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WO2010028130A2 - Composés antidépresseurs - Google Patents

Composés antidépresseurs Download PDF

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Publication number
WO2010028130A2
WO2010028130A2 PCT/US2009/055865 US2009055865W WO2010028130A2 WO 2010028130 A2 WO2010028130 A2 WO 2010028130A2 US 2009055865 W US2009055865 W US 2009055865W WO 2010028130 A2 WO2010028130 A2 WO 2010028130A2
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WO
WIPO (PCT)
Prior art keywords
compound
deuterium
disorder
compounds
composition
Prior art date
Application number
PCT/US2009/055865
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English (en)
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WO2010028130A3 (fr
Inventor
Roger Tung
Original Assignee
Concert Pharmaceuticals, Inc.
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Filing date
Publication date
Application filed by Concert Pharmaceuticals, Inc. filed Critical Concert Pharmaceuticals, Inc.
Publication of WO2010028130A2 publication Critical patent/WO2010028130A2/fr
Publication of WO2010028130A3 publication Critical patent/WO2010028130A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the nontricyclic Compound 1 known as venlafaxine or by its chemical name l-[2-(dimethylamino)-l-(4- methoxyphenyl)ethyl]cyclohexanol and as l-[ ⁇ -[(dimethyl-amino)methyl]-p- methoxybenzyl] cyclohexanol, is an antidepressant which has been studied extensively and which is described in, for example, U. S. Patent No. 4,761,501 and Pento, J. T. Drugs of the Future 13 (9): 839-840 (1988). Its hydrochloride salt is a clinically and commercially important antidepressant agent with annual sales in 2005 of $3.5B (Wyeth 2005 annual report).
  • Venlafaxine contains an asymmetric carbon atom and is sold as a racemate. In humans, venlafaxine is transformed by a saturable metabolic pathway into one major O-demethylated metabolite, desvenlafaxine.
  • Desvenlafaxine is a more potent inhibitor of norepinephrine and dopamine reuptake than venlafaxine (Muth, E. A. et al. Drug Develop. Res. 23: 191-199, 1991). Desvenlafaxine has been reported to have a half- life (tj /2 ) of about 10 hours, which is approximately 2.5 times the half-life of venlafaxine (Klamerus, K. J. et al., supra). Desvenlafaxine has been studied extensively in clinical trials and has also proven to be an effective antidepressive agent. Indeed, desvenlafaxine is now marketed by Wyeth in the United States for the treatment of major depressive disorder under the name Pristiq. Desvenlafaxine is registered for the treatment of postmenopausal syndrome, and is in Phase III for fibromyalgia and neuropathic pain
  • treat includes both therapeutic and prophylactic treatment. 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).
  • Disease means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ. 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 Compound 3 will inherently contain small amounts of deuterated isotopologues.
  • a position designated as having deuterium when a particular position is designated as having deuterium, it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is 0.015%.
  • a position designated as having deuterium typically has a minimum isotopic enrichment factor of at least 3000 (45% deuterium incorporation) at each atom designated as deuterium in said compound.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a compound of this invention has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is designated specifically as “H” or “hydrogen”
  • the position is understood to have hydrogen at its natural abundance isotopic composition.
  • a position is designated specifically as “D” or “deuterium”
  • the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium).
  • isotopologue refers to a species that differs from a specific compound of this invention only in the isotopic composition thereof.
  • compound 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.
  • the relative amount of such isotopologues in a compound of this invention 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 49.9% of the compound. In other embodiments, the relative amount of such isotopologues in toto will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.
  • the invention also provides salts of the compounds of the invention.
  • a salt of a compound of this invention 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.
  • the compound is a pharmaceutically acceptable acid addition salt.
  • pharmaceutically acceptable 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 the like, and are commensurate with a reasonable benefit/risk ratio.
  • a “pharmaceutically acceptable salt” means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention.
  • 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.
  • Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids.
  • inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid
  • Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylprop
  • pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.
  • the compounds of the present invention may contain an asymmetric carbon atom, for example, as the result of deuterium substitution or otherwise.
  • compounds of this invention can exist as either individual enantiomers, or mixtures of the two enantiomers. Accordingly, a compound of the present invention may exist as either a racemic mixture or a scalemic mixture, or as individual respective stereoisomers that are substantially free from another possible stereoisomer.
  • substantially free of other stereoisomers means less than 25% of other stereoisomers, preferably less than 10% of other stereoisomers, more preferably less than 5% of other stereoisomers and most preferably less than 2% of other stereoisomers, or less than "X"% of other stereoisomers (wherein X is a number between 0 and 100, inclusive) are present.
  • stable compounds 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).
  • variable may be referred to generally (e.g., "each R") or may be referred to specifically (e.g., R 1 , R 2 , R 3 , etc.). Unless otherwise indicated, when a variable is referred to generally, it is meant to include all specific embodiments of that particular variable.
  • the present invention provides deuterium-containing nontricyclic antidepressants having advantageous biopharmaceutical properties for the treatment of psychological disorders, including depressive diseases and anxiety disorders.
  • the invention provides compounds of Formula I: (Formula I), or a pharmaceutically acceptable salt thereof, wherein: each Y is independently selected from deuterium or hydrogen; each hydrogen is independently optionally replaced with deuterium; with the proviso that at least one Y is deuterium.
  • each Y 1 is the same and each Y 2 is the same, e.g. if Y la is deuterium, then Y lb and Y lc are also deuterium. In one aspect of this embodiment, each Y 1 is deuterium. In another aspect of this embodiment, each Y 1 and each Y 2 is deuterium. 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.
  • 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.
  • Certain intermediates can be used with or without purification (e.g., filtration, distillation, sublimation, crystallization, trituration, solid phase extraction, and chromatography).
  • Scheme 1 depicts a general route to preparing compounds of Formula I.
  • Compound 15 is debenzylated via transfer hydrogenation utilizing Pd/C and cyclohexadiene to yield compounds of Formula I.
  • One example of an appropriately-deuterated dimethylamine 12 that can be used according to Scheme 1 to provide compounds of Formula I wherein all Y are deuterium is commercially- available dimethyl-d6-amine.
  • Compounds of Formula 1 can be made by means known in the art of organic synthesis. For instance, relevant routes to the all-hydrogen isotopologues of compounds of this invention are described in US Patent Nos. 4,535,186; 6,197,828; and 6,689,912; Yardley JP et al., J. Med.Chem. 1990 33: 2899; European patent publication EP 0112669; and PCT patent application nos. WO2005049560,
  • reaction schemes and protocols may be determined by the skilled artisan by use of commercially- available structure- searchable database software, for instance, SciFinder® (CAS division of the American Chemical Society) and CrossFire Beilstein® (Elsevier MDL), or by appropriate keyword searching using an internet search engine such as Google® or keyword databases such as the US Patent and Trademark Office text database.
  • SciFinder® CAS division of the American Chemical Society
  • CrossFire Beilstein® Elsevier MDL
  • keyword databases such as the US Patent and Trademark Office text database.
  • 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 1 , R 2 , R 3 , etc.) or not.
  • the suitability of a chemical group in a compound structure for use in the synthesis of another compound
  • compositions comprising an effective amount of a compound of Formula I (e.g., including any of the formulae herein), or a pharmaceutically acceptable salt of said compound; and an acceptable carrier.
  • a composition of this invention 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 of this invention 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.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphate
  • solubility and bioavailability of the compounds of the present invention 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 “Oral Lipid-Based Formulations: Enhancing the Bioavailability of Poorly Water- Soluble Drugs (Drugs and the Pharmaceutical Sciences),” David J. Hauss, ed. Informa Healthcare, 2007; and “Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery: Basic Principles and Biological Examples," Kishor M. Wasan, ed. Wiley-Interscience, 2006.
  • Another known method of enhancing bioavailability is the use of an amorphous form of a compound of this invention optionally formulated with a poloxamer, such as LUTROLTM and PLURONICTM (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. See United States patent 7,014,866; and United States patent publications 20060094744 and 20060079502.
  • compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • 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, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th ed. 1985).
  • 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.
  • ingredients such as the carrier that constitutes one or more accessory ingredients.
  • 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.
  • compositions of the present invention 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.
  • carriers that are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • 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 nonaqueous 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.
  • sterile liquid carrier for example water for injections
  • 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 80) 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 1,3- butanediol.
  • a non-toxic parenterally- acceptable diluent or solvent for example, as a solution in 1,3- butanediol.
  • acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • 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 of this invention may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention 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.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may 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.: Rabinowitz JD and Zaffaroni AC, US Patent 6,803,031, assigned to Alexza Molecular Delivery Corporation.
  • Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
  • 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 of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, and water.
  • 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 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.
  • the pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention. Application of the subject therapeutics may be local, so as to be administered at the site of interest.
  • 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.
  • the compounds of this invention may be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, or catheters.
  • 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 US Patents 6,099,562; 5,886,026; and 5,304,121.
  • 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.
  • the invention provides 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.
  • the invention provides a method of impregnating an implantable drug release device comprising the step of contacting said drug release device with a compound or composition of this invention.
  • Implantable drug release devices include, but are not limited to, biodegradable polymer capsules or bullets, non-degradable, diffusible polymer capsules and biodegradable polymer wafers.
  • the invention provides an implantable medical device coated with a compound or a composition comprising a compound of this invention, such that said compound is therapeutically active.
  • the invention provides an implantable drug release device impregnated with or containing a compound or a composition comprising a compound of this invention, such that said compound is released from said device and is therapeutically active.
  • a composition of this invention further comprises a second therapeutic agent.
  • the second therapeutic agent may be selected from any compound or therapeutic agent known to have or that demonstrates advantageous properties when administered with a compound having the same mechanism of action as Compound 3.
  • the second therapeutic agent is an agent useful in the treatment or prevention of a disease or condition selected from disorders of the central nervous system, including anxiety and convulsions; and neuropathic, inflammatory and migraine associated pain.
  • the invention provides separate dosage forms of a compound of this invention and one or more of any of the above-described second therapeutic agents, wherein the compound and second therapeutic agent are associated with one another.
  • association with one another 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 24 hours of one another, consecutively or simultaneously).
  • the compound of the present invention is present in an effective amount.
  • 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 Freireich et al., (1966) Cancer Chemother. Rep 50: 219. Body surface area may be approximately determined from height and weight of the patient.
  • an effective amount of a compound of this invention can range from about 0.01 to about 5000 mg per treatment. In more specific embodiments the range is from about 0.1 to 2500 mg, or from 0.2 to 1000 mg, or most specifically from about 1 to 500 mg. Treatment typically is administered one to three times daily. 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 patient, 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 L-838417.
  • an effective amount of the second therapeutic agent is between about 20% and 100% of the dosage normally utilized in a monotherapy regime using just that agent. In one embodiment, an effective amount is between about 70% and 100% of the normal monotherapeutic dose.
  • the normal monotherapeutic dosages of these second therapeutic agents are well known in the art. See, e.g., Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), each of which references are incorporated herein by reference in their entirety.
  • compositions comprising a compound of Formula I and related methods for preventing or ameliorating a psychological disorder, such as a depressive disease or anxiety disorder, including, but not limited to, major depressive disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, postmenopausal syndrome and posttraumatic stress disorder or symptoms thereof by administering to a subject a compound of Formula I.
  • a psychological disorder such as a depressive disease or anxiety disorder
  • compositions comprising Formula I are useful for the treatment of pain including neuropathic pain and fibromyalgia.
  • Compounds of the invention can be employed for the treatment of virtually any disease or disorder where Compound 1 or a metabolite thereof is used, including diseases and disorders disclosed in US Patents 5,506,270; 5,744,474; 5,788,986; 5,788,986; 5,916,923; 5,922,341; 6,001,848; 6,211,171; 6,441,048; 6,552,014; 6,703,044; 6,911,479; and 7,001,920.
  • the methods comprise administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of the formulae herein (e.g.,
  • Formula I) to a subject e.g., a mammal such as a human.
  • a subject e.g., a mammal such as a human.
  • the method includes the step of administering to the mammal a therapeutic amount of an amount of a compound herein sufficient to treat the disease or disorder or symptom thereof, under conditions such that the disease or disorder is treated.
  • the methods herein include administering to the subject (including a subject identified as in need of such treatment) an effective amount of a compound described herein, or a composition described herein to produce such effect. Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method). As used herein, the terms “treat,” “treating,” “treatment,” and the like refer to reducing or ameliorating a disorder and/or symptoms associated therewith. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated.
  • the terms "prevent,” “preventing,” “prevention,” “prophylactic treatment” and the like refer to reducing the probability of developing a disorder or condition in a subject, who does not have, but is at risk of or susceptible to developing a disorder or condition.
  • the therapeutic methods of the invention in general comprise administration of a therapeutically effective amount of the compounds herein, such as a compound of the formulae herein to a subject (e.g., animal, human) in need thereof, including a mammal, particularly a human.
  • a subject e.g., animal, human
  • Such treatment will be suitably administered to subjects, particularly humans, suffering from, having, susceptible to, or at risk for a mood or cognitive disease, disorder, or symptom thereof.
  • Determination of those subjects "at risk” can be made by any objective or subjective determination by a diagnostic test or opinion of a subject or health care provider (e.g., genetic test, enzyme or protein marker, Marker (as defined herein, such as the level or reuptake of a bioactive amine, such as norepinephrine, serotonin, or dopamine), family history, and the like).
  • a diagnostic test or opinion of a subject or health care provider e.g., genetic test, enzyme or protein marker, Marker (as defined herein, such as the level or reuptake of a bioactive amine, such as norepinephrine, serotonin, or dopamine), family history, and the like).
  • the compounds herein may be also used in the treatment of any other disorders in which the reuptake of a bioactive amine, such as norepinephrine, serotonin, or dopamine, may be implicated.
  • compositions comprising an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof; and an acceptable carrier.
  • a composition of the invention is formulated for pharmaceutical use ("a pharmaceutical composition"), wherein the carrier is a pharmaceutically acceptable carrier.
  • the carrier(s) must be "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 amounts typically used in medicaments.
  • compositions comprising compounds of Formula I are obtained using the methods disclosed herein.
  • Pharmaceutical compositions comprising such compounds may be administered systemically, for example, formulated in a pharmaceutically-acceptable buffer, such as physiological saline.
  • Preferable routes of administration include, for example, subcutaneous, intravenous, interperitoneally, intramuscular, or intradermal injections that provide continuous, sustained levels of the drug in the patient.
  • Treatment of human patients or other animals will be carried out using a therapeutically effective amount of a compound of Formula 1 in a physiologically-acceptable carrier.
  • Suitable carriers and their formulation are described, for example, in Remington's Pharmaceutical Sciences by E. W. Martin.
  • the amount of the therapeutic agent to be administered varies depending upon the manner of administration, the age and body weight of the patient, and with the clinical symptoms of a depressive disease or anxiety disorder. Generally, amounts will be in the range of those used for other agents used in the treatment of other depressive diseases or anxiety disorders, although in certain instances lower amounts will be needed because of the decreased oxidation and increased half-life of the compound.
  • a compound is administered at a dosage that controls the clinical or physiological symptoms of a depressive disease or anxiety disorder as determined by a diagnostic method known to one skilled in the art.
  • compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including for instance subcutaneous, intramuscular, intravenous, intrathecal and intradermal) administration.
  • 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 and sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 18th ed.
  • compositions according to the invention may be formulated to release the active compound substantially immediately upon administration or at any predetermined time or time period after administration.
  • controlled release formulations which include (i) formulations that create a substantially constant concentration of the drug within the body over an extended period of time; (ii) formulations that after a predetermined lag time create a substantially constant concentration of the drug within the body over an extended period of time; (iii) formulations that sustain action during a predetermined time period by maintaining a relatively, constant, effective level in the body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the active substance (sawtooth kinetic pattern); (iv) formulations that localize action by, e.g., spatial placement of a controlled release composition adjacent to or in the tissue to be treated; (v) formulations that allow for convenient dosing, such that doses are administered, for example, once every day; once every 2 or 3 days, or once per week or per two weeks; and (vi) formulations that target
  • Extended release formulations such as those disclosed in US Patent nos. 6,274,171; 6,403,120; 6,482,440; 6,607,751; 6,706,283; and 6,893,661; and PCT patent application nos. WO2004091580, WO2004096186, WO2005039555, WO2005048923, and WO2006010605 can be valuable to enhance efficacy or reduce adverse effects.
  • Inhaled forms of Compound 1 also comprise useful approaches to delivering the drug; see Rabinowitz JD and Zaffaroni AC, US Patents 6,783,753; 7,029,658; and 7,060,254; each to Alexza.
  • controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings.
  • the therapeutic is formulated with appropriate excipients into a pharmaceutical composition that, upon administration, releases the therapeutic in a controlled manner. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, molecular complexes, nanoparticles, patches, and liposomes.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain, for example, 0.5 mg to 1200 mg, preferably 1 mg to lOOOmg, more preferably 5 mg to 400 mg of a compound of Formula I, depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
  • therapeutics described herein are administered in combination with any other standard therapy for the treatment of depression or anxiety; such methods are known to the skilled artisan and described in Remington's Pharmaceutical Sciences by E. W. Martin.
  • compounds of Formula I may be employed where Compound 1 therapy is used in combination with additional bioactive agents.
  • compounds of Formula I are used in combination with any one or more of the following agents that are conventionally used for the treatment of a psychological disorder: 5-HT1 A antagonist or ligand; an NKl -receptor antagonist; a serotonin receptor antagonist; 2-amino- 4,5,6,7-tetrahydro-6-propylamino-benzothiazole (pramipexole), the (+)- or (-)- enantiomer thereof; a sulfamate anticonvulsant agent; a precursor or prodrug of serotonin, or an intermediate in the biosynthesis of serotonin; selective agonists and antagonists of one or both of the 5-HT1A and 5-HT1D receptors; a composition containing dimethylaminoethanol (DMAE), omega 3-fatty acids, betaine, oligomeric proanthocyanidins, folic acid, vitamins C, E, B 12, B6, B5 and beta-carotene and minerals (calcium, magnesium, zinc and se
  • 5-HT1A antagonists and ligands include, but are not limited to, alprenolol, WAY 100135, WAY 100635, spiperone, pindolol, (S)-UH-301, penbutolol, propranolol, tertatolol; (R)-5-carbamoyl-8-fluoro-3-N,N-disubstituted- amino-3,4-dihydro-2H-l-benzopyran; and those disclosed in US Patents 5,776,969; 5,958,429; 6,136,861; 6,656,951; 6,780,860; 6,815,448; 6,821,981; 6,861,427; 6,894,053; and US Patent Application 20050085475.
  • NKl -receptor antagonists include, but are not limited to, those disclosed in US Patents 6,162,805; 6,878,732; US Patent Application 20050137208; as well as CNS-penetrant agents capable of inhibiting NK-I receptor agonist-induced foot tapping in the gerbil, or attenuating separation-induced vocalizations by guinea- pig pups.
  • sulfamate anticonvulsant agents include, but are not limited to, topiramate and those disclosed in and referenced by US Patent 5,384,327.
  • precursors or prodrugs of serotonin, and intermediates in the biosynthesis of serotonin include but are not limited to, L-tryptophan, L-5- hydroxytryptophan, diethyl N-benzyloxycarbonyl-5-benzyloxycarbonyloxy-L- tryptophyl-L-aspartate, dibenzyl N-benzyloxycarbonyl-5-hydroxy-L- tryptophanylaspartate, 5-Hydroxy-L-tryptophyl-L-aspartic acid trihydrate, diethyl N- benzyloxycarbonyl-5-hydroxy-L-tryptophyl-L-glutamate, diethyl 5-hydroxy-L- tryptophyl-L-glutamate hydrochloride, dibenzyl L-benzyloxycarbonyl-5- hydroxytryptophyl-L-glutamate, 5-hydroxy-L-tryptophyl-L-glutamic acid, pentachloropheny
  • Examples of an atypical antipsychotic agent include, but are not limited to, risperidone, clozapine, seroquel, sertindole, ziprasidone, zotepine, olanzapine, iloperidone, Org 5222, melperone, amperozide, SM-9018, JL-13, and pharmaceutically acceptable salts thereof.
  • Examples of neuroleptic agents include, but are not limited to, quetiapine, aripiprazole, ziprasidone, risperidone, olanzapine, clozapine, desmethyclozapine, and iloperidone.
  • aldose reductase inhibitors include, but are not limited to, fidarestat, epalrestat, minalrestat, SPR-210, and zenarestat or zopolrestat, or a prodrug thereof.
  • Examples of selective agonists and antagonists of one or both of the 5-HT1 A and 5-HT1D receptors include, but are not limited to, those disclosed in US Patent 6,562,813.
  • Type III phosphodiesterase inhibitors include, but are not limited to, bipyridines such as amrinone, milrinone and olprinone; anagrelide, bemoradan, ibudilast, isomazole, lixazinone, motapizone, olprinone, phthalazinol, pimobendan, quazinone, siguazodan and trequinsin
  • Examples of calcium channel blockers include, but are not limited to, amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, and verapamil.
  • Examples of mixed type Ill-type IV phosphodiesterase inhibitors include, but are not limited to, anagrelide, bemoradan, ibudilast, isomazole, lixazinone, motapizone, olprinone, phthalazinol, pimobendan, quazinone, siguazodan and trequinsin.
  • type IV phosphodiesterase inhibitors include, but are not limited to, pyrrolidinones, in particular rolipram; quinazolinediones, xanthine derivatives, phenyl ethyl pyridines, tetrahydropyrimidones, diazepine derivatives, oxime carbamates, naphthyridinones, benzofurans, naphthalene derivatives, purine derivatives, imidazolidinones, cyclohexane carboxylic acids, benzamidespyridopyridazinones, benzothiophenes, etazolate, S-(+)-glaucine, substituted phenyl compounds and substituted biphenyl compounds as further disclosed in US Patent 6,403,597.
  • type V phosphodiesterase inhibitors include, but are not limited to, sildenafil, vardenafil, tadalafil, zaprinast, dipyridamole, 3-isobutyl-8-(6-methoxy- isoquinolin-4-ylmethyl)-l-methyl-3,7-dihydro-purine-2,6-dione; and those disclosed in US Patent Applications 20030055070; 20040044005; 20030139429.
  • substituted indole estrogenic agents include, but are not limited to, those disclosed in and referenced by US Patent 6,369,051.
  • DRD2-specific dopamine agonist includes, but is not limited to, bromocriptine.
  • 5HT4 receptor antagonists include, but are not limited to, A- 85380, SB 204070, SB 207226, SB 207058, SB 207710, SB 205800, SB 203186, SDZ 205557, N 3389, FK 1052, SC 56184, SC 53606, DAU 6285, GR 125487, GR 113808, RS 23597, RS 39604, LY-353433 and R 50595.
  • cyclooxygenase-2 selective inhibitors include, but are not limited to, celecoxib, valdecoxib, deracoxib, rofecoxib, etoricoxib, tilmacoxib, cimicoxib, and those disclosed in and referenced by US Patent Applications 20050080084 and 20050085477.
  • 5-HT2a receptor antagonists include, but are not limited to, those disclosed and referenced by US Patent application 20050070577.
  • CBl receptor antagonists include, but are not limited to, rimonabant and those disclosed in and referenced by US Patent applications 20040248956, 20050009870, 20050014786, 20050054659, 20050080087, and 20050143381.
  • selective MCH-IR receptor antagonists include, but are not limited to, those disclosed in and referenced by US Patent applications 20050009815 and 20050026915.
  • Examples of tetra-substituted pyrimidopyrimidines include, but are not limited to, dipyridamole, mopidamole, dipyridamole monoacetate, 2,6-di-(2,2-dimethyl-l,3- dioxolan-4-yl)-methoxy-4,8-di-piperidinopyrimido- pyrimidine; 2,6-bis-(2,3- dimethyoxypropoxy)-4,8-di-piperidinopyrimidopyrimidine; 2,6-bis[N,N-di(2- methoxy)ethyl]-4,6-di-piperidinopyrimidopyrimidine-; and 2,6-bis(diethanolamino)- 4,8-di-4-methoxybenzylaminopyrimidopyrimidine-.
  • Examples of selective dopamine D4 receptor ligands include, but are not limited to, pipamperone, fananserin, L
  • NMDA partial receptor agonist includes, but is not limited to, D-cycloserine.
  • NMDA receptor antagonists include, but are not limited to, dextromethorphan, dextrorphan, amantadine, and memantine.
  • cholinesterase inhibitors include, but are not limited to, tacrine, donepezil, edrophonium, galantamine, physostigmine, eptastigmine, pyridostigmine, neostigmine, ganstigmine, rivastigmine, demecarium, ambenonium, sarin, metrifonate, soman, tabun, and diisopropyl fluorophosphates.
  • GSK-3 inhibitors include, but are not limited to, those disclosed and referenced in US Patent Application 20050026946.
  • alpha-2-delta ligands include, but are not limited to, gabapentin, pregabalin, [(lR,5R,6S)-6-(aminomethyl)bicyclo[-3.2.0]hept-6-yl]acetic acid, 3-(l- aminomethylcyclohexylmethyl)-4H-[l,2,4]-oxadiazol-5-one, C-[l-(lH-tetrazol-5- ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(l-aminomethyl-3,4- dimethylcyclopentyl)-acetic acid, (la,3a,5a)(3-aminomethyl-bicyclo[3.2.0]hept-3-yl)- acetic acid, (3S,5R)-3-aminomethyl-5-methyloctanoic acid, (3S,5R)-3-amino-5- methylheptanoic acid, (3S,5R)-3-amin
  • norepinephrine reuptake inhibitors include, but are not limited to, bupropion, desipramine, imipramine, amoxapine, nortriptyline, protriptyline, atomoxetine, oxaprotiline, maprotiline, reboxetine, l-[l-(3-chlorophenyl)-2-(4- methyl-l-piperazinyl)ethyl]cyclohexanol; and those disclosed in US Patent Application 20050014848.
  • corticosteroids examples include, but are not limited to, prednisolone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, fluticasone, prednisone, triamcinolone, and diflorasone.
  • non-steroidal immunophilin-dependent immunosuppressants include, but are not limited to, cyclosporine, tacrolimus, ISAtx247, ascomycin, pimecrolimus, rapamycin, and everolimus.
  • selective neuronal nitric oxide synthase inhibitors include, but are not limited to, those disclosed in US Patent Application 20040229911.
  • An example of a selective oxytocin antagonist includes, but is not limited to, L-368,899.
  • nicotine receptor antagonists include, but are not limited to, mecamylamine, amantadine, pempidine, dihydro-beta-erythroidine, hexamethonium, erysodine, chlorisondamine, trimethaphan camsylate, tubocurarine chloride, d- tubocurarine, and their optical isomers.
  • adenosine A2a receptor antagonists include, but are not limited to, those disclosed in US Patent Application 20030139395.
  • 5-HT2C receptor antagonists examples include, but are not limited to, ketanserin, SB 242084, SB 206553, SB 243213, SB 228356, ritanserin, deramciclane, mirtazepine, mianserine, sertindole, YM 35 992, Ro 60-0795, Org 38457, Org 12962, EGIS 8465 and RS 102221.
  • AMPA receptor potentiators include, but are not limited to, [(methylethyl)sulf onyl] ⁇ 2- [4-(4- ⁇ 2-
  • Examples of nicotine receptor partial agonists include, but are not limited to, those disclosed in US Patent Applications 20010036943 and 20030109544.
  • delta opioid receptor ligands include, but are not limited to, those disclosed in and referenced by US Patent Application 20020077323.
  • growth hormone secretagogues examples include, but are not limited to, MK-0677 (Merck); NN703 (Novo Nordisk); L-162752 and L-163022 (Merck); hexarelin (Pharmacia & Upjohn); GPA-748 (KP102, GHRP-2) (American Home Products); ipamorelin (Novo Nordisk); and LY444711 (Eli Lilly).
  • GHRH/GRF receptor The following agents that stimulate GH release via GHRH/GRF receptor (including GHRH/GRF derivatives, analogs and mimetics) are known in the art: Geref (Ares/Serono); GHRH (1-44) (BioNebraska); Somatorelin (GRF 1-44) (Fujisawa/ICN); and ThGRF (Theratechnologies) .
  • Combination therapies according to the present invention thus include the administration of at least one compound of Formula I as well as optional use of other therapeutic agents including other anti-depressive or anti-anxiolytic agents. Such combination of agents may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order, both close and remote in time.
  • the amounts of the compound of Formula I and the other pharmaceutically active agent (s) the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • compounds described herein are tested in vivo or in vitro for their ability to ameliorate a depressive disease or anxiety disorder; or for their ability to inhibit the reuptake of a bioactive amine (e.g., norepinephrine, dopamine, serotonin).
  • a bioactive amine e.g., norepinephrine, dopamine, serotonin
  • Such methods include, but are not limited to, assaying compounds of the invention for the inhibition of bioactive amine reuptake.
  • compounds of the invention are assayed in vitro for binding to rat cortical membranes as described by Habert E et. al., Eur. J. Pharmacol. 1985 118: 107.
  • Radiolabeled Compound 1 was found to bind to a single, high affinity, saturable site; compounds that have a similar binding profile in such assays are identified as useful in the methods of the invention.
  • Compounds that are therapeutically efficacious against a psychological disease described herein are those that reduce the reuptake of a bioactive amine (e.g., serotonin, dopamine, norepinephrine).
  • Bioactive amines are stored in a pre-synaptic cell and upon release into the synapse the amines act on a post-synaptic cell to induce a physiological response.
  • bioactive amines are terminated either by re-uptake into cells from which they have been released (e.g., pre-synaptic neurons) or by enzymatic degradation.
  • Compounds of the invention that reduce the reuptake of bioactive amines can acutely increase extracellular amine concentrations, leading to an increase in negative feedback mediated by inhibitory presynaptic and somatodendritic receptors.
  • action potential firing frequency and amounts of bioactive amines released from presynaptic button can decrease.
  • downregulation and/or desensitization of inhibitory receptors can occur, resulting in increased action potential firing frequency and higher bioactive amines concentrations in the synaptic cleft.
  • the efficacy of a compound of the invention is evaluated in a human subject using, for example, the Hamilton Rating Scale for Depression, the Hamilton Rating Scale for Anxiety (HAM-A), Clinical Global Impression-Severity of Illness (CGI-S), Panic and Anticipatory Anxiety Scale
  • PAAS Panic Disorder Severity Scale
  • CGI-S Clinical Global Impressions-Severity
  • CGI-I -Improvement
  • While compounds of Formula I are specifically described as useful for the treatment of depressive diseases or anxiety disorders, the invention is not so limited.
  • Compounds of Formula I may be used for the treatment of a variety of diseases and disorders, including without limitation, depression, hypertension, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, and sexual dysfunction; eating disorders including bulimia, anorexia nervosa, and binge eating; obesity, chemical dependencies, cluster headache, migraine; pain, including neuropathic pain, diabetic nephropathy, post-operative pain, psychogenic pain disorders, and chronic pain syndrome; Alzheimer's disease, obsessive-compulsive disorder, panic disorder with or without agoraphobia, memory disorders, Parkinson's diseases, endocrine disorders, vasospasm, cerebellar ataxia, gastrointestinal tract disorders, negative symptoms of schizophrenia, premenstrual syndrome, postmenopausal syndrome, neuropathic pain, fibromyalgia, urinary incontinence, including stress incontine
  • kits for use to treat depressive diseases and anxiety disorders comprise (a) a pharmaceutical composition comprising a compound of Formula I or a salt thereof, wherein said pharmaceutical composition is in a container; and (b) instructions describing a method of using the pharmaceutical composition to treat depressive diseases or anxiety disorders.
  • the container may be any vessel or other sealed or sealable apparatus that can hold said pharmaceutical composition.
  • 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 one embodiment, the container is a blister pack.
  • kits of this invention may also comprise a device to administer or to measure out a unit dose of the pharmaceutical composition.
  • a device to administer or to measure out a unit dose of the pharmaceutical composition 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.
  • kits of this invention may comprise in a separate vessel of container a pharmaceutical composition comprising a second therapeutic agent, such as one of those listed above for use for co-administration with a compound of this invention.
  • a pharmaceutical composition comprising a second therapeutic agent, such as one of those listed above for use for co-administration with a compound of this invention.
  • Microsomal Assay Human liver microsomes (20 mg/mL) are obtained from Xenotech, LLC (Lenexa, KS). ⁇ -nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCl 2 ), and dimethyl sulfoxide (DMSO) are purchased from Sigma- Aldrich. Determination of Metabolic Stability: 7.5 mM stock solutions of test compounds are prepared in DMSO. The 7.5 mM stock solutions are diluted to 12.5-50 ⁇ M in acetonitrile (ACN).
  • ACN acetonitrile
  • the 20 mg/mL human liver microsomes are diluted to 0.625 mg/mL in 0.1 M potassium phosphate buffer, pH 7.4, containing 3 mM MgCl 2 .
  • the diluted microsomes are added to wells of a 96-well deep-well polypropylene plate in triplicate.
  • a 10 ⁇ L aliquot of the 12.5-50 ⁇ M test compound is added to the microsomes and the mixture is pre-warmed for 10 minutes. Reactions are initiated by addition of pre-warmed NADPH solution.
  • the final reaction volume is 0.5 mL and contains 0.5 mg/mL human liver microsomes, 0.25-1.0 ⁇ M test compound, and 2 mM NADPH in 0.1 M potassium phosphate buffer, pH 7.4, and 3 mM MgCl 2 .
  • the reaction mixtures are incubated at 37 0 C, and 50 ⁇ L aliquots are removed at 0, 5, 10, 20, and 30 minutes and added to shallow-well 96-well plates which contain 50 ⁇ L of ice-cold ACN with internal standard to stop the reactions.
  • the plates are stored at 4 0 C for 20 minutes after which 100 ⁇ L of water is added to the wells of the plate before centrifugation to pellet precipitated proteins.

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Abstract

La présente invention porte sur des formes deutérées de desvenlafaxine et sur l'utilisation de tels composés dans une composition pharmaceutique et pour le traitement de troubles psychologiques.
PCT/US2009/055865 2008-09-03 2009-09-03 Composés antidépresseurs WO2010028130A2 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8138226B2 (en) 2005-12-01 2012-03-20 Auspex Pharmaceuticals Substituted phenethylamines with serotoninergic and/or norepinephrinergic activity
CN104326923A (zh) * 2014-09-05 2015-02-04 南京华威医药科技开发有限公司 一种琥珀酸去甲文拉法辛的合成方法
US10421710B2 (en) 2007-03-15 2019-09-24 Auspex Pharmaceuticals, Inc. Substituted phenethylamines with serotoninergic and/or norepinephrinergic activity

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GT200600397A (es) * 2005-09-07 2007-08-28 Formulas topicas conteniendo o-desmetil venlafaxina (odv) o sus sales
US7893053B2 (en) * 2006-06-16 2011-02-22 Theracos, Inc. Treating psychological conditions using muscarinic receptor M1 antagonists
EP2514740B1 (fr) * 2007-03-15 2018-12-19 Auspex Pharmaceuticals, Inc. O-desmethylvenlafaxines deuteres a action sérotoninergique et/ou norepinephrinergique
US20090076162A1 (en) * 2007-09-17 2009-03-19 Protia, Llc Deuterium-enriched desvenlafaxine

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8138226B2 (en) 2005-12-01 2012-03-20 Auspex Pharmaceuticals Substituted phenethylamines with serotoninergic and/or norepinephrinergic activity
US9422225B2 (en) 2005-12-01 2016-08-23 Auspex Pharmaceuticals, Inc. Substituted phenethylamines with serotoninergic and/or norepinephrinergic activity
US9458082B2 (en) 2005-12-01 2016-10-04 Auspex Pharmaceuticals, Inc. Substituted phenethylamines with serotoninergic and/or norepinephrinergic activity
US10421710B2 (en) 2007-03-15 2019-09-24 Auspex Pharmaceuticals, Inc. Substituted phenethylamines with serotoninergic and/or norepinephrinergic activity
CN104326923A (zh) * 2014-09-05 2015-02-04 南京华威医药科技开发有限公司 一种琥珀酸去甲文拉法辛的合成方法
CN104326923B (zh) * 2014-09-05 2016-02-10 南京华威医药科技开发有限公司 一种琥珀酸去甲文拉法辛的合成方法

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