WO2009105218A2 - Dérivés de propiophénone - Google Patents

Dérivés de propiophénone Download PDF

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Publication number
WO2009105218A2
WO2009105218A2 PCT/US2009/001040 US2009001040W WO2009105218A2 WO 2009105218 A2 WO2009105218 A2 WO 2009105218A2 US 2009001040 W US2009001040 W US 2009001040W WO 2009105218 A2 WO2009105218 A2 WO 2009105218A2
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compound
dependence
disease
depression
seasonal
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PCT/US2009/001040
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English (en)
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WO2009105218A3 (fr
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Scott L. Harbeson
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Concert Pharmaceuticals, Inc.
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Publication of WO2009105218A2 publication Critical patent/WO2009105218A2/fr
Publication of WO2009105218A3 publication Critical patent/WO2009105218A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
    • C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
    • 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

  • Bupropion also known as ( ⁇ )-2-(tert-butylamino)l-(3-chlorophenyl)propan- 1-one hydrochloride, Wellbutrin®, and Zyban® is a weak inhibitor of the neuronal uptake of norepinephrine and dopamine. It does not inhibit monoamine oxidase or the re-uptake of serotonin.
  • Bupropion is currently approved for the treatment of depression, major depression, for the cessation of smoking, and for prevention of seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder. It is currently in clinical trials for the treatment of female orgasmic disorders, Crohn's disease, treatment of marijuana dependence, treatment of methamphetamine dependence, seasonal affective disorder, depressive disorders, cocaine-related disorders, and treatment of pathological gambling. Bupropion is also being investigated as an agent for causing weight loss and for the treatment of attention deficit-hyperactivity (ADHD).
  • ADHD attention deficit-hyperactivity
  • radafaxine is in phase I clinical trials for the treatment of obesity, fibromyalgia and neuropathic pain. It has also been studied for the treatment of bipolar disorder and was in phase II clinical trials for the treatment of depression. Radafaxine is also being investigated as a treatment for obesity.
  • Other active metabolites of bupropion are hydroxybupropion, formed by hydroxylation of the t-butyl moiety; and ery//zro-hydrobupropion and threo- hydrobupropion, diastereomeric forms of the metabolite formed by reduction of the carbonyl moiety to a hydroxyl.
  • Bupropion is associated with seizures in approximately 0.4% (4/1,000) of patients treated at doses up to 450 mg/day. Adverse events commonly encountered in patients treated with bupropion are agitation, dry mouth, insomnia, headache/migraine, nausea/vomiting, constipation, and tremor. It is unknown what, if any, contribution the metabolites of bupropion make to the adverse event profile. Because cytochrome P450IIB6 (CYP2B6) is the principle isoenzyme responsible for formation of the metabolite, hydroxybupropion, there is potential for drug-drug interactions, particularly with drugs metabolized by the CYP2B6 isoenzyme. (See the FDA label for Wellbutrin at fda.gov/cder).
  • This invention relates to novel compounds that are propiophenones derivatives and pharmaceutically acceptable salts thereof. More specifically, this invention relates to novel propiophenones derivatives that are derivatives of bupropion.
  • This invention also provides compositions comprising one or more compounds of this invention and a carrier and use of the disclosed compounds and compositions in methods of treating diseases and conditions that are beneficially treated by administering a norepinephrine dopamine reuptake inhibitor, such as bupropion.
  • ameliorate and “treat” are used interchangeably and include both therapeutic treatment and 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.
  • 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.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom unless otherwise stated.
  • 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).
  • a compound of this invention 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 3500 (52.5% deuterium incorporation), 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).
  • isotopologue refers to a species that differs from a specific compound of this invention only in the isotopic composition of its molecules and ions. Isotopologues can differ in the level of isotopic enrichment at one or more - A -
  • the term "compound,” when referring to a compound of this invention, 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.
  • 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 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 in toto 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, solvates or hydrates 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.
  • 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
  • hydrate means a compound which further includes a stoichiometric or non-stoichiometric amount of water bound by non- covalent intermolecular forces.
  • solvate means a compound which further includes a stoichiometric or non-stoichiometric amount of solvent such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, or the like, bound by non-covalent intermolecular forces.
  • the compounds of the present invention (e.g., compounds of Formula I, Ha, lib and III) contain one or more asymmetric carbon atoms, for example, as the result of deuterium substitution or otherwise.
  • compounds of this invention can exist as either individual enantiomers, or mixtures of multiple enantiomers. Accordingly, a compound of the present invention will include both racemic mixtures, and also individual specific 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).
  • D refers to deuterium.
  • R 1 is selected from CH 3 , CH 2 D, CHD 2 and CD 3 ;
  • R 2 is t-butyl, wherein 1 to 9 hydrogen atoms are optionally replaced with deuterium;
  • R 1 is selected from CH 3 and CD 3 ; b) R 2 is selected from -C(CH 3 ) 3 and -C(CD 3 ) 3 ; or c) The stereochemistry at * is not racemic
  • a compound of Formula I has the features set forth in at least two of a) - c) (e.g, a and b, a and c, and b and c). [34] In yet another embodiment, the compound of Formula I is selected from any one of:
  • each R is independently selected from CH 3 , CH 2 D, CHD 2 and CD 3 ; and each Y is independently selected from hydrogen and deuterium.
  • each R is independently selected from CH 3 and CD 3 ; b) R 3 and R 4 are the same; or c) each Y is the same.
  • a compound of Formula I has the features set forth in at least two of a) - c) (e.g., a and b, b and c, and a and c).
  • R 3 and R 4 are CH 3 ; and each Y is hydrogen.
  • R 1 is selected from CH 3 and
  • CD 3 ; R 3 and R 4 are CH 3 ; and each Y is hydrogen.
  • R 3 and R 4 are CD 3 and each Y is deuterium.
  • R 1 is selected from CH 3 and
  • CD 3 ; R 3 and R 4 are CD 3 and each Y is deuterium.
  • the compound of Formula Ha is selected from any one of:
  • the compound of Formula lib is selected from any one of:
  • the invention provides a compound of Formula III:
  • R 1 is selected from CH 3 , CH 2 D, CHD 2 and CD 3 ;
  • R 2 is t-butyl, wherein 1 to 9 hydrogen atoms are optionally replaced with deuterium;
  • Y 3 is selected from hydrogen and deuterium; and each "*" represents a stereocenter.
  • R 1 is selected from CH 3 and CD 3 ;
  • R 2 is selected from -C(CH 3 ) 3 and -C(CD 3 ) 3 ; or c) the stereochemistry at each * is the same.
  • a compound of Formula III has the features set forth in at least two of a) - c) (e.g., a and b, a and c, b and c).
  • the compound is a mixture of enantiomers in which the stereochemistry at each * is the same (i.e., a mixture of (S 1 S) and (R, R) enantiomers, also known as a "threo pair").
  • the compound in another specific embodiment, is a mixture of enantiomers in which the stereochemistry at each * is different (i.e., a mixture of (S 1 R) and (R 1 S) enantiomers, also known as an "erythro pair").
  • the compound is a single enantiomer substantially free of all other enantiomers.
  • each enantiomer of a compound of Formula III whether substantially free of other enantiomers or part of a threo pair or an erythro pair also has the properties of at least one of a) or b), above.
  • the compound of Formula III is selected from any one of:
  • each one of compounds 1 1 1-1 19 may exist as threo pairs, erythro pairs, or specific enantiomers.
  • any atom not designated as deuterium in any of the embodiments of Formulae I, Ha, lib and III set forth above is present at its natural isotopic abundance.
  • Scheme 1 above depicts a convenient method for synthesizing compounds of Formula I.
  • a deuterated m-chloropropiophenone 10 may be converted to the silyl enol ether 11 (Z:E 99: 1) by treatment with LDA at -78° C followed by reaction with TBDMS-Cl.
  • Sharpless asymmetric dihydroxylation (Hashiyama, et al., J Org Chem, 1992, 57: 5067-5068) with commercially available AD-mix ⁇ or AD-mix ⁇ catalyst provides the (S) 12 or (R) 13 ⁇ -hydroxyketones, respectively.
  • the ⁇ - hydroxyketones 12 and 13 may be converted to the corresponding triflates 12a and 13a with triflic anhydride followed by reaction with a deuterated t-butylamine (such as commercially available c/p-t-butylamine) to provide single enantiomer compounds of Formula I.
  • a deuterated t-butylamine such as commercially available c/p-t-butylamine
  • Scheme 2 above depicts the synthesis of a deuterated m- chloropropiophenone 10.
  • a deuterated propiophenone 15 may be converted to the m-choro derivative 10 as disclosed by Su, W et al., Org Lett, 2007, 9: 993-996 by reaction with triphosgene and aluminum chloride in chloroform.
  • propiophenone may be used as starting material 15 to produce m-chloropropiophenones 10, wherein R 1 is CH 3 , or CD 3 , respectively.
  • R 1 is CH 3 , or CD 3 , respectively.
  • Scheme 4 above depicts a convenient method for the synthesis of deuterated amino alcohol 14.
  • Commercially available ck-2-nitropropane (16) may be reacted with deuterated formaldehyde in the presence of base as disclosed in Kambe, S et al., Bull Chem Soc Jap, 1968, 41 : 1444-1446; and Dornow, A et al., Chem Ber, 1960, 93: 41-44 to provide nitro alcohol 17.
  • the nitro group may be reduced to the amine in the presence of iron under acidic conditions as disclosed by Senkus, M, J Industrial Eng Chem, 1948, 40: 506-508 to provide the desired amino alcohol 14.
  • Scheme 5a Synthesis of Ervthro Pair of Formula HI.
  • the racemic threo pair may be obtained by reduction of a racemic compound of Formula I with borane (or deuteroborane) to provide compounds of Formula III that are enriched in the racemic threo pair.
  • the purified racemic threo pair may be obtained by conversion to the HCl salt followed by recrystallization from IPA.
  • Scheme 6a Synthesis of a Single Ervthro Enantiomer of Formula HI.
  • Schemes 5a and 5b may also be used to prepare single erythro or threo enantiomers as shown in Schemes 6a and 6b.
  • a single enantiomer of Formula I prepared according to Scheme 1 may be selectively reduced to produce a compound of Formula III enriched in the corresponding erythro or threo enantiomer, which then may be further purified by conversion to the HCl salts and recrystallization from IPA.
  • Synthetic chemistry transformations and protecting group methodologies useful in synthesizing the applicable compounds are known in the art and include, for example, those described in Larock R, Comprehensive Organic Transformations, VCH Publishers (1989); Greene TW et al., Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley and Sons (1999); Fieser L et al., Fieser and Fieser 's Reagents for Organic Synthesis, John Wiley and Sons (1994); and Paquette L, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.
  • the invention also provides pyrogen-free compositions comprising an effective amount of a compound of any of the formulae described herein (e.g., Formula I, Ha, lib or III), 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 phosphat
  • the 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.
  • 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.
  • 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 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.
  • suitable 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.
  • 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. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols. [80] The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation.
  • 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.
  • compositions at the site of interest 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 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 may be painted onto the organ, or a composition of this invention may be applied in any other convenient way.
  • 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 bupropion.
  • Such agents include those indicated as being useful in combination with bupropion, including but not limited to, those described in PCT patent publications WO 2003097046, WO 2004052461, WO 2006017504, WO 2007016108, WO 2007048080, and WO 2007064586.
  • the second therapeutic agent is an agent useful in the treatment or prevention of a disease or condition selected from depression, major depression, nicotine dependence, seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder, female orgasmic disorders, Crohn's disease, marijuana dependence, methamphetamine dependence, seasonal affective disorder, depressive disorders, cocaine-related disorders, pathological gambling, obesity, attention deficit-hyperactivity (ADHD), obsessive-compulsive disorder (OCD), and restless-legs syndrome.
  • a disease or condition selected from depression, major depression, nicotine dependence, seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder, female orgasmic disorders, Crohn's disease, marijuana dependence, methamphetamine dependence, seasonal affective disorder, depressive disorders, cocaine-related disorders, pathological gambling, obesity, attention deficit-hyperactivity (ADHD), obsessive-compulsive disorder (OCD), and restless-legs syndrome.
  • a disease or condition selected from depression, major depression, nicotine dependence, seasonal major depressive episodes
  • the second therapeutic agent is selected from zonisamide, naltrexone, mecamylamine, varenicline, eszopiclone, the transdermal nicotine patch, nefazodone, escitalopram, mirtazapine, and venlafaxine.
  • 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.
  • 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 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 treat (therapeutically or prophylactically) the target disorder. For example, and effective amount 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 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. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N. Y., 1970, 537.
  • an effective amount of a compound of this invention can range from about 2 mg/day to about 3000 mg/day. In more specific embodiments the range is from about 20 mg/day to 1500 mg/day, or from about 40 mg/day to 600 mg/day, or most specifically from about 200 mg/day to 300 mg/day.
  • the dose per day can be administered in a single dose or multiple doses (e.g., 2 or 3 or more). When multiple doses are used, the amounts administered per dose can be the same or different. Treatment typically is administered 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 bupropion.
  • 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.
  • 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.
  • the invention provides a method of inhibiting the uptake of norepinephrine and dopamine in a neuronal cell, comprising contacting such a cell with one or more compounds of any of Formula I, Ha, lib or III herein.
  • the invention provides a method of treating a disease that is beneficially treated by bupropion in a patient in need thereof comprising the step of administering to said patient an effective amount of a compound or a composition of this invention.
  • diseases are well known in the art and are disclosed in, but not limited to the following patents and published applications: US 3819706, WO 2003097046, WO 2004017951, WO 1999037305 (radafaxine), and WO 2007064586.
  • Such diseases include, but are not limited to, depression, major depression, nicotine dependence, seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder, female orgasmic disorders, Crohn's disease, marijuana dependence, methamphetamine dependence, seasonal affective disorder, depressive disorders, cocaine-related disorders, pathological gambling, obesity, attention deficit-hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and restless-legs syndrome.
  • ADHD attention deficit-hyperactivity disorder
  • OCD obsessive-compulsive disorder
  • the method of this invention is used to treat a disease or condition in a patient in need thereof selected from depression, major depression, nicotine dependence, seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder, female orgasmic disorders, Crohn's disease, marijuana dependence, methamphetamine dependence, seasonal affective disorder, depressive disorders, cocaine-related disorders, pathological gambling, obesity, and attention deficit-hyperactivity disorder (ADHD).
  • a disease or condition in a patient in need thereof selected from depression, major depression, nicotine dependence, seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder in a patient in need thereof.
  • Methods delineated herein also include those wherein the patient is identified as in need of a particular stated treatment. Identifying a patient in need of such treatment can be in the judgment of a patient or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method).
  • any of the above methods of treatment comprises the further step of co-administering to the patient one or more second therapeutic agents.
  • the choice of second therapeutic agent may be made from any second therapeutic agent known to be useful for co-administration with bupropion.
  • the choice of second therapeutic agent is also dependent upon the particular disease or condition to be treated. Examples of second therapeutic agents that may be employed in the methods of this invention are those set forth above for use in combination compositions comprising a compound of this invention and a second therapeutic agent.
  • the combination therapies of this invention include coadministering a compound of Formula I and a second therapeutic agent for treatment of the following conditions (with the particular second therapeutic agent indicated in parentheses following the indication): depression (escitalopram, mirtazapine, and venlafaxine); obesity (zonisamide and naltrexone); nicotine dependence (mecamylamine, naltrexone, varenicline, eszopiclone, and the transdermal nicotine patch); marijuana dependence (nefazodone).
  • depression escitalopram, mirtazapine, and venlafaxine
  • obesity zonisamide and naltrexone
  • nicotine dependence mecamylamine, naltrexone, varenicline, eszopiclone, and the transdermal nicotine patch
  • marijuana dependence nefazodone
  • co-administered means that the second therapeutic agent may be administered together with a compound of this invention as part of a single dosage form (such as a composition of this invention comprising a compound of the invention and an second therapeutic agent as described above) or as separate, multiple dosage forms. Alternatively, the additional agent may be administered prior to, consecutively with, or following the administration of a compound of this invention. In such combination therapy treatment, both the compounds of this invention and the second therapeutic agent(s) are administered by conventional methods.
  • composition of this invention comprising both a compound of the invention and a second therapeutic agent, to a patient does not preclude the separate administration of that same therapeutic agent, any other second therapeutic agent or any compound of this invention to said patient at another time during a course of treatment.
  • Effective amounts of these second therapeutic agents 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 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), and other medical texts. However, it is well within the skilled artisan's purview to determine the second therapeutic agent's optimal effective-amount range.
  • the effective amount of the compound of this invention is less than its effective amount would be where the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount would be where the compound of this invention 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.
  • the invention provides the use of a compound of Formula I alone or together with one or more of the above-described second therapeutic agents in the manufacture of a medicament, either as a single composition or as separate dosage forms, for treatment or prevention in a patient of a disease, disorder or symptom set forth above.
  • Another aspect of the invention is a compound of Formula I for use in the treatment or prevention in a patient of a disease, disorder or symptom thereof delineated herein.
  • kits comprise (a) a pharmaceutical composition comprising a compound of any of Formula I, Ha, lib or III 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 depression, major depression, nicotine dependence, and seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder.
  • 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.
  • kits of this invention 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.
  • 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.
  • Example 2 Synthesis of (S)-2-(ftert-butyl-dQ)aminoVl-(3-chlorophenylV2- d-propan- 1 -one deuterochloride (Compound 101b).
  • Compound 101b was prepared as outlined in Scheme 7 above using AD-mix- ⁇ in place of AD-mix- ⁇ for the conversion of intermediate 22 to intermediate 23b (R enantiomer of 23a). Details of the synthesis are as follows.
  • Example 7 Metabolism Studies in Human Liver Microsomes.
  • the metabolic stability of compounds of the invention is tested using pooled liver microsomal incubations. Full scan LC-MS analysis is then performed to detect major metabolites. Samples of the test compounds, exposed to pooled human liver microsomes, are analyzed using HPLC-MS (or MS/MS) detection. For determining metabolic stability, multiple reaction monitoring (MRM) is used to measure the disappearance of the test compounds. For metabolite detection, Ql full scans are used as survey scans to detect the major metabolites.
  • MRM multiple reaction monitoring
  • HMM Human liver microsomes
  • Xenotech, LLC Lidexa, KS
  • ⁇ -nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCl 2 ), and dimethyl sulfoxide (DMSO) are purchased from Sigma-Aldrich.
  • Stock solutions of test compounds (7.5 mM) are prepared in DMSO. The 7.5 mM stock solutions are diluted to 50 ⁇ M in acetonitrile (ACN).
  • 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 (375 ⁇ L) are added to wells of a 96-well deep-well polypropylene plate in triplicate.
  • Ten ⁇ L of the 50 ⁇ M test compound solution is added to the microsomes and the mixture is pre- warmed for 10 minutes. Reactions are initiated by addition of 125 ⁇ L of pre- warmed NADPH solution (8 mM NADPH in 0. IM potassium phosphate buffer, pH 7.4, containing 3 mM MgCl 2 ).
  • the final reaction volume is 0.5 mL and contains 0.5 mg/mL human liver microsomes, 1 ⁇ 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° C, and 50 ⁇ L aliquots were 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° C for 20 minutes after which 100 ⁇ L of water is added to the wells of the plate before centrifugation to pellet precipitated proteins.
  • Supernatants are transferred to another 96-well plate and analyzed for amounts of parent remaining by LC-MS/MS using an Applied Bio- systems API 4000 mass spectrometer.
  • Aliquots (50 ⁇ L) are removed from each sample and placed in wells of a multi-well plate at various time points (e.g., 0, 2, 5, 7, 12, 20, and 30 minutes) and to each aliquot is added 50 ⁇ L of ice cold acetonitrile with 3 ⁇ M haloperidol as an internal standard to stop the reaction.
  • Plates containing the removed aliquots are placed in -20° C freezer for 15 minutes to cool. After cooling, 100 ⁇ L of deionized water is added to all wells in the plate. Plates are then spun in the centrifuge for 10 minutes at 3000 rpm. A portion of the supernatant (100 ⁇ L) is then removed, placed in a new plate and analyzed using Mass Spectrometry.

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Abstract

Cette invention porte sur de nouveaux composés qui sont des dérivés de propiophénones et sur les sels pharmaceutiquement acceptables de ces dérivés. Plus spécifiquement, cette invention porte sur de nouveaux dérivés de propiophénones qui sont des dérivés de bupropion. Cette invention porte également sur des compositions comprenant un ou plusieurs composés de cette invention et un transporteur et sur l'utilisation des composés décrits et des compositions décrites dans des procédés de traitement de maladies et affections qui sont traitées de façon avantageuse par administration d'un inhibiteur de la recapture de la norépinéphrine et de la dopamine, tel que le bupropion.
PCT/US2009/001040 2008-02-21 2009-02-19 Dérivés de propiophénone WO2009105218A2 (fr)

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WO2015095713A1 (fr) * 2013-12-20 2015-06-25 Deuterx, Llc Méthodes pour traiter des troubles neurologiques ou d'autres troubles au moyen de bupropion enrichi en deutérium énantiopure
US20160311757A1 (en) * 2013-12-20 2016-10-27 Deuterx, Llc Methods of treating neurological and other disorders using enantiopure deuterium-enriched bupropion
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