Patent Description:
Many current medicines suffer from poor absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use. Poor ADME properties are also a major reason for the failure of drug candidates in clinical trials. While formulation technologies and prodrug strategies can be employed in some cases to improve certain ADME properties, these approaches have failed to overcome the inherent ADME problems that exist for many drugs and drug candidates. One inherent problem is the rapid metabolism that causes a number of drugs, which otherwise would be highly effective in treating a disease, to be cleared too rapidly from the body. A possible solution to rapid drug clearance is frequent or high dosing to attain a sufficiently high plasma level of drug. This, however, introduces a number of potential treatment problems, such as poor patient compliance with the dosing regimen, side effects that become more acute with higher doses, and increased cost of treatment.

In some select cases, a metabolic inhibitor will be co-administered with an important drug that is rapidly cleared. Such is the case with the protease inhibitor class of drugs that are used to treat HIV infection. These drugs are typically co-dosed with ritonavir, an inhibitor of cytochrome P450 enzyme CYP3A4, the enzyme responsible for their metabolism. Ritonavir itself has side effects and it adds to the pill burden for HIV patients who must already take a combination of different drugs. Similarly, dextromethorphan which undergoes rapid CYP2D6 metabolism is being tested in combination with the CYP2D6 inhibitor quinidine for the treatment of pseudobulbar disease.

In general, combining drugs with cytochrome P450 inhibitors is not a satisfactory strategy for decreasing drug clearance. The inhibition of a CYP enzyme activity can affect the metabolism and clearance of other drugs metabolized by that same enzyme. This can cause those other drugs to accumulate in the body to toxic levels.

A potentially attractive strategy, if it works, for improving a drug's metabolic properties is deuterium modification. In this approach, one attempts to slow the CYP-mediated metabolism of a drug by replacing one or more hydrogen atoms with deuterium atoms. Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Deuterium forms stronger bonds with carbon than hydrogen does. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug efficacy, safety, and tolerability. At the same time, because the size and shape of deuterium are essentially identical to hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.

Over the past <NUM> years, the effects of deuterium substitution on the rate of metabolism have been reported for a very small percentage of approved drugs (see, e.g., <NPL>; <NPL> ("Foster"); <NPL>; <NPL> ("Fisher")). The results have been variable and unpredictable. For some compounds deuteration caused decreased metabolic clearance in vivo. For others, there was no change in metabolism. Still others demonstrated decreased metabolic clearance. The variability in deuterium effects has also led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting adverse metabolism. (See Foster at p. <NUM> and Fisher at p.

The effects of deuterium modification on a drug's metabolic properties are not predictable even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated drug can one determine if and how the rate of metabolism will differ from that of its undeuterated counterpart. Many drugs have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each drug.

Dextromethorphan, also known by its chemical name (+)-<NUM>-methoxy-<NUM>-methyl-(9α, 13α, 14α)-morphinan, is currently one of the most widely used antitussives.

In addition to the physiological activity noted above, dextromethorphan is also an agonist of the σ2 receptor, an N-methyl-D-aspartate (NMDA) antagonist, and an α3β4 nicotinic receptor antagonist. Dextromethorphan inhibits neurotransmitters, such as glutamate, from activating receptors in the brain. Uptake of dopamine and serotonin are also inhibited.

Dextromethorphan is approved for use in over the counter cough suppressant products. It is currently in Phase I clinical trials for treating subjects with voice spasms, and Phase III clinical studies for treating Rett Syndrome (http://www. clinicaltrials. Dextromethorphan is being studied with other drugs in a Phase II clinical trial characterizing pain processing mechanisms in subjects with irritable bowel syndrome (http://www. clinicaltrials. Dextromethorphan is also in Phase I clinical trials for treating hyperalgesia in methadone-maintained subjects (http://www. clinicaltrials.

Dextromethorphan when administered alone has also shown limited efficacy in the treatment of other diseases and conditions, including involuntary emotional expression disorder ("IEED") or pseudobulbar affect ("PBA"), neurodegenerative diseases, neuropathic pain, and brain injuries.

Although dextromethorphan has shown therapeutic effect in the above mentioned conditions and disorders, its rapid first-pass metabolism remains a major obstacle in the development of effective treatments. Dextromethorphan is metabolized in the liver. Degradation begins with O- and N-demethylation to form primary metabolites dextrorphan and <NUM>-methoxy-morphinan, both of which are further N- and O- demethylated respectively to <NUM>-hydroxy-morphinan. These three metabolites are believed to be therapeutically active. A major metabolic catalyst is the cytochrome P450 enzyme 2D6 (CYP2D6), which is responsible for the O-demethylation reactions of dextromethorphan and <NUM>-methoxymorphinan. N-demethylation of dextromethorphan and dextrorphan are catalyzed by enzymes in the related CYP3A family. Conjugates of dextrorphan and <NUM>-hydroxymorphinan can be detected in human plasma and urine within hours of its ingestion. Aspects of the metabolism discussed above are reflected in, for example, <NPL>.

A combination of dextromethorphan hydrobromide and quinidine sulfate is currently in Phase III clinical trials for the treatment of PBA in patients suffering from Alzheimer's disease, stroke, Parkinson's disease and traumatic brain injury. (http://www. clinicaltrials. The co-administration of quinidine (a potent inhibitor of the cytochrome P450 enzyme 2D6) increases both the blood level and the duration of action of dextromethorphan.

PBA is a neurological disorder characterized by inappropriate and uncontrollable outbursts of crying, laughing, or other emotional displays, often times with no relevant trigger or disproportionate with the actual mood of the person. Although rarely life threatening, PBA can significantly impact a person's professional and social life. PBA is commonly associated with certain neurological disorders such as traumatic brain injury, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson disease, traumatic brain injury, progressive supranuclear palsy, multiple systems atrophy, normal pressure hydrocephalus, olivopontine cerebellar atrophy, brain tumors, Wilson's disease, and stroke. Over one million people in the United States suffer from PBA.

At the present time there are no treatments specifically approved by the Food and Drug Administration for the treatment of PBA. First line treatment for PBA is limited to the off-label use of antidepressants. Studies have demonstrated the therapeutic effect of tricylic antidepressants and selective serotonin reuptake inhibitors in the treatment of PBA. These agents are believed to have PBA-specific therapeutic effects independent of their antidepressant action. Antidepressants that have shown a therapeutic effect include amitriptyline, nortriptyline, citalopram, fluoxetine, paroxetine, and sertraline.

Although treatments for neurological diseases and conditions are known, there still exists a need to develop more efficacious treatments. The present disclosure fulfills this need and has other related advantages.

Other publications include <CIT> which discloses pharmaceutical compositions comprising certain dextromethorphan analogs and methods for treating neurological disorders, and <CIT> which discloses compositions comprising dextromethorphan and an inhibitor of debrisoquin hydrolase, including quinidine, useful in the preparation of medicaments for treatment of chronic or intractable conditions including intractable coughing, dermatitis, chronic pain and tinnitus.

In one embodiment, provided is a combination of:.

In certain embodiments R<NUM> is -CH<NUM>, -CHD<NUM>, or -CD<NUM>. In certain embodiments R<NUM> is - OCF<NUM>, -OCD<NUM>, or -OCHF<NUM>.

In certain instances, the selective serotonin reuptake inhibitor is an inhibitor of a cytochrome p450 2D6 enzyme.

In certain instances, the selective serotonin reuptake inhibitor is selected from the group consisting of fluoxetine, norfluoxetine, citalopram, dapoxetine, escitalopram, fluvoxamine, paroxetine, and sertraline, or pharmaceutically acceptable salts thereof.

In certain instances, the selective serotonin reuptake inhibitor is selected from the group consisting of citalopram, norfluoxetine, dapoxetine, escitalopram, fluvoxamine, paroxetine, and sertraline, or pharmaceutically acceptable salts thereof.

In certain instances, the selective serotonin reuptake inhibitor is paroxetine, or a pharmaceutically acceptable salt thereof.

In certain instances, the selective serotonin reuptake inhibitor is selected from the group consisting of citalopram, fluvoxamine, norfluoxetine, fluoxetine, paroxetine and sertraline, and the compound of formula II is selected from the group consisting of:
<CHM>
or pharmaceutically acceptable salts thereof; in certain instances, the selective serotonin reuptake inhibitor being selected from the group consisting of citalopram, fluvoxamine, paroxetine and sertraline, or a pharmaceutically acceptable salt thereof; in certain instances, the selective serotonin reuptake inhibitor being paroxetine, or a pharmaceutically acceptable salt thereof.

<FIG> depicts the metabolic stability of compounds provided herein in CYP2D6 SUPERSOMES™.

The terms "ameliorate" and "treat" are used interchangeably and include both therapeutic treatment and/or prophylactic treatment (reducing the likelihood of development). Both terms mean decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease.

"Disease" means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.

The term "alkyl" refers to a monovalent saturated hydrocarbon group. C<NUM>-C<NUM> alkyl is an alkyl having from <NUM> to <NUM> carbon atoms. An alkyl may be linear or branched. Examples of alkyl groups include methyl; ethyl; propyl, including n-propyl and isopropyl; butyl, including n-butyl, isobutyl, sec-butyl, and t-butyl.

It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis. Thus, a preparation of dextromethorphan or dextromethorphan analogs will inherently contain small amounts of deuterated isotopologues. The concentration of naturally abundant stable hydrogen and carbon isotopes, notwithstanding this variation, is small and immaterial as compared to the degree of stable isotopic substitution of compounds provided herein. See, for instance, <NPL>; <NPL>.

Unless otherwise stated, when a position is designated specifically as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Also unless otherwise stated, when a position is designated specifically as "D" or "deuterium", the position is understood to have deuterium at an abundance that is at least <NUM> times greater than the natural abundance of deuterium, which is <NUM>% (i.e., the term "D" or "deuterium" indicates at least <NUM>% incorporation of deuterium).

The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance of D at a specified position in a compound provided herein and the naturally occurring abundance of that isotope.

In other embodiments, a compound provided herein has an isotopic enrichment factor for each deuterium present at a site designated as a potential site of deuteration on the compound of at least <NUM> (<NUM>% deuterium incorporation), at least <NUM> (<NUM>% deuterium incorporation), at least <NUM> (<NUM>% deuterium incorporation), at least <NUM> (<NUM>% deuterium), at least <NUM> (<NUM>% deuterium incorporation), at least <NUM> (<NUM>% deuterium incorporation), at least <NUM> (<NUM>% deuterium incorporation), at least <NUM> (<NUM>% deuterium incorporation), at least <NUM> (<NUM>% deuterium incorporation), or at least <NUM> (<NUM>% deuterium incorporation).

The term "isotopologue" refers to a species that has the same chemical structure and formula as a specific compound provided herein, with the exception of the positions of isotopic substitution and/or level of isotopic enrichment at one or more positions, e.g., H vs. D.

The term "compound," as used herein, refers to a collection of molecules having an identical chemical structure, except that there may be isotopic variation among the constituent atoms of the molecules. Thus, it will be clear to those of skill in the art that a compound represented by a particular chemical structure containing indicated deuterium atoms, will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound provided herein will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound. However, as set forth above the relative amount of such isotopologues will be less than <NUM>% of the compound.

A salt of a compound provided herein is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

The term "pharmaceutically acceptable," as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and are commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable salt" means any suitable salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound provided herein. A "pharmaceutically acceptable counterion" is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.

The term "stable compounds," as used herein, refers to compounds which possess stability sufficient to allow for their manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds, treating a disease or condition responsive to therapeutic agents).

"Stereoisomer" refers to both enantiomers and diastereomers. "D" refers to deuterium. "Tert", " t ", and " t " each refer to tertiary. "US" refers to the United States of America. "RT" refers to room temperature. "h" refers to hours. "DMF" refers to dimethylformamide. "TsOH" refers to p-toluenesulfonic acid.

Throughout this specification, a variable may be referred to generally (e.g., "each R") or may be referred to specifically (e.g., R<NUM> or R<NUM>). Unless otherwise indicated, when a variable is referred to generally, it is meant to include all specific embodiments of that particular variable.

Described herein are combinations for use in the treatment of chronic or intractable pain in a subject in need thereof. The treatment comprises the administration of a deuterated dextromethorphan analog described herein and an antidepressant. In certain instances, the dextromethorphan analogs have enhanced metabolic profiles. The antidepressant is a selective serotonin reuptake inhibitor. The deuterated dextromethorphan analogs described herein and the antidepressant can be administered together in a single composition or administered in separate compositions.

The deuterated dextromethorphan analog is a compound of Formula II:
<CHM>
or a pharmaceutically acceptable salt thereof, wherein:.

In one embodiment, R<NUM> is selected from -CH<NUM>D, -CHD<NUM>, and -CD<NUM>. In a further embodiment, R<NUM> is -OCD<NUM>.

In one embodiment, R<NUM> is -CH<NUM>, -CHD<NUM> or -CD<NUM>. In another embodiment, R<NUM> is -CH<NUM>. In another embodiment, R<NUM> is -CD<NUM>.

In yet another embodiment, the compound is selected from any one of the compounds set forth in Table <NUM>.

In another set of embodiments, any atom not designated as deuterium in any of the embodiments set forth above is present at its natural isotopic abundance.

In another set of embodiments, the compound of Formula II is purified, e.g., the compound of Formula II is present at a purity of at least <NUM>% by weight (e.g., at least <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>% or <NUM>%) of the total amount of isotopologues of Formula II present, respectively. Thus, in some embodiments, a composition comprising a compound of Formula II can include a distribution of isotopologues of the compound, provided at least <NUM>% of the isotopologues by weight are the recited compound.

In another set of embodiments, the compounds of Formula II are provided in isolated form, e.g., the compound is not in a cell or organism and the compound is separated from some or all of the components that typically accompany it in nature.

In some embodiments, any position in the compound of Formula II designated as having D has a minimum deuterium incorporation of at least <NUM>% (e.g., at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, or at least <NUM>%) at the designated position(s) of the compound of Formula II. Thus, in some embodiments, a composition comprising a compound of Formula II can include a distribution of isotopologues of the compound, provided at least <NUM>% of the isotopologues include a D at the designated position(s).

In some embodiments, a compound of Formula II is "substantially free of" other isotopologues of the compound, e.g., less than <NUM>%, less than <NUM>%, less than <NUM>%, less than <NUM>%, less than <NUM>%, less than <NUM>%, or less than <NUM>% of other isotopologues are present.

The synthesis of compounds of Formula II can be readily achieved by synthetic chemists of ordinary skill by reference to the Exemplary Synthesis and Examples disclosed herein. Relevant procedures and intermediates are disclosed, for instance, in <NPL>; <CIT>); <CIT>); <NPL>. Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure.

The co-agent for inclusion in the combination for use in the methods is useful in the treatment of chronic or intractable pain, and is an antidepressant that is a selective serotonin reuptake inhibitor. In certain instances the co-agent is an inhibitor of a cytochrome p450 2D6 enzyme.

In certain instances the selective serotonin reuptake inhibitor can be citalopram, dapoxetine, escitalopram, fluvoxamine, norfluoxetine, fluoxetine, paroxetine, sertraline, or zimelidine, or pharmaceutically acceptable salts thereof.

The co-agents disclosed herein are commercially available or can be prepared using techniques known to those having ordinary skill in the art. Compounds of the disclosed dextromethorphan analog genuses can be prepared by a person skilled in the art using the appropriately deuterated reagents and/or intermediates according to the general procedures provided herein and described in the following publications and patents: (<NPL>; <CIT>); <CIT>); <NPL>).

The following deuterated reagents and building blocks are commercially available: iodoethane-ds, ethyl-<NUM>,<NUM>,<NUM>-d<NUM> iodide, ethyl-<NUM>,<NUM>-d<NUM> iodide, isopropyl-d<NUM> iodide, isopropyl-d<NUM> bromide, isopropyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-d<NUM> iodide, and <NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-d<NUM> bromide.

Compounds of Formula II may be prepared from one of the known intermediates X, XI, and XII shown below, and from related intermediates that may be readily obtained from known procedures.

The scheme shown below shows a general route to the compounds of Formula II. <CHM>
<CHM>.

The scheme above shows a general route for preparing compounds of Formula II. The HBr salt, <NUM>, after treatment with NH<NUM>OH produces free base 22b. The free base 22b is then N-demethylated via an acylative demethylation reaction followed by hydrolysis of the resulting acetamide to yield <NUM>. Acylation of the amine <NUM> using the ethylchloroformate provides the carbamate <NUM> which is then O-demethylated using BBr<NUM> to yield the alcohol <NUM>. Compound <NUM> is treated, in the presence of base, with an appropriately deuterated iodomethane to yield the ether <NUM>, which is reduced using either lithium aluminum deuteride (LAD) to yield compounds of Formula II wherein R<NUM>= -CD<NUM> or lithium aluminum hydride (LAH) to yield compounds of Formula II wherein R<NUM>= -CH<NUM>. For those compounds of Formula II wherein R<NUM> is -OCH<NUM>, carbamate <NUM> is directly treated with LAD to produce a compound where R<NUM> is -CD<NUM>.

Various R<NUM> groups (as defined in Formula II) may be introduced by O-alkylation of the appropriate phenol intermediate using an alkylating agent, such as an alkyl halide, according to methods generally known in the art. Various R<NUM> groups (as defined in Formula II) may be introduced by N-alkylation using an R<NUM>-alkylating agent (for example, iodo-R<NUM>), or by reduction of the N-formyl group with a deuterated reagent, such as deuteroborane according to methods generally known in the art.

The specific approaches and compounds shown above are not intended to be limiting. The chemical structures in the schemes herein depict variables that are hereby defined commensurately with chemical group definitions (moieties, atoms, etc.) of the corresponding position in the compound formulae herein, whether identified by the same variable name (i.e., R<NUM> or R<NUM>) or not. The suitability of a chemical group in a compound structure for use in the synthesis of another compound is within the knowledge of one of ordinary skill in the art.

Additional methods of synthesizing compounds of Formula II and their synthetic precursors, including those within routes not explicitly shown in schemes herein, are within the means of chemists of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the applicable compounds are known in the art and include, for example, those described in <NPL>); <NPL>);<NPL>); and <NPL>) and subsequent editions thereof.

Provided herein are pyrogen-free compositions comprising an effective amount of a compound of Formula II (e.g., including any of the formulae herein), or a pharmaceutically acceptable salt of said compound; a co-agent; and an acceptable carrier. In certain instances the composition is formulated for pharmaceutical use ("a pharmaceutical composition"), wherein the carrier is a pharmaceutically acceptable carrier. The carrier(s) are "acceptable" in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions provided herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

If required, the solubility and bioavailability of the compounds provided herein in pharmaceutical compositions may be enhanced by methods well-known in the art. One method includes the use of lipid excipients in the formulation. See "<NPL>; and "<NPL>.

Another known method of enhancing bioavailability is the use of an amorphous form of a compound provided herein optionally formulated with a poloxamer, such as LUTROL™ and PLURONIC™ (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. See <CIT>; and <CIT>and <CIT>.

The pharmaceutical compositions provided herein include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. In certain embodiments, the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch or iontophoretic techniques). Other formulations may conveniently be presented in unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, <NPL>).

Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.

In certain embodiments, the compounds are administered orally. The compositions provided herein suitable for oral administration may be presented as discrete units such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.

In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

Compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.

Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween <NUM>) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in <NUM>,<NUM>-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

The pharmaceutical compositions provided herein may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound provided herein with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions provided herein can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, e.g.: <CIT>.

Topical administration of the pharmaceutical compositions provided herein are useful when the desired treatment involves areas or organs readily accessible by topical application. For topical application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds provided herein include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate <NUM>, cetyl esters wax, cetearyl alcohol, <NUM>-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions provided herein may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation.

Application of the subject therapeutics may be local, so as to be administered at the site of interest. Various techniques can be used for providing the subject compositions at the site of interest, such as injection, use of catheters, trocars, projectiles, pluronic gel, stents, sustained drug release polymers or other device which provides for internal access.

Thus, according to yet another embodiment, the compounds provided herein may be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, or catheters. Suitable coatings and the general preparation of coated implantable devices are known in the art and are exemplified in <CIT>; <CIT>; and <CIT>. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Coatings for invasive devices are to be included within the definition of pharmaceutically acceptable carrier, adjuvant or vehicle, as those terms are used herein.

According to another embodiment, provided is a method of coating an implantable medical device comprising the step of contacting said device with the coating composition described above. It will be obvious to those skilled in the art that the coating of the device will occur prior to implantation into a mammal.

According to another embodiment, provided is a method of impregnating an implantable drug release device comprising the step of contacting said drug release device with a compound or composition provided herein. Implantable drug release devices include, but are not limited to, biodegradable polymer capsules or bullets, non-degradable, diffusible polymer capsules and biodegradable polymer wafers.

According to another embodiment, provided is an implantable medical device coated with a compound or a composition comprising a compound provided herein, such that said compound is therapeutically active.

According to another embodiment, provided is an implantable drug release device impregnated with or containing a compound or a composition comprising a compound provided herein, such that said compound is released from said device and is therapeutically active.

Where an organ or tissue is accessible because of removal from the subject, such organ or tissue may be bathed in a medium containing a composition provided herein, a composition provided herein may be painted onto the organ, or a composition provided herein may be applied in any other convenient way.

In another embodiment, provided are separate dosage forms of a compound of Formula II; and one or more of any of the above-described co-agents, wherein the compound of Formula II; and the co-agent are associated with one another. The term "associated with one another" as used herein means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than <NUM> hours of one another, consecutively or simultaneously).

In the pharmaceutical compositions provided herein, the compound of Formula II is present in an effective amount. As used herein, the term "effective amount" refers to an amount which, when administered in a proper dosing regimen, is sufficient to reduce or ameliorate the severity, duration or progression of the disorder being treated, prevent the advancement of the disorder being treated, cause the regression of the disorder being treated, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.

The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described in <NPL>. Body surface area may be approximately determined from height and weight of the subject. See, e.g.,<NPL>.

In one embodiment, an effective amount of a compound of Formula II can range from <NUM> to <NUM>, from <NUM> to <NUM>, from <NUM> to <NUM>, or from <NUM> to <NUM>, inclusive, which can be given once, twice, or up to three times daily depending on various factors recognized by those skilled in the art.

Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician. For example, guidance for selecting an effective dose can be determined by reference to the prescribing information for dextromethorphan.

An effective amount of the co-agent can be between about <NUM>% to about <NUM>% of the dosage normally utilized in a monotherapy regime using only that agent. The normal monotherapeutic dosages of these co-agents are well known in the art. See, e.g., <NPL>);<NPL>).

Provided herein is a method of treating chronic or intractable pain. Chronic or intractable pain includes pain related to stroke, trauma, cancer, cancer treatment, fibromyalgia, and pain due to neuropathies such as herpes zoster infection (i.e., postherpetic neuralgia), and diabetes (diabetic neuropathy). Neuropathic pain also includes phantom limb pain, trigeminal neuralgia, and sciatica. The method comprises the step of administering to a subject a therapeutically effective amount of a co-agent and a deuterated dextromethorphan analog. The co-agent is an antidepressant that is a selective serotonin reuptake inhibitor; or pharmaceutically acceptable salts thereof. The deuterated dextromethorphan analog is a compound of Formula II:
<CHM>
or a pharmaceutically acceptable salt thereof, wherein:.

In certain embodiments R<NUM> is -CH<NUM>, -CHD<NUM>, or -CD<NUM>. In certain embodiments R<NUM> is -OCD<NUM>.

In some instances, the co-agent described above is capable of inhibiting the action of a cytochrome p450 2D6 enzyme.

The co-agent is a selective serotonin reuptake inhibitor. The selective serotonin reuptake inhibitor can be fluoxetine, norfluoxetine, citalopram, dapoxetine, escitalopram, fluvoxamine, paroxetine, or sertraline, or pharmaceutically acceptable salts thereof. In certain instances the co-agent is citalopram, norfluoxetine, dapoxetine, escitalopram, fluvoxamine, paroxetine, or sertraline, or pharmaceutically acceptable salts thereof. In another embodiment the co-agent is paroxetine, or a pharmaceutically acceptable salt thereof.

Also provided is use in a method of treating chronic or intractable pain in a subject in need thereof, the method comprising the step of administering to the subject a therapeutically effective amount of a co-agent selected from the grouping consisting of citalopram, fluvoxamine, norfluoxetine, fluoxetine, paroxetine, sertraline, or pharmaceutically acceptable salts thereof, and a therapeutically effective amount of a compound selected from the group consisting of:
<CHM>
or pharmaceutically acceptable salts thereof.

Another embodiment relates to the aforementioned use in a method where in the co-agent can be citalopram, fluvoxamine, paroxetine, sertraline, or pharmaceutically acceptable salts thereof. The co-agent can also be paroxetine, or a pharmaceutically acceptable salt thereof.

Another embodiment relates to any of the aforementioned use in methods for treating chronic or intractable pain, where the chronic or intractable pain is a neuropathic pain.

Another embodiment relates to any of the aforementioned use in methods for treating chronic or intractable pain, where the chronic or intractable pain is diabetic neuropathic pain.

The co-agent may be administered together with a compound of Formula II as part of a single dosage form or as separate, multiple dosage forms. Alternatively, the co-agent may be administered prior to, consecutively with, or following the administration of a compound of Formula II. In such combination therapy treatment, both the compound of Formula II; and the co-agent are administered by conventional methods.

Effective amounts of the co-agent are well known to those skilled in the art and guidance for dosing may be found in patents and published patent applications referenced herein, as well as in <NPL>);<NPL>), and other medical texts. However, it is well within the skilled artisan's purview to determine the co- agent's optimal effective-amount range.

In certain embodiments, the effective amount of the co-agent is less than its effective amount would be where the compound of Formula II is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art.

In one embodiment, the therapeutically effective amount of the compound of Formula II is lower than the therapeutically effective amount of dextromethorphan that is sufficient to achieve the same therapeutic effect as the compound for Formula II.

In one embodiment, a therapeutically effective amount of the compound of Formula II is administered with a co-agent wherein the amount of the co-agent is less than its amount would be where the co-agent is administered in the absence of the compound of Formula II and with an amount of dextromethorphan equal to the therapeutically effective amount of the compound of Formula II. In this way, undesired side effects associated with high doses of the co-agent may be minimized. In an example of this embodiment, the co-agent is quinidine or a pharmaceutically acceptable salt thereof, such as quinidine sulfate.

In one aspect of this embodiment, an amount of the compound of Formula II or a pharmaceutically acceptable salt thereof, such as the hydrobromide salt, wherein the amount is between about <NUM> and about <NUM>, such as between about <NUM> and about <NUM>, is administered with (a) an amount of quinidine sulfate between about <NUM> and about <NUM>, such as between about <NUM> and about <NUM>, or (b) an amount of quinidine or of a pharmaceutically acceptable salt thereof other than quinidine sulfate that is equimolar with an amount of quinidine sulfate between about <NUM> and about <NUM>, such as between about <NUM> and about <NUM>. As an example, the compound of Formula II or a pharmaceutically acceptable salt thereof, such as the hydrobromide salt, and the quinidine sulfate, quinidine, or pharmaceutically acceptable salt thereof other than quinidine sulfate may be administered in the therapeutically effective amounts above to a subject to treat diabetic neuropathy or neuropathic pain such as diabetic neuropathic pain.

In another aspect of this embodiment, an amount of the compound of Formula Formula II or a pharmaceutically acceptable salt thereof, such as the hydrobromide salt, wherein the amount is between about <NUM> and about <NUM>, such as between about <NUM> and about <NUM>, is administered with an amount of (a) an amount of quinidine sulfate between about <NUM> and about <NUM>, such as between about <NUM> and about <NUM>, or (b) an amount of quinidine or of a pharmaceutically acceptable salt thereof other than quinidine sulfate that is equimolar with an amount of quinidine sulfate between about <NUM> and about <NUM>, such as between about <NUM> and about <NUM>.

Certain embodiments relate to any of the aforementioned methods, where an effective amount of a compound of Formula II can range from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>. The dose be given once, twice, or up to three times daily depending on various factors recogonized by those skilled in the art.

Certain embodiments relate to any of the aforementioned methods, where the co-agent is paroxetine. In certain instances, an effective amount of paroxetine, when dosed with a compound of Formula II, can range from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>.

In yet another aspect, provided is the use of a compound of Formula II together with one or more of the above-described co-agents in the manufacture of a medicament, either as a single composition or as separate dosage forms, for treatment or prevention in a subject of a disease, disorder or symptom set forth above.

Also provided are kits for use to treat chronic or intractable pain. These kits comprise (a) a pharmaceutical composition comprising a compound of Formula II and a co-agent, as described above, or pharmaceutically acceptable salts thereof, wherein said pharmaceutical composition is in a container; and (b) instructions describing a method of using the pharmaceutical composition to treat chronic or intractable pain.

In certain embodiments, the kits comprise (a) a first pharmaceutical composition comprising a compound of Formula II or pharmaceutically acceptable salts thereof; (b) a second pharmaceutical composition comprising a co-agent as described above or a pharmaceutically acceptable salt thereof, wherein the first pharmaceutical composition and the second pharmaceutical composition are contained in separate containers; and (c) instructions describing a method of using the first pharmaceutical composition and the second pharmaceutical composition to treat chronic or intractable pain.

The container(s) may be any vessel or other sealed or sealable apparatus that can hold said pharmaceutical composition(s). Examples include bottles, ampules, divided or multi-chambered holders bottles, wherein each division or chamber comprises a single dose of said composition, a divided foil packet wherein each division comprises a single dose of said composition, or a dispenser that dispenses single doses of said composition. The container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule. The container employed can depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle, which is in turn contained within a box. In on embodiment, the container is a blister pack.

The kits may also comprise a device to administer or to measure out a unit dose of the pharmaceutical composition. Such device may include an inhaler if said composition is an inhalable composition; a syringe and needle if said composition is an injectable composition; a syringe, spoon, pump, or a vessel with or without volume markings if said composition is an oral liquid composition; or any other measuring or delivery device appropriate to the dosage formulation of the composition present in the kit.

Example <NUM> (reference). Synthesis of (+)-<NUM>-(Ethoxy-d<NUM>)-<NUM>-(methyl-d<NUM>)-(9α,13α,14α)-morphinan hydrochloride (<NUM>).

Synthesis of (+)-<NUM>-methoxy-<NUM>-methyl-(9α,13α,14α)-morphinan (free base, 22b). To a reaction vessel was added (+)-<NUM>-methoxy-<NUM>-methyl-(9α,13α,14α)-morphinan, HBr salt (<NUM>; <NUM>, <NUM> mmol), NH<NUM> in CH<NUM>OH (<NUM>, <NUM>, <NUM> mmol), and a stir bar. The reaction mixture was stirred at RT for <NUM>. The resulting material was concentrated on a rotary evaporator, then diluted with CHCl<NUM> (<NUM>) and H<NUM>O (<NUM>). The layers were separated and the water layer was extracted with CHCl<NUM> (<NUM>). The combined organic layers were dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to yield <NUM> of 22b as a fluffy white solid.

<NUM>H-NMR (<NUM>, CDCl<NUM>): δ <NUM> (ddd, J<NUM>=<NUM>, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (td, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (dt, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (td, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (dd, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (dd, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>).

Synthesis of (+)-<NUM>-methoxy-(9α,13α,14α)-morphinan (<NUM>). The solid (+)-<NUM>-methoxy-<NUM>-methyl-(9α,13α,14α)-morphinan (22b; <NUM>, <NUM> mmol) was placed in a reaction vessel with CHCl<NUM> and a stir bar. K<NUM>CO<NUM> (<NUM>, <NUM> mmol) was added and the mixture was stirred at RT under an atmosphere of N<NUM> for <NUM> before the addition of acetyl chloride (<NUM>, <NUM> mmol). The resulting reaction mixture, still under an atmosphere of N<NUM>, was stirred under reflux conditions for <NUM>, then filtered through a pad of celite. The organic filtrate was concentrated on a rotary evaporator and the resulting crude material was dissolved in CH<NUM>OH then stirred under reflux conditions for <NUM>. The solution was concentrated on a rotary evaporator then dried under vacuum to yield <NUM> of <NUM> as an off-white solid.

<NUM>H-NMR (<NUM>, CDCl<NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (bs, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>).

Synthesis of (+)-<NUM>-ethylcarbamate-<NUM>-methoxy-(9α,13α,14α)-morphinan (<NUM>). To a reaction vessel fit with a stirbar was added <NUM> (<NUM>, <NUM> mmol) dissolved in CHCl<NUM> (<NUM>). Diisopropylethylamine (DIEA; <NUM>, <NUM> mmol) was added and the mixture was stirred for <NUM> at room temperature under nitrogen before the addition of ethylchloroformate (<NUM>, <NUM> mmol). The reaction mixture was stirred under reflux conditions under nitrogen for <NUM>, at which point TLC (<NUM>% ethylacetate/hexane) showed complete consumption of the starting material. The organic layer was removed and washed first with <NUM> HCl, and then with saturated NaHCO<NUM>. The aqueous layers from each wash were combined and back extracted with <NUM> of CHCl<NUM>. The organic layer from the back extraction was combined with the organic layer from the washes and the combined organic layers were dried over Na<NUM>SO<NUM>. The organic solution was then filtered, concentrated on a rotary evaporator then was purified via automated flash column chromatography (<NUM>-<NUM>% ethylacetate/hexane) to yield <NUM> of <NUM> as a clear light yellow oil.

<NUM>H-NMR (<NUM>, CDCl<NUM>): δ <NUM> (ddd, J<NUM>=<NUM>, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (ddd, J<NUM>=<NUM>, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (q, J=<NUM>, <NUM>), <NUM> (dt, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (dd, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (apparent t, J=<NUM>, <NUM>).

(+)-<NUM>-ethylcarbamate-<NUM>-hydroxy-(9α,13α,14α)-morphinan (<NUM>). In a reaction vessel fit with a stirbar the carbamate <NUM> (<NUM>, <NUM> mmol) was dissolved in DCM (<NUM>) and the resulting solution was cooled to <NUM>. BBr<NUM> (<NUM>, <NUM> mmol) was added and the reaction mixture was stirred under an atmosphere of N<NUM> at <NUM> for <NUM> (at which time tlc in <NUM>% ethylacetate/hexane showed the reaction to be complete). A solution of <NUM>% NH<NUM>OH in ice was placed in a beaker with a stir bar and the reaction mixture was slowly added with stirring. The resulting mixture was stirred for <NUM> then was extracted with <NUM>:<NUM> CHCl<NUM>/CH<NUM>OH (<NUM>). The organic layer was dried over Na<NUM>SO<NUM>, filtered, then concentrated on a rotary evaporator. The crude material was purified via automated flash column chromatography (CH<NUM>OH with <NUM>% NH<NUM>OH / CHCl<NUM>, <NUM>-<NUM>%). The pure fractions were concentrated on a rotary evaporator to yield <NUM> of <NUM> as a white solid.

<NUM>H-NMR (<NUM>, CDCl<NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dt, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (ddd, J<NUM>=<NUM>, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dt, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (apparent t, J=<NUM>, <NUM>).

Synthesis of (+)-<NUM>-(ethoxy-d<NUM>)-<NUM>-ethoxycarbonyl-(9α,13α,14α)-morphinan (<NUM>). To a solution of alcohol <NUM> (<NUM>, <NUM> mmol) in DMF (<NUM>), was added K<NUM>CO<NUM> (<NUM>, <NUM> mmol, <NUM> eq) and iodoethane-ds (<NUM>, <NUM> mmol, <NUM> eq) with stirring. The reaction mixture was stirred overnight at room temperature under an atmosphere of N<NUM>, was quenched by the addition of H<NUM>O, and extracted with Et<NUM>O (<NUM> x <NUM>). The combined organics were dried over Na<NUM>SO<NUM>, filtered and concentrated in vacuo to a yellow oil. Purification via automated flash column chromatography (<NUM>-<NUM>% EtOAc/hexanes) afforded intermediate <NUM> (<NUM>, <NUM>% yield).

Synthesis of (+)-<NUM>-(ethoxy-d<NUM>)-<NUM>-(methyl-d<NUM>)-(9α,13α,14α)-morphinan hydrochloride (<NUM>). To a slurry of LiAlD<NUM> (<NUM>, <NUM> mmol, <NUM> eq) in THF (<NUM>) stirring at -<NUM> was added a solution of the carbamate <NUM> (<NUM>, <NUM> mmol) in THF (<NUM>). After <NUM> of stirring at rt, no reaction was detected by tlc and an additional <NUM> eq of LiAlD<NUM> (<NUM>, <NUM> mmol, <NUM> eq) was added. The reaction mixture was stirred overnight at rt, then was quenched by the addition of magnesium sulfate heptahydrate until cessation of gas evolution. The mixture was filtered, concentrated in vacuo and the resultant crude material was purified via automated flash column chromatography (CHCl<NUM>/CH<NUM>OH/NH<NUM>OH - <NUM>/<NUM>/<NUM>) to yield the free amine <NUM>. This material was dissolved in <NUM> HCl in CH<NUM>OH then was concentrated under reduced pressure and dried under high vacuum to yield <NUM> of product <NUM> as the HCl salt. <NUM>H-NMR (<NUM>, DMSO-d<NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (br s, <NUM>). HPLC (method: <NUM> C18-RP column - gradient method <NUM>-<NUM>% ACN; Wavelength: <NUM>): retention time: <NUM>, purity: <NUM>%. MS (M+H): <NUM>.

Example <NUM> (reference). Synthesis of (+)-<NUM>-(Ethoxy-d<NUM>)-<NUM>-methyl-(9α,13α,14α)-morphinan hydrochloride (<NUM>). <NUM> was used in place of LiAlD<NUM> for the reduction of the carbamate <NUM> to <NUM>.

Synthesis of (+)-<NUM>-(ethoxy-d<NUM>)-<NUM>-methyl-(9α,13α,14α)-morphinan hydrochloride (<NUM>). To a slurry of LiAlH<NUM> (<NUM>, <NUM> mmol, <NUM> eq) in THF (<NUM>) stirring at -<NUM> was added a solution of the carbamate <NUM> (<NUM>, <NUM> mmol) in THF (<NUM>). After <NUM> an additional <NUM> eq of LiAlH<NUM> (<NUM>, <NUM> mmol, <NUM> eq) was added. The reaction mixture was stirred overnight at rt, then was quenched by the addition of magnesium sulfate heptahydrate until cessation of gas evolution. The mixture was filtered, concentrated in vacuo and the resultant crude material was purified via automated flash column chromatography (CHCl<NUM>/CH<NUM>OH/NH<NUM>OH - <NUM>/<NUM>/<NUM>) to yield the free-amine <NUM>. This material was dissolved in <NUM> HCl in CH<NUM>OH then was concentrated under reduced pressure and dried under high vacuum to yield <NUM> of product <NUM> as the HCl salt. <NUM>H-NMR (<NUM>, DMSO-d<NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (br s, <NUM>). HPLC (method: <NUM> C18-RP column - gradient method <NUM>-<NUM>% ACN; Wavelength: <NUM>): retention time: <NUM>, purity: <NUM>%. MS (M+H): <NUM>.

Example <NUM> (reference). Synthesis of (+)-<NUM>-(Isopropoxy-d<NUM>)-<NUM>-(methyl-d<NUM>)-(9α,13α,14α)-morphinan (<NUM>).

Synthesis of (+)-<NUM>-(isopropoxy-d<NUM>)-<NUM>-ethoxycarbonyl-(9α,13α,14α)-morphinan (<NUM>). To a solution of alcohol <NUM> (<NUM>, <NUM> mmol; produced according to Example <NUM>) in DMF (<NUM>), was added K<NUM>CO<NUM> (<NUM>, <NUM> mmol, <NUM> eq) and <NUM>-iodopropane-d<NUM> (<NUM>, <NUM> mmol, <NUM> eq) with stirring. The reaction mixture was stirred overnight at room temperature under an atomosphere of N<NUM>, was quenched by the addition of H<NUM>O, and extracted with Et<NUM>O (<NUM> x <NUM>). The combined organics were dried over Na<NUM>SO<NUM>, filtered and concentrated in vacuo to a colorless oil. Purification via automated flash column chromatography (<NUM>-<NUM>% EtOAc/hexanes) afforded intermediate <NUM> (<NUM>, <NUM>% yield).

Synthesis of (+)-<NUM>-(isopropoxy-d<NUM>)-<NUM>-(methyl-d<NUM>)-(9α,13α,14α)-morphinan (<NUM>). To a slurry of LiAlD<NUM> (<NUM>, <NUM> mmol, <NUM> eq) in THF (<NUM>) stirring at -<NUM> was added a solution of the carbamate <NUM> (<NUM>, <NUM> mmol) in THF (<NUM>). The reaction mixture was stirred overnight at rt, then was quenched by the addition of magnesium sulfate heptahydrate until cessation of gas evolution. The mixture was filtered, the filtrate concentrated in vacuo and the resultant material was dissolved in CH<NUM>OH. The resulting solution was acidified to pH <NUM> with fumaric acid resulting in salt precipitation. The mixture was stirred for <NUM>, and Et<NUM>O was added to bring remaining salt out of solution. The salt was isolated by filtration and dried to yield <NUM> of final product <NUM> as the fumaric acid salt. <NUM>H-NMR (<NUM>, CDCl<NUM>): δ <NUM> (qd, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (td, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>). HPLC (method: <NUM> C18-RP column - gradient method <NUM>-<NUM>% ACN; Wavelength: <NUM>): retention time: <NUM>, purity: <NUM>%. MS (M+H): <NUM>.

Example <NUM> (reference). Synthesis of (+)-<NUM>-(Isopropoxy-d<NUM>)-<NUM>-methyl-(9α,13α,14α)-morphinan (<NUM>). <NUM> was used in place of LiAlD<NUM> for the reduction of the carbamate <NUM> to <NUM>.

Synthesis of (+)-<NUM>-(isopropoxy-d<NUM>)-<NUM>-methyl-(9α,13α,14α)-morphinan (<NUM>). To a slurry of LiAlH<NUM> (<NUM>, <NUM> mmol, <NUM> eq) in THF (<NUM>) stirring at -<NUM> was added a solution of the carbamate <NUM> (<NUM>, <NUM> mmol) in THF (<NUM>). The reaction mixture was stirred overnight at rt, then was quenched by the addition of magnesium sulfate heptahydrate until cessation of gas evolution. The mixture was filtered, the filtrate concentrated in vacuo and the resultant material was dissolved in CH<NUM>OH. The resulting solution was acidified to pH <NUM> with fumaric acid resulting in salt precipitation. The mixture was stirred for <NUM>, and Et<NUM>O was added to bring remaining salt out of solution. The salt was isolated by filtration and dried to yield <NUM> of final product <NUM> as the fumaric acid salt. <NUM>H-NMR (<NUM>, CDCl<NUM>): δ <NUM> (qd, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (td, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>). HPLC (method: <NUM> C18-RP column - gradient method <NUM>-<NUM>% ACN; Wavelength: <NUM>): retention time: <NUM>, purity: <NUM>%. MS (M+H): <NUM>.

Example <NUM>. Synthesis of (+)-<NUM>-(Methoxy-d<NUM>)-<NUM>-(methyl-d<NUM>)-(9α,13α,14α)-morphinan (<NUM>). <CHM>
(+)-<NUM>-methoxy-<NUM>-methyl-(9α, 13α, <NUM>α)-morphinan (22b). To a reaction vessel was added (+)-<NUM>-methoxy-<NUM>-methyl-(9α,13α,14α)-morphinan, HBr salt <NUM> (<NUM>, <NUM> mmol), NH<NUM> in CH<NUM>OH (<NUM>, <NUM>, <NUM> mmol), and a stir bar. The reaction mixture was stirred at RT for <NUM>. The resulting material was concentrated on a rotary evaporator, then diluted with CHCl<NUM> (<NUM>) and H<NUM>O (<NUM>). The layers were separated and the water layer was extracted with CHCl<NUM> (<NUM>). The combined organic layers were dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to yield <NUM> of 22b as a fluffy white solid.

<NUM>H-NMR (<NUM>, CDCl<NUM>): δ <NUM> (ddd, J<NUM>=<NUM>, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (td, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (dt, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (td, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (dd, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (dd, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>).

(+)-<NUM>-methoxy-(9α,13α,14α)-morphinan (<NUM>). The solid 22b (<NUM>, <NUM> mmol) was placed in a reaction vessel with CHCl<NUM> and a stir bar. K<NUM>CO<NUM> (<NUM>, <NUM> mmol) was added and the mixture was stirred at RT under an atmosphere of N<NUM> for <NUM> before the addition of acetyl chloride (<NUM>, <NUM> mmol). The resulting reaction mixture, still under an atmosphere of N<NUM>, was stirred under reflux conditions for <NUM>, then filtered through a pad of celite. The organic filtrate was concentrated on a rotary evaporator and the resulting crude material was dissolved in CH<NUM>OH then stirred under reflux conditions for <NUM>. The solution was concentrated on a rotary evaporator then dried under vacuum to yield <NUM> of <NUM> as an off-white solid.

<NUM>H-NMR (<NUM>, CDCl<NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (bs, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (d, J =<NUM>, <NUM>), <NUM> (d, J =<NUM>, <NUM>).

(+)-<NUM>-ethylcarbamate-<NUM>-methoxy-(9α,13α,14α)-morphinan (<NUM>). To a reaction vessel fit with a stirbar was added <NUM> (<NUM>, <NUM> mmol) dissolved in CHCl<NUM> (<NUM>). Diisopropylethylamine (DIEA; <NUM>, <NUM> mmol) was added and the mixture was stirred for <NUM> at room temperature under nitrogen before the addition of ethylchloroformate (<NUM>, <NUM> mmol). The reaction mixture was stirred under reflux conditions under nitrogen for <NUM>, at which point tlc (<NUM>% ethylacetate/hexane) showed complete consumption of starting material, <NUM>. The organic layer was removed and washed first with <NUM> HCl, and then with saturated NaHCO<NUM>. The aqueous layers from each wash were combined and back extracted with <NUM> of CHCl<NUM>. The organic layer from the back extraction was combined with the organic layer from the washes and the combined organic layers were dried over NaSO<NUM>. The organic solution was then filtered, concentrated on a rotary evaporator then was purified via automated flash column chromatography (<NUM>-<NUM>% ethylacetate/hexane) to yield <NUM> of <NUM> as a clear light yellow oil.

<NUM>H-NMR (<NUM>, CDCl<NUM>): δ <NUM> (ddd, J<NUM>=<NUM>, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (ddd, J<NUM>=<NUM>, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (q, J=<NUM>, <NUM>), <NUM> (dt, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (dd, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (d, J =<NUM>, <NUM>), <NUM> (apparent t, J =<NUM>, <NUM>).

<NUM>H-NMR (<NUM>, CDCl<NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dt, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (ddd, J<NUM>=<NUM>, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dt, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (apparent t, J =<NUM>, <NUM>).

(+)-<NUM>-ethylcarbamate-<NUM>-d<NUM>-methoxy-(9α,13α,14α)-morphinan (24a; R<NUM>= -OCD<NUM>). The compound <NUM> (<NUM>, <NUM> mmol) was dissolved in DMF (<NUM>) in a reaction vessel fit with a stir bar. To this solution was added K<NUM>CO<NUM> (<NUM>, <NUM> mmol). The mixture was stirred under an atmosphere of N<NUM> at RT for <NUM> before the addition of CD<NUM>I (<NUM>, <NUM> mmol). The resulting reaction mixture was stirred overnight at RT at which time tlc (<NUM>% ethylacetate/hexane) showed complete reaction. The mixture was diluted with H<NUM>O then was extracted with ethyl ether (<NUM> x <NUM>). The combined organic layers were dried over Na<NUM>SO<NUM>, filtered, and the filtrate concentrated on a rotary evaporator to a clear yellow oil. Purification via automated flash column chromatography (<NUM>-<NUM>% ethylacetate/hexane) and concentration of pure fractions on a rotary evaporator afforded <NUM> of product.

<NUM>H-NMR (<NUM>, CDCl<NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (ddd, J<NUM>=<NUM>, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dt, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (dd, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (apparent t, J=<NUM>, <NUM>).

(+)-<NUM>-d<NUM>-methoxy-<NUM>-d<NUM>-methyl-(9α,13α,14α)-morphinan (Compound <NUM>). To a reaction vessel fit with a stir bar, was added THF (<NUM>) and LAD (<NUM>, <NUM> mmol). The slurry was cooled to <NUM> followed by the addition of a solution of product 24a (R<NUM>= -OCD<NUM>, <NUM>, <NUM> mmol) in THF (<NUM>). The reaction mixture was stirred under an atmosphere of N<NUM> for <NUM> at which time tlc (<NUM>% ethylacetate/hexane) showed the reaction to be complete. The mixture was then quenched by the addition of magnesium sulfate heptahydrate until cessation of gas evolution. Ethyl ether (<NUM>) was added to the flask, the slurry was filtered, and the organic filtrate was concentrated on a rotary evaporator to an oil. The crude product was purified via automated flash column chromatography (CH<NUM>OH with <NUM>% NH<NUM>OH / CHCl<NUM>, <NUM>-<NUM>%), concentrated on a rotary evaporator, then dissolved in a saturated solution of HBr in dioxane. The mixture was stirred for <NUM>, was concentrated on a rotary evaporator, then dried under vacuum for <NUM> d to yield <NUM> of Compound <NUM>.

<NUM>H-NMR (<NUM>, CDCl<NUM>): δ <NUM> (ddd, J<NUM>=<NUM>, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (dt, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (t, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>). HPLC (method: <NUM> C18-RP column - gradient method <NUM>-<NUM>% ACN; Wavelength: <NUM>): retention time: <NUM>. MS (M+H+): <NUM>.

(+)-<NUM>-d<NUM>-methoxy-<NUM>-methyl-(9α,13α,14α)-morphinan (Compound <NUM>). To a reaction vessel fit with a stir bar, was added THF (<NUM>) and LAH (<NUM>, <NUM> mmol). The slurry was cooled to <NUM> followed by the addition of product 24a (R<NUM>= -OCD<NUM>, <NUM>, <NUM> mmol) dissolved in THF (<NUM>). The reaction mixture was stirred under an atmosphere of N<NUM> for <NUM> at which time tlc (<NUM>% ethylacetate/hexane) showed the reaction to be complete. The mixture was then quenched by the addition of magnesium sulfate heptahydrate until cessation of gas evolution. Ethyl ether (<NUM>) was added to the flask, the slurry was filtered, and the organic filtrate was concentrated on a rotary evaporator to an oil. The crude product was purified via automated flash column chromatography (CH<NUM>OH with <NUM>% NH<NUM>OH / CHCl<NUM>, <NUM>-<NUM>%), concentrated on a rotary evaporator, then dissolved in a saturated solution of HBr in dioxane. The mixture was stirred for <NUM>, was concentrated on a rotary evaporator, then dried under vacuum for <NUM> d to yield <NUM> of Compound <NUM>.

<NUM>H-NMR (<NUM>, CDCl<NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (t, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (t, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (dd, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J =<NUM>, <NUM>). HPLC (method: <NUM> C18-RP column - gradient method <NUM>-<NUM>% ACN; Wavelength: <NUM>): retention time: <NUM>. MS (M+H+): <NUM>.

(+)-<NUM>-methoxy-<NUM>-d<NUM>-methyl-(9α,13α,14α)-morphinan (Compound <NUM>). To a reaction vessel fit with a stir bar, was added THF (<NUM>) and LAD (<NUM>, <NUM> mmol). The slurry was cooled to <NUM> followed by the gradual addition of carbamate <NUM> (<NUM>, <NUM> mmol) dissolved in THF (<NUM>). The reaction mixture was stirred under an atmosphere of N<NUM> for <NUM> at which time tlc (<NUM>% ethylacetate/hexane) showed the reaction to be complete. The mixture was then quenched by the addition of magnesium sulfate heptahydrate until cessation of gas evolution. The resulting solid was washed with ethyl ether, filtered, and the organic filtrate was concentrated on a rotary evaporator to an oil. The crude product was purified via automated flash column chromatography (CH<NUM>OH with <NUM>% NH<NUM>OH / CHCl<NUM>, <NUM>%), concentrated on a rotary evaporator, and then dissolved in a saturated solution of HBr in dioxane. The mixture was stirred for <NUM>, and then concentrated on a rotary evaporator to yield <NUM> of product.

<NUM>H-NMR (<NUM>, CDCl<NUM>): δ <NUM> (ddd, J<NUM>=<NUM>, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (td, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (bs, <NUM>). HPLC (method: <NUM> C18-RP column - gradient method <NUM>-<NUM>% ACN; Wavelength: <NUM>): retention time: <NUM>. MS (M+H+): <NUM>.

Example <NUM> (reference). Evaluation of Metabolic Stability in CYP2D6 SUPERSOMES™. Human CYP2D6 SUPERSOMES™ were purchased from GenTest (Woburn, MA, USA). <NUM> stock solutions of test compounds (Compounds <NUM>, <NUM>, <NUM>, <NUM>, dextromethorphan, a deuterated analog of dextromethorphan wherein each methyl group was replaced with CD<NUM> ("d<NUM>-dextromethorphan", chemical name (+)-<NUM>-d<NUM>-methoxy-<NUM>-d<NUM>-methyl-(9α,13α,14α)-morphinan, also referred to as Compound <NUM> in <CIT>, and as "Test Compound" in <FIG> and Table <NUM> below), the ethyl ether analog of dextromethorphan ("dextroethorphan") or the isopropyl ether analog of dextromethorphan ("dextroisoproporphan")) were prepared in DMSO. The <NUM> stock solutions were diluted to <NUM> in acetonitrile (ACN). The <NUM> pmol/mL CYP2D6 SUPERSOMES™ were diluted to <NUM> pmol/mL in <NUM> potassium phosphate buffer, pH <NUM>, containing <NUM> MgCl<NUM>. The diluted SUPERSOMES™ were added to wells of a <NUM>-well deep-well polypropylene plate in triplicate. <NUM>µL of the <NUM> test compound was added to the SUPERSOMES™ and the mixture was pre-warmed for <NUM> minutes. Reactions were initiated by addition of pre-warmed NADPH solution. The final reaction volume was <NUM> and contained <NUM> pmol/mL CYP2D6 SUPERSOMES™, <NUM> test compound, and <NUM> NADPH in <NUM> potassium phosphate buffer, pH <NUM>, and <NUM> MgCl<NUM>. The reaction mixtures were incubated at <NUM> and <NUM>µL aliquots were removed at <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> minutes and added to shallow-well <NUM>-well plates which contained <NUM>µL of ice-cold ACN with internal standard to stop the reactions. The plates were stored at <NUM> for <NUM> minutes after which <NUM>µL of water was added to the wells of the plate before centrifugation to pellet precipitated proteins. Supernatants were transferred to another <NUM>-well plate and analyzed for amounts of parent remaining by LC-MS/MS using an Applied Bio-systems API <NUM> mass spectrometer.

The in vitro half-life (t<NUM>/<NUM>) for each of the test compounds was calculated from the slopes of the linear regression of % parent remaining (ln) vs incubation time relationship: in vitro t ½ = <NUM>/k, where k = -[slope of linear regression of % parent remaining(ln) vs incubation time]. Data analysis was performed using Microsoft Excel Software.

<FIG> and Table <NUM>, below, show the results of the SUPERSOMES™ experiment. Note that in <FIG>, the curves for Compounds <NUM> and <NUM> overlap one another. "Test Compound" in <FIG> and Table <NUM> refers to deuterated dextromethorphan ("d6-dextromethorphan", (+)-<NUM>-d3-methoxy-<NUM>-d3-methyl-(9α,13α,14α)-morphinan, which is also referred to as Compound <NUM> in <CIT>).

Claim 1:
A combination of:
(a) a therapeutically effective amount of a selective serotonin reuptake inhibitor; and
(b) a therapeutically effective amount of a compound of Formula II:
<CHM>
or a pharmaceutically acceptable salt thereof, wherein:
R<NUM> is selected from -OCH<NUM>D, -OCHD<NUM>, and -OCD<NUM>;
R<NUM> is selected from -CH<NUM>, -CH<NUM>D, -CHD<NUM>, and -CD<NUM>;
provided that when R<NUM> is -OCD<NUM>, then R<NUM> is not -CH<NUM>;
for use in treating chronic or intractable pain.