, wherein said compound is Substantially a single enantiomer, a mixture of about 90% or more by weight of the (-)-enantiomerand about 10% or less by weight of the (+)-enantiomer, a mixture of (I) about 90% or more by weight of the (+)-enantiomerand about 10% or less by weight of the (-)-enantiomer, substantially an wherein R-R-7 and Rss-Rs are independently selected individual diastereomer, or a mixture of about 90% or more from the group consisting of hydrogen and deuterium; by weight of an individual diastereomer and about 10% or at least one of R-R-7 and Rss-Rs is deuterium; less by weight of any other diastereomer. US 2008/02342.57 A1 Sep. 25, 2008 63

85. The compound as recited in claim 83, wherein at least one of Rs-Ro, independently has deuterium enrichment of -continued no less than about 1%. 86. The compound as recited in claim 83, wherein at least one of Rs-Ro, independently has deuterium enrichment of N N no less than about 5%. 87. The compound as recited in claim 83, wherein at least D one of Rs-Ro, independently has deuterium enrichment of no less than about 10%. HO 88. The compound as recited in claim 83, wherein at least one of Rs-Ro, independently has deuterium enrichment of HO no less than about 20%. 89. The compound as recited in claim 83, wherein at least one of Rs-Ro, independently has deuterium enrichment of no less than about 50%. p 90. The compound as recited in claim 83, wherein at least N one of Rs-Ro, independently has deuterium enrichment of N no less than about 90%. D 91. The compound as recited in claim 83, wherein at least one of Rs-Ro, independently has deuterium enrichment of HO no less than about 98%. 92. The compound as recited in claim 83, or a pharmaceu HO tically acceptable salt, Solvate, or prodrug thereof, having a structural formula selected from the group consisting of CD3 f N YCD, N N D

HO HO

HO CD3 D N D N N YCD, D HO

HO HO CD HO R D N D N D N D

HO HO HO CD3 CD3 D N R D YCD, D N D

HO HO HO HO CD3 N D N SN D D YCD, D

HO D D HO HO D D D HO D D US 2008/02342.57 A1 Sep. 25, 2008 64

-continued -continued P p N N SN D SN D D D D D D HO HO D D HO D D HO D D D D D D D D

N Sn D N D D D D HO D HO

HO D D HO D US 2008/02342.57 A1 Sep. 25, 2008 65

-continued -continued CD3 CD3 NS NS

HO HO HOOcto HO CD3 N YCD, D

HO HO

R D N

HO HO

D CD3 CD3

D R N

HO HO

D CD3 CD3 R D YCD, CD3 D

HO HO

N N D D

HO HO US 2008/02342.57 A1 Sep. 25, 2008 66

-continued -continued f p N Sn D N SN D D D D D D D D HO HO D D HO D D HO D D D D D D D D D D

D D D HO

HO D D HO D US 2008/02342.57 A1 Sep. 25, 2008 67

-continued -continued P CD3 D NS N N

HO HO

HO D HO

CD3 CD

D Yep, CD D

HO HO

HO D HO

D N D D N

HO HO

HO D HO

D R CD3 CD3 D D N

HO HO

HO D HO

D CD3 CD3 D N D D YCD, CD3 D

HO HO

HO D HO

D N D D

HO D US 2008/02342.57 A1 Sep. 25, 2008 68

-continued -continued CD3 CD3 N

SN D D SN D

HO HO

93. The compound as recited in claim 92, wherein said compound is Substantially a single enantiomer, a mixture of about 90% or more by weight of the (-)-enantiomerand about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomerand about 10% or less by weight of the (-)-enantiomer, substantially an individual diastereomer, or a mixture of about 90% or more by weight of an individual diastereomer and about 10% or less by weight of any other diastereomer. 94. The compound as recited in claim 92, wherein each of said positions represented as Dhave deuterium enrichment of at least 1%. US 2008/02342.57 A1 Sep. 25, 2008 69

95. The compound as recited in claim 92, wherein each of sisting of psychotropic disorders, anxiety disorder, general said positions represented as Dhave deuterium enrichment of ized anxiety disorder, depression, post-traumatic stress dis at least 5%. order, obsessive-compulsive disorder, panic disorder, hot 96. The compound as recited in claim 92, wherein each of flashes, senile dementia, migraine, hepatopulmonary Syn said positions represented as Dhave deuterium enrichment of drome, chronic pain, nociceptive pain, neuropathic pain, at least 10%. painful diabetic retinopathy, bipolar depression, obstructive 97. The compound as recited in claim 92, wherein each of sleep apnea, psychiatric disorders, premenstrual dysphoric said positions represented as Dhave deuterium enrichment of disorder, Social phobia, Social anxiety disorder, urinary at least 20%. incontinence, anorexia, bulimia nervosa, obesity, ischemia, 98. The compound as recited in claim 92, wherein each of head injury, calcium overload in brain cells, drug depen said positions represented as Dhave deuterium enrichment of dence, Gilles de la Tourette syndrome, Shy Drager syndrome, at least 50%. vasomotor flushing, chronic fatigue syndrome, cognition 99. The compound as recited in claim 92, wherein each of enhancement, attention deficit hyperactivity disorder, fibro said positions represented as Dhave deuterium enrichment of myalgia, irritable bowel syndrome, and premature ejacula at least 90%. tion. 100. The compound as recited in claim 92, wherein each of 112. The method as recited in claim 111 wherein said said positions represented as Dhave deuterium enrichment of disorder is drug dependence. at least 98%. 113. The method as recited in claim 112, wherein said drug 101. The compound as recited in claim 83, or a pharma dependence is selected from the group consisting of tobacco ceutically acceptable salt, Solvate, or prodrug thereof, having addiction, alcohol addiction, marijuana addiction, and the structural formula: cocaine addiction. 114. The method as recited in claim 112, wherein said compoundelicits an improved clinical effect for the treatment CD3 of drug dependence selected from the group consisting of accelerated rate of healing, accelerated rate of symptom relief, improved patient compliance, and reduced withdrawal CD3 symptomology during the treatment. 115. The method as recited in claim 110, wherein said compound elicits an improved clinical effect selected from HO the group consisting of improvement of pain indices and HO improvement of depression indices. 116. The method as recited in claim 110, wherein said compound has at least one of the following properties: 102. The compound as recited in claim 101, wherein said a. decreased inter-individual variation in plasma levels of compound contains about 50% or more by weight of the said compound or a metabolite thereofas compared to (-)-enantiomer of said compound and about 50% or less by the non-isotopically enriched compound; weight of (+)-enantiomer of said compound or about 50% or b. increased average plasma levels of said compound per more by weight of the (+)-enantiomer of said compound and dosage unit thereofas compared to the non-isotopically about 50% or less by weight of (-)-enantiomer of said com enriched compound; pound. c. decreased average plasma levels of at least one metabo 103. A pharmaceutical composition comprising the com lite of said compound per dosage unit thereofas com pound as recited in claim 1 and one or more pharmaceutically pared to the non-isotopically enriched compound; acceptable carriers. d. increased average plasma levels of at least one metabo 104. The pharmaceutical composition as recited in claim lite of said compound per dosage unit thereofas com 103, further comprising one or more release-controlling car pared to the non-isotopically enriched compound; and riers. e. an improved clinical effect during the treatment in said 105. The pharmaceutical composition as recited in claim Subject per dosage unit thereofas compared to the non 103, further comprising one or more non-release controlling isotopically enriched compound. carriers. 117. The method as recited in claim 110, wherein said 106. The pharmaceutical composition as recited in claim compound has at least two of the following properties: 103, wherein the composition is suitable for oral, parenteral, a. decreased inter-individual variation in plasma levels of or intravenous infusion administration. said compound or a metabolite thereofas compared to 107. The pharmaceutical composition as recited in claim the non-isotopically enriched compound; 106, wherein the oral dosage form is a tablet or capsule. b. increased average plasma levels of said compound per 108. The pharmaceutical composition as recited in claim dosage unit thereofas compared to the non-isotopically 103, wherein the compound is administered in a dose of about enriched compound; 0.5 milligrams to about 1,000 milligrams. c. decreased average plasma levels of at least one metabo 109. The pharmaceutical composition as recited in claim lite of said compound per dosage unit thereofas com 108, wherein the compound is administered in a dose of about pared to the non-isotopically enriched compound; 0.5 milligrams to about 400 milligrams. d. increased average plasma levels of at least one metabo 110. A method for the treatment of a monoamine-related lite of said compound per dosage unit thereofas com disorder, comprising administering to a Subject a therapeuti pared to the non-isotopically enriched compound; and cally effective amount of the compound as recited in claim 1. e. an improved clinical effect during the treatment in said 111. The method as recited in claim 110, wherein the Subject per dosage unit thereofas compared to the non monoamine-related disorder is selected from the group con isotopically enriched compound. US 2008/02342.57 A1 Sep. 25, 2008 70

118. The method as recited in claim 110, wherein said 130. The method as recited in claim 129 wherein said compound has a decreased metabolism by at least one poly opioid antagonist is selected from the group consisting of morphically-expressed cytochrome Paso isoform in said Sub nalmefene, naltrexone, and naloxone. ject per dosage unit thereofas compared to the non-isotopi 131. The method as recited in claim 124 wherein said therapeutic agent is an anesthetic or sedative. cally enriched compound. 132. The method as recited in claim 131 wherein said 119. The method as recited in claim 118, wherein said anesthetic or sedative is selected from the group consisting of cytochrome Paso isoform is selected from the group consist propofol, procaine, lidocaine, prilocaine, bupivacaine, ing of CYP2C8, CYP2C9, CYP2C19, and CYP2D6. levobupivicaine, nitrous oxide, halothane, enflurane, isoflu 120. The method as recited in claim 110, wherein said rane, sevoflurane, desflurane, thiopental, methohexital, eto midate, diazepam, midazolam, lorazepam, Succinylcholine, compound is characterized by decreased inhibition of at least Vecuroniurn, rocuronium, pipecuronium, rapacuronium, tub one cytochrome Paso or monoamine oxidase isoform in said ocurarine, and gallamine. Subject per dosage unit thereofas compared to the non-iso 133. A pharmaceutical composition comprising the com topically enriched compound. pound as recited in claim 83 and one or more pharmaceuti 121. The method as recited in claim 120, wherein said cally acceptable carriers. cytochrome Paso or monoamine oxidase isoform is selected 134. The pharmaceutical composition as recited in claim from the group consisting of CYP1A1, CYP1A2, CYP1B1, 133, further comprising one or more release-controlling car CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, 1S. 135. The pharmaceutical composition as recited in claim CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1. 133, further comprising one or more non-release controlling CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, carriers. CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, 136. The pharmaceutical composition as recited in claim CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, 133, wherein the composition is suitable for oral, parenteral, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, or intravenous infusion administration. CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, 137. The pharmaceutical composition as recited in claim CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, 136, wherein the oral dosage form is a tablet or capsule. CYP27A1, CYP27B1, CYP39, CYP46, CYP51, MAO and 138. The pharmaceutical composition as recited in claim MAO. 133, wherein the compound is administered in a dose of about 122. The method as recited in claim 110, wherein the 0.5 milligrams to about 1,000 milligrams. method affects the treatment of the disorder while reducing or 139. The pharmaceutical composition as recited in claim eliminating a deleterious change in a diagnostic hepatobiliary 138, wherein the compound is administered in a dose of about function endpoint, as compared to the corresponding non 0.5 milligrams to about 400 milligrams. isotopically enriched compound. 140. A method for the treatment of a monoamine-related disorder, comprising administering to a subject a therapeuti 123. The method as recited in claim 122, wherein the cally effective amount of the compound as recited in claim 83. diagnostic hepatobiliary function endpoint is selected from 141. The method as recited in claim 140, wherein the the group consisting of alanine aminotransferase (ALT). monoamine-related disorder is selected from the group con serum glutamic-pyruvic transaminase (“SGPT), aspartate sisting of psychotropic disorders, anxiety disorder, general aminotransferase (AST,” “SGOT), ALT/AST ratios, serum ized anxiety disorder, depression, post-traumatic stress dis aldolase, alkaline phosphatase (ALP), ammonia levels, order, obsessive-compulsive disorder, panic disorder, hot bilirubin, gamma-glutamyl transpeptidase (“GGTP flashes, senile dementia, migraine, hepatopulmonary Syn “Y-GTP “GGT), leucine aminopeptidase (“LAP), liver drome, chronic pain, nociceptive pain, neuropathic pain, biopsy, liver ultrasonography, liver nuclear Scan, 5'-nucleoti painful diabetic retinopathy, bipolar depression, obstructive dase, and blood protein. sleep apnea, psychiatric disorders, premenstrual dysphoric 124. The method as recited in claim 110 wherein said disorder, Social phobia, Social anxiety disorder, urinary compound is administered in combination with another thera incontinence, anorexia, bulimia nervosa, obesity, ischemia, peutic agent. head injury, calcium overload in brain cells, drug depen dence, Gilles de la Tourette syndrome, Shy Drager syndrome, 125. The method as recited in claim 124 wherein said vasomotor flushing, chronic fatigue syndrome, cognition therapeutic agent is a modulator of an NMDA-receptor. enhancement, attention deficit hyperactivity disorder, fibro 126. The method as recited in claim 124 wherein said myalgia, irritable bowel syndrome, and premature ejacula therapeutic agent is selected from the group consisting of tion. phencyclidine (PCP), amantadine, ibogaine, memantine, 142. The method as recited in claim 141 wherein said dextrorphan, ketamine, nitrous oxide, and dextromethorphan. disorder is drug dependence. 127. The method as recited in claim 124 wherein said 143. The method as recited in claim 142, wherein said drug therapeutic agent is an opiod. dependence is selected from the group consisting of tobacco 128. The method as recited in claim 127 wherein said addiction, alcohol addiction, marijuana addiction, and opioid is selected from the group consisting of morphine, cocaine addiction. 144. The method as recited in claim 142, wherein said codeine, thebain, diacetylmorphine, oxycodone, hydroc compoundelicits an improved clinical effect for the treatment odone, hydromorphone, oxymorphone, nicomorphine, fenta of drug dependence selected from the group consisting of nyl, C.-methyl fentanyl, alfentanil, Sufentanil, remifentanyl. accelerated rate of healing, accelerated rate of symptom carfentanyl, ohmefentanyl, pethidine, ketobemidone, pro relief, improved patient compliance, and reduced withdrawal poxyphene, dextropropoxyphene, methadone, loperamide, symptomology during the treatment. pentazocine, buprenorphine, etorphine, butorphanol, nal 145. The method as recited in claim 144, wherein said bufine, levorphanol, naloxone, naltrexone, and tramadol. improved clinical effect is selected from the group consisting 129. The method as recited in claim 124 wherein said of improvement of pain indices and improvement of depres therapeutic agent is an opiod antagonist. sion indices. US 2008/02342.57 A1 Sep. 25, 2008 71

146. The method as recited in claim 140, wherein said eliminating a deleterious change in a diagnostic hepatobiliary compound has at least one of the following properties: function endpoint, as compared to the corresponding non a. decreased inter-individual variation in plasma levels of isotopically enriched compound. said compound or a metabolite thereofas compared to 153. The method as recited in claim 152, wherein the the non-isotopically enriched compound; diagnostic hepatobiliary function endpoint is selected from ... increased average plasma levels of said compound per the group consisting of alanine aminotransferase (ALT). dosage unit thereofas compared to the non-isotopically serum glutamic-pyruvic transaminase (“SGPT), aspartate enriched compound; aminotransferase (AST,” “SGOT), ALT/AST ratios, serum c. decreased average plasma levels of at least one metabo aldolase, alkaline phosphatase (ALP), ammonia levels, lite of said compound per dosage unit thereofas com bilirubin, gamma-glutamyl transpeptidase (“GGTP pared to the non-isotopically enriched compound; “Y-GTP “GGT), leucine aminopeptidase (“LAP), liver ... increased average plasma levels of at least one metabo biopsy, liver ultrasonography, liver nuclear Scan, 5'-nucleoti lite of said compound per dosage unit thereofas com dase, and blood protein. pared to the non-isotopically enriched compound; and 154. The method as recited in claim 140 wherein said compound is administered in combination with another thera ... an improved clinical effect during the treatment in said peutic agent. Subject per dosage unit thereofas compared to the non 155. The method as recited in claim 154 wherein said isotopically enriched compound. therapeutic agent is a modulator of a target selected from the 147. The method as recited in claim 140, wherein said group consisting of a serotonin receptor, a norepinephrine compound has at least two of the following properties: receptor, a serotonin transporter, and a norepinephrine trans a. decreased inter-individual variation in plasma levels of porter. said compound or a metabolite thereofas compared to 156. The method as recited in claim 154 wherein said the non-isotopically enriched compound; therapeutic agent is selected from the group consisting of ... increased average plasma levels of said compound per phencyclidine (PCP), amantadine, ibogaine, memantine, dosage unit thereofas compared to the non-isotopically dextrorphan, ketamine, nitrous oxide, and dextromethorphan. enriched compound; 157. The method as recited in claim 154 wherein said c. decreased average plasma levels of at least one metabo therapeutic agent is an opiod. lite of said compound per dosage unit thereofas com 158. The method as recited in claim 157 wherein said pared to the non-isotopically enriched compound; opioid is selected from the group consisting of morphine, ... increased average plasma levels of at least one metabo codeine, thebain, diacetylmorphine, oxycodone, hydroc lite of said compound per dosage unit thereofas com odone, hydromorphone, Oxymorphone, nicomorphine, fenta pared to the non-isotopically enriched compound; and nyl, C.-methyl fentanyl, alfentanil, Sufentanil, remifentanyl. ... an improved clinical effect during the treatment in said carfentanyl, ohmefentanyl, pethidine, ketobemidone, pro Subject per dosage unit thereofas compared to the non poxyphene, dextropropoxyphene, methadone, loperamide, isotopically enriched compound. pentazocine, buprenorphine, etorphine, butorphanol, nal 148. The method as recited in claim 140, wherein said bufine, levorphanol, naloxone, naltrexone, and tramadol. compound has a decreased metabolism by at least one poly 159. The method as recited in claim 154 wherein said morphically-expressed cytochrome Paso isoform in said Sub therapeutic agent is an opiod antagonist. ject per dosage unit thereofas compared to the non-isotopi 160. The method as recited in claim 159 wherein said cally enriched compound. opioid antagonist is selected from the group consisting of 149. The method as recited in claim 148, wherein said nalmefene, naltrexone, and naloxone. cytochrome Paso isoform is selected from the group consist 161. The method as recited in claim 154 wherein said ing of CYP2C8, CYP2C9, CYP2C19, and CYP2D6. therapeutic agent is an anesthetic or sedative. 150. The method as recited in claim 140, wherein said 162. The method as recited in claim 161 wherein said compound is characterized by decreased inhibition of at least anesthetic or sedative is selected from the group consisting of one cytochrome Paso or monoamine oxidase isoform in said propofol, procaine, lidocaine, prilocaine, bupivacaine, Subject per dosage unit thereofas compared to the non-iso levobupivicaine, nitrous oxide, halothane, enflurane, isoflu topically enriched compound. rane, sevoflurane, desflurane, thiopental, methohexital, eto 151. The method as recited in claim 150, wherein said midate, diazepam, midazolam, lorazepam, Succinylcholine, cytochrome Paso or monoamine oxidase isoform is selected Vecuroniurn, rocuronium, pipecuronium, rapacuronium, tub from the group consisting of CYP1A1, CYP1A2, CYP1B1, ocurarine, and gallamine. CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, 163. A method for modulating a target selected from the CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1. group consisting of a serotonin receptor, a norepinephrine CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, receptor, a serotonin transporter, and a norepinephrine trans CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, porter, comprising contacting said target with the pharmaceu CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, tically acceptable acid addition salt as recited in claim 1. CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, 164. A method for modulating a target selected from the CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, group consisting of a serotonin receptor, a norepinephrine CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, receptor, a serotonin transporter, and a norepinephrine trans CYP27A1, CYP27B1, CYP39, CYP46, CYP51, MAO and porter, comprising contacting said target with the compound MAO. as recited in claim 83. 152. The method as recited in claim 140, wherein the method affects the treatment of the disorder while reducing or c c c c c