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WO2010019560A1 - Dérivés deutérés de donépézil - Google Patents

Dérivés deutérés de donépézil Download PDF

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Publication number
WO2010019560A1
WO2010019560A1 PCT/US2009/053390 US2009053390W WO2010019560A1 WO 2010019560 A1 WO2010019560 A1 WO 2010019560A1 US 2009053390 W US2009053390 W US 2009053390W WO 2010019560 A1 WO2010019560 A1 WO 2010019560A1
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Prior art keywords
dementia
composition
syndrome
compound
disease
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Ceased
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PCT/US2009/053390
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English (en)
Inventor
Julie F. Liu
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Concert Pharmaceuticals Inc
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Concert Pharmaceuticals Inc
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Publication of WO2010019560A1 publication Critical patent/WO2010019560A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C07B59/002—Heterocyclic compounds

Definitions

  • This invention relates to novel benzyl piperidines and pharmaceutically acceptable salts thereof.
  • This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering acetylcholinesterase inhibitors.
  • Donepezil also known as ( ⁇ )-l-benzyl-4-(5,6-dimethoxy-l-oxoindan-2- ylmethyl)piperidine hydrochloride, is thought to enhance cholinergic function by increasing the concentration of acetylcholine through reversible inhibition of acetylcholinesterase.
  • Donepezil is currently approved for the treatment of Alzheimer's type dementia and vascular dementia and is in clinical trials for the treatment of post-stroke aphasia, dementia associated with Parkinson's disease, Rett syndrome, neurological disorders, autism, cocaine dependency, Fragile X syndrome, memory loss associated with multiple sclerosis, mild cognitive impairment (MCI) and for the prevention of migraine, and postoperative cognitive decline.
  • MCI mild cognitive impairment
  • M2 O- demethylated at positions 5 (M2) and 6 (Ml) which are further converted to their glucuronides; N-dealkylated at the piperidine nitrogen (M4); and piperidine N-oxide (M5 and M6).
  • Ml shows efficacy in vitro comparable to parent while M2 exhibits 140 fold lower activity than parent.
  • the pharmacological contribution of Ml and M2 is thought to be negligible due to their inaccessibility to the brain.
  • CYP2D6 is mainly responsible for the formation of Ml and M2, whereas CYP3A4 and to a lesser extent, 2C9, are responsible for the formation of M4.
  • Adverse events associated with the use of donepezil include but are not limited to nausea, diarrhea, insomnia, fatigue, vomiting, muscle cramps, and anorexia
  • each of R 1 and R 2 is independently selected from hydrogen and deuterium; each of R 3 and R 4 is independently selected from hydrogen, -CH 3 , -CH 2 D, -CHD 2 and -CD 3 ; and at least one R variable comprises a deuterium atom.
  • a pyrogen-free composition comprising a compound of Formula I; and an acceptable carrier.
  • a disease selected from Alzheimer's type dementia, vascular dementia, Lewy Body dementia, AIDS dementia, post-stroke aphasia, dementia associated with Parkinson's disease, age-associated memory impairments, cognitive impairments and/or dementia associated with neurologic and/or psychiatric conditions, including epilepsy, brain tumors, brain lesions, multiple sclerosis, Down's syndrome, Rett's syndrome, progressive supranuclear palsy, frontal lobe syndrome, and schizophrenia and related psychiatric disorders, cognitive impairments caused by traumatic brain injury, post coronary artery by-pass graft surgery, electroconvulsive shock therapy, and chemotherapy, autism, cocaine dependency, Tourette's syndrome; myasthenia gravis, dyslexia, mania, depression, apathy, myopathy associated with diabetes, sleep apn
  • ameliorate and “treat” are used interchangeably and include 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.
  • isotopic enrichment factor means the ratio between the isotopic abundance of D at a specified position in a compound of this invention and the naturally occurring abundance of that isotope. The natural abundance of deuterium is 0.015%.
  • 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).
  • the isotopic enrichment factor of each deuterium present at a site designated as a site of deuteration is independent of other deuterated sites. For example, if there are two sites of deuteration on a compound one site could be deuterated at 52.5% while the other could be deuterated at 75%. The resulting compound would be considered to be a compound wherein the isotopic enrichment factor is at least 3500 (52.5%).
  • isotopologue refers to a species that differs from a specific compound of this invention only in the isotopic composition thereof. Isotopologues can differ in the level of isotopic enrichment at one or more positions and/or in the positions(s) of isotopic enrichment.
  • the term "compound,” as used herein, refers to a collection of molecules having an identical chemical structure, except that there may be isotopic variation among the constituent atoms of the molecules.
  • 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 will be less than 49.9% of the compound.
  • the invention also includes pharmaceutically acceptable salts of the compounds of this 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 abase and an acidic group of the compound, such as a carboxyl functional group.
  • the salt 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
  • 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 disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds which differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms. "R” and “S” represent the configuration of substituents around one or more chiral carbon atoms.
  • the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to the other stereoisomers.
  • the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure. Percent optical purity by weight is the ratio of the weight of the enantiomer over the weight of the enantiomer plus the weight of its optical isomer.
  • 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
  • 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
  • R 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 a compound of Formula I:
  • each of R 1 and R 2 is independently selected from hydrogen and deuterium; and each of R 3 and R 4 is independently selected from hydrogen, -CH 3 , -CH 2 D, -CHD 2 and -CD 3 .
  • R 3 is selected from -CH 3 and -CDy, and R is selected from hydrogen, -CH 3 and -CD 3 .
  • each of R 3 and R 4 is independently selected from -CH 3 and -CD 3 .
  • R 1 and R 2 are the same, hi still another aspect, each of R 3 and R 4 is independently selected from -CH 3 and -CD 3 ; and R 1 and R 2 are the same.
  • R 3 is hydrogen, and R 4 is selected from -CH 3 and -CD 3 .
  • R 1 and R 2 are the same.
  • R and R are the same.
  • the compound is selected from any one of the compounds (Cmpd) set forth in Table 1 (below):
  • any atom not designated as deuterium in any of the embodiments set forth above is present at its natural isotopic abundance.
  • the synthesis of compounds of Formula I can be readily achieved by synthetic chemists of ordinary skill with references to the schemes below, which illustrate how the present compounds may be prepared. Relevant procedures analogous to those of use for the preparation of compounds of Formula I and intermediates thereof are disclosed, for instance in United States patent Nos. 4,895,841 and 5,100,901; US Patent publication Nos. US2004143121 and US2006122227; PCT patent publication Nos.
  • WO2004082685 WO2005044805, WO2005105742, WO2005076749, WO2005003092, WO2006070396 and WO2007015052; Iimura, Y et al, J Label Compd Radiopharm 1989, 27(7):835; De Vos, F et al., J Label Compd Radiopharm 2000, 43(6):595; Elati, C et al., Synth Comm 2006, 36(2): 169-174; Fillion, E et al., J Org Chem 2005, 70(4): 1316-1327; and Sugimoto, H et al., Bioorg Med Chem Lett 1992, 2(8):871-6.
  • 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).
  • Reagents and conditions (1) BBr 3 , CH 2 Cl 2 ; and (2) CD 3 I, K 2 CO 3 , acetone.
  • Scheme 2 above shows a route for preparing indanone intermediate XIa, corresponding to XI in Scheme 1 wherein R 3 and R 4 are each -CD 3 .
  • Deprotection of the methyl ethers in indanone XIm with boron tribromide provides the diol XVI using a protocol similar to that described in Bioorganic and Medicinal Chemistry 15(1), 518-525, 2007.
  • Treatment of XVI with deuterated methyl iodide using a protocol similar to that described in Bioorg Med Chem 2004, 13(2):433-444 provides the deuterated indanone XIa.
  • Scheme 3 Method for Synthesizing Intermediate XIb.
  • Scheme 4 above shows a route for preparing indanone intermediate XIc, corresponding to XI in Scheme 1 wherein R 3 is -CD 3 and R 4 is -CH 3 .
  • Hydrogenation of compound XX can provide carboxylic acid XXI using a protocol similar to that described in Bioorg Med Chem, 2003, 11(17): 3795-3805.
  • Treatment of XXI with polyphosphoric acid provides the indanone XIc' wherein R 3 is hydrogen and R 4 is -CH 3 , which when treated with deuterated methyl iodide using the technique described in J Med Chem, 2000, 33(7): 2000-2006 yields XIc wherein R 3 is -CD 3 and R 4 is -CH 3 .
  • Scheme 5 Method for Synthesizing Intermediates XId and XIe.
  • Scheme 7 above shows how useful indanones XIj and XIk may be prepared, respectively, from XIh and XIc by treating with tert-butyldimethyl silyl chloride and imidazole.
  • the invention also provides pyrogen-free compositions comprising 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.
  • the composition comprises an effective amount of the compound of formula I.
  • 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
  • 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: The Science and Practice of Pharmacy, Lippincott, Williams & Wilkins, Baltimore, MD (20th ed. 2000).
  • 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, hi general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • the compound is administered orally.
  • 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.
  • 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.
  • 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 anon-toxic parenterally- acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the 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.
  • 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.
  • a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • the pharmaceutical compositions 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.
  • Application of the subject therapeutics may be local, so as to be administered at the site of interest.
  • Various techniques can be used for providing the subject compositions at the site of interest, such as injection, use of catheters, trocars, projectiles, pluronic gel, stents, sustained drug release polymers or other device which provides for internal access.
  • 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.
  • 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 fluoro silicone, 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.
  • 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 donepezil.
  • Such agents include those indicated as being useful in combination with donepezil, including but not limited to, those described in WO 1999025363, WO 2002032412, WO 2003101458, WO 2004037234, WO 2004052348, WO 2004103357, WO 2005027975, WO 2005039580, WO 2005087212, WO 2005051426, WO 2005051389, WO 2005099823, WO 2005112946, WO 2005051297, and WO 2005014002.
  • the second therapeutic agent is an agent useful in the treatment or prevention of a disease or condition selected from Alzheimer's type dementia, vascular dementia, Lewy Body dementia, AIDS dementia, post-stroke aphasia, dementia associated with Parkinson's disease, age-associated memory impairments, cognitive impairments and/or dementia associated with neurologic and/or psychiatric conditions, including epilepsy, brain tumors, brain lesions, multiple sclerosis, Down's syndrome, Rett's syndrome, progressive supranuclear palsy, frontal lobe syndrome, and schizophrenia and related psychiatric disorders, cognitive impairments caused by traumatic brain injury, post coronary artery by-pass graft surgery, electroconvulsive shock therapy, and chemotherapy, autism, cocaine dependency, Tourette's syndrome; myasthenia gravis, dyslexia, mania, depression, apathy, myopathy associated with diabetes, sleep apnea, dysfunctions of Huntingdon's disease, Fragile X syndrome, delirium, mild cognitive dysfunctions, a disease
  • the second therapeutic agent is selected from escitalopram, venlafaxine, duloxetine, sertraline, rosiglitazone-XR, PRX-03140, memantine, valproate, perphenazine, vitamin E, physostigmine, galantamine, and citalopram.
  • 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.
  • 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.
  • Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y.,
  • an effective amount of a compound of this invention can range from about 0.05 to 100 mg per treatment. In more specific embodiments the range is from about 0.5 to 50 mg or from about 1 to 20 mg or most specifically from about 5 to
  • Treatment typically is administered once per day.
  • 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 donepezil.
  • 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 invention provides a method of inhibiting the activity of acetylcholinesterase in a cell, comprising contacting a cell with one or more compounds of Formula I herein or pharmaceutically acceptable salts thereof.
  • the invention provides a method of treating a patient suffering from, or susceptible to, a disease that is beneficially treated by donepezil comprising the step of administering to said patient an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof or a composition of this invention.
  • Such diseases include, but are not limited to, Alzheimer's type dementia, vascular dementia, Lewy Body dementia, ATDS dementia, post-stroke aphasia, dementia associated with Parkinson's disease, age-associated memory impairments, cognitive impairments and/or dementia associated with neurologic and/or psychiatric conditions, including epilepspy, brain tumors, brain lesions, multiple sclerosis, Down's syndrome, Rett's syndrome, progressive supranuclear palsy, frontal lobe syndrome, and schizophrenia and related psychiatric disorders, cognitive impairments caused by traumatic brain injury, post coronary artery by-pass graft surgery, electroconvulsive shock therapy, and chemotherapy, autism, cocaine dependency, Tourette's syndrome; myasthenia gravis, dyslexia, mania, depression, apathy, myopathy associated with diabetes, sleep apnea, dysfunctions of Huntingdon's disease, Fragile X syndrome, delirium, mild cognitive impairment (MCI), migraine, post-operative cognitive decline,
  • the method of this invention is used to treat a patient suffering from or susceptible to a disease or condition selected from Alzheimer's type dementia, vascular dementia, post-stroke aphasia, dementia associated with Parkinson's disease, Rett syndrome, neurological disorders, autism, cocaine dependency, Fragile X syndrome, memory loss associated with Multiple Sclerosis, mild cognitive impairment (MCI), migraine, and post-operative cognitive decline.
  • a disease or condition selected from Alzheimer's type dementia, vascular dementia, post-stroke aphasia, dementia associated with Parkinson's disease, Rett syndrome, neurological disorders, autism, cocaine dependency, Fragile X syndrome, memory loss associated with Multiple Sclerosis, mild cognitive impairment (MCI), migraine, and post-operative cognitive decline.
  • MCI mild cognitive impairment
  • the method of this invention is used to treat a patient suffering from or susceptible to a disease or condition selected from Alzheimer's type dementia and vascular dementia.
  • any of the above methods of treatment comprises the further step of co-administering to said 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 donepezil. The choice of second therapeutic agent is also dependent upon the particular disease or condition to be treated.
  • the combination therapies of this invention include co-administering a compound of Formula I or a pharmaceutically acceptable salt thereof and a second therapeutic agent for treatment of the following conditions: Alzheimer's type dementia (rosiglitazone-XR, PRX-03140, memantine, valproate, perphenazine, vitamin E); depression in later life (escitalopram, venlafaxine, duloxetine, sertraline); opioid-induced delirium (physostigmine); and dementia (galantamine, memantine, citalopram).
  • Alzheimer's type dementia rosiglitazone-XR, PRX-03140, memantine, valproate, perphenazine, vitamin E
  • depression in later life escitalopram, venlafaxine, duloxetine, sertraline
  • opioid-induced delirium physostigmine
  • dementia galantamine, memantine, citalopram
  • 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 a pharmaceutical composition comprising 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 or a pharmaceutical composition comprising a compound of Formula I for use in the treatment or prevention in a patient of a disease, disorder or symptom thereof delineated herein.
  • a composition comprising a compound of Formula I is for use in the treatment of a disease selected from Alzheimer's type dementia, vascular dementia, Lewy Body dementia, AIDS dementia, post-stroke aphasia, dementia associated with Parkinson's disease, age- associated memory impairments, cognitive impairments and/or dementia associated with neurologic and/or psychiatric conditions, including epilepsy, brain tumors, brain lesions, multiple sclerosis, Down's syndrome, Rett's syndrome, progressive supranuclear palsy, frontal lobe syndrome, and schizophrenia and related psychiatric disorders, cognitive impairments caused by traumatic brain injury, post coronary artery by-pass graft surgery, electroconvulsive shock therapy, and chemotherapy, autism, cocaine dependency, Tourette's syndrome; myasthenia gravis, dyslexia, mania, depression, apathy, myopathy associated with diabetes, sleep apnea, dysfunctions of Huntingdon's disease, Fragile X syndrome, delirium,
  • a disease selected
  • a composition comprising a compound of Formula I is for use in the treatment of Alzheimer's type dementia, vascular dementia, post-stroke aphasia, dementia associated with Parkinson's disease, Rett syndrome, neurological disorders, autism, cocaine dependency, Fragile X syndrome, memory loss associated with Multiple Sclerosis, mild cognitive impairment (MCI), migraine, or post-operative cognitive decline.
  • a composition comprising a compound of Formula I is for use in the treatment of Alzheimer's type dementia or vascular dementia.
  • the composition for any of the uses described above is used in conjunction with a second therapeutic agent selected from Alzheimer's type dementia, vascular dementia, Lewy Body dementia, AIDS dementia, post-stroke aphasia, dementia associated with Parkinson's disease, age-associated memory impairments, cognitive impairments and/or dementia associated with neurologic and/or psychiatric conditions, including epilepsy, brain tumors, brain lesions, multiple sclerosis, Down's syndrome, Rett's syndrome, progressive supranuclear palsy, frontal lobe syndrome, and schizophrenia and related psychiatric disorders, cognitive impairments caused by traumatic brain injury, post coronary artery by-pass graft surgery, electroconvulsive shock therapy, and chemotherapy, autism, cocaine dependency, Tourette's syndrome; myasthenia gravis, dyslexia, mania, depression, apathy, my
  • the composition comprising a compound of Formula I is for use in the treatment of Alzheimer's type dementia, and the composition is used in conjunction with a second therapeutic agent selected from rosiglitazone-XR, PRX-03140, memantine, valproate, perphenazine and vitamin E.
  • the composition comprising a compound of Formula I is for use in the treatment of depression in later life, and the composition is used in conjunction with a second therapeutic agent selected from escitalopram, venlafaxine, duloxetine and sertraline.
  • the composition comprising a compound of Formula I is for use in the treatment of opioid-induced delirium, and the composition is used in conjunction with physostigmine.
  • composition comprising a compound of Formula I is for use in the treatment of dementia, and the composition is used in conjunction with a second therapeutic agent selected from galantamine, memantine and citalopram.
  • a second therapeutic agent selected from galantamine, memantine and citalopram.
  • the present invention also provides kits for use to treat Alzheimer's type dementia, vascular dementia, post-stroke aphasia, dementia associated with Parkinson's disease, Rett syndrome, neurological disorders, autism, cocaine dependency, Fragile X syndrome, memory loss associated with Multiple Sclerosis, mild cognitive impairment (MCI), migraine, and post-operative cognitive decline.
  • kits 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 Alzheimer's type dementia, vascular dementia, post- stroke aphasia, dementia associated with Parkinson's disease, Rett syndrome, neurological disorders, autism, cocaine dependency, Fragile X syndrome, memory loss associated with Multiple Sclerosis, mild cognitive impairment (MCI), migraine, and post-operative cognitive decline.
  • a pharmaceutical composition comprising a compound of Formula I or a salt thereof, wherein said pharmaceutical composition is in a container
  • instructions describing a method of using the pharmaceutical composition to treat Alzheimer's type dementia, vascular dementia, post- stroke aphasia, dementia associated with Parkinson's disease, Rett syndrome, neurological disorders, autism, cocaine dependency, Fragile X syndrome, memory loss associated with Multiple Sclerosis, mild cognitive impairment (MCI), migraine, and post-operative cognitive decline.
  • MCI mild cognitive impairment
  • 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.
  • EXAMPLE 1 EVALUATION OF METABOLIC STABILITY [110] 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.
  • 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 °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

Cette invention porte sur des dérivés deutérés de donépézil, leurs métabolites, et leurs sels pharmaceutiquement acceptables. Cette invention porte également sur des compositions comprenant un composé de cette invention et sur l'utilisation de telles compositions dans des procédés consistant à traiter des maladies et des états qui sont traités avantageusement par l'administration d'inhibiteurs de l'acétylcholinestérase.
PCT/US2009/053390 2008-08-12 2009-08-11 Dérivés deutérés de donépézil Ceased WO2010019560A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2014008629A1 (fr) * 2012-07-10 2014-01-16 Suzhou Shangzhi Biotech Limited Nouveau dérivés du donépézil
WO2014076965A1 (fr) * 2012-11-16 2014-05-22 学校法人北里研究所 Dérivé 1-indane ayant une activité anti-protozoaire
WO2015140265A1 (fr) * 2014-03-20 2015-09-24 Centre Hospitalier Universitaire De Clermont Ferrand Inhibiteurs de l'acétylcholinestérase d'action centrale pour la prévention et/ou le traitement des neuropathies chimio-induites et leurs symptômes, compositions, utilisations, méthodes et trousse correspondantes
CN104520272B (zh) * 2012-07-10 2016-11-30 苏州尚智生物科技有限公司 多奈哌齐衍生物
CN111056989A (zh) * 2018-10-16 2020-04-24 浙江京新药业股份有限公司 手性氘代多奈哌齐化合物及其制备方法和应用

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014008629A1 (fr) * 2012-07-10 2014-01-16 Suzhou Shangzhi Biotech Limited Nouveau dérivés du donépézil
CN104520272A (zh) * 2012-07-10 2015-04-15 苏州尚智生物科技有限公司 新型多奈哌齐衍生物
CN104520272B (zh) * 2012-07-10 2016-11-30 苏州尚智生物科技有限公司 多奈哌齐衍生物
WO2014076965A1 (fr) * 2012-11-16 2014-05-22 学校法人北里研究所 Dérivé 1-indane ayant une activité anti-protozoaire
WO2015140265A1 (fr) * 2014-03-20 2015-09-24 Centre Hospitalier Universitaire De Clermont Ferrand Inhibiteurs de l'acétylcholinestérase d'action centrale pour la prévention et/ou le traitement des neuropathies chimio-induites et leurs symptômes, compositions, utilisations, méthodes et trousse correspondantes
FR3018689A1 (fr) * 2014-03-20 2015-09-25 Ct Hospitalier Universitaire De Clermont Ferrand Inhibiteurs de l'acetylcholinesterase d'action centrale pour la prevention et/ou le traitement des neuropathies chimio-induites et leurs symptomes, compositions, utilisations, methodes et trousse correspondantes.
CN111056989A (zh) * 2018-10-16 2020-04-24 浙江京新药业股份有限公司 手性氘代多奈哌齐化合物及其制备方法和应用

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