WO2012172449A1 - Lactames convenant comme inhibiteurs des bêta-sécrétases - Google Patents

Lactames convenant comme inhibiteurs des bêta-sécrétases Download PDF

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Publication number
WO2012172449A1
WO2012172449A1 PCT/IB2012/052722 IB2012052722W WO2012172449A1 WO 2012172449 A1 WO2012172449 A1 WO 2012172449A1 IB 2012052722 W IB2012052722 W IB 2012052722W WO 2012172449 A1 WO2012172449 A1 WO 2012172449A1
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Prior art keywords
compound
disorder
disorders
salt
disease
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PCT/IB2012/052722
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English (en)
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Michael Aaron Brodney
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Pfizer Inc.
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Publication of WO2012172449A1 publication Critical patent/WO2012172449A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • 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

Definitions

  • the present inventions relate to a small molecule inhibitor of ⁇ -site amyloid precursor protein (APP) Cleaving Enzyme 1 (BACE 1 ) and it's pharmaceutically acceptable salts.
  • the invention also relates to processes for the preparation of, intermediates used in the preparation of, pharmaceutical compositions containing and the uses of the compound in the treating of Alzheimer's disease (AD) and other neurodegenerative and/or neurological disorders in mammals, including humans.
  • AD Alzheimer's disease
  • other neurodegenerative and/or neurological disorders in mammals, including humans.
  • the present teachings also relate to inhibiting in mammals, including humans, the production of A-beta peptides that may contribute to the formation of neurological deposits of amyloid protein. Additionally, the present teachings relate to a spiro- piperidine compound useful in the treatment of neurodegenerative and/or neurological disorders, such as Alzheimer's disease and Down's Syndrome, related to A-beta peptide production.
  • the compound of the invention is, therefore, useful in the treatment of a wide range of disorders, particularly Alzheimer's disease (AD) and other neurodegenerative and/or neurological disorders (such as migraine; epilepsy; Alzheimer's disease;
  • AD Alzheimer's disease
  • other neurodegenerative and/or neurological disorders such as migraine; epilepsy; Alzheimer's disease;
  • Parkinson's disease brain injury; stroke; cerebrovascular disease; cognitive disorder; sleep disorder.
  • Other conditions that may be treated with the compound of the invention include: a psychiatric disorder (such as anxiety; factitious disorder; impulse control disorder; mood disorder; psychomotor disorder; psychotic disorder; drug dependence; eating disorder; and pediatric psychiatric disorder) in a mammal, including a human, comprising administering to said mammal a therapeutically effective amount of a compound of the invention or pharmaceutically acceptable salt thereof.
  • a psychiatric disorder such as anxiety; factitious disorder; impulse control disorder; mood disorder; psychomotor disorder; psychotic disorder; drug dependence; eating disorder; and pediatric psychiatric disorder
  • BACE inhibitors are currently undergoing human clinical evaluation such as SCH745966 (Merck/Scherring), JNJ-715754 (J&J), AMG-0683 (Amgen) and inhibiting ASP-1702 (CoMentis) to name but a few.
  • SCH745966 Merck/Scherring
  • JNJ-715754 J&J
  • AMG-0683 Amgen
  • ASP-1702 CoMentis
  • This present invention relates to the compound, 1 -(3-fluorophenyl)-8-(4-hydroxy-
  • the compound of the invention may exist in the form of pharmaceutically acceptable salts such as, e.g., an acid addition salt of the compound of the invention.
  • pharmaceutically acceptable salt(s) includes salts of the compound of the invention which has basic functionality (e.g., piperdine nitrogen) and thus capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare a pharmaceutically acceptable salt are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the acetate, ascorbate, benzoate, bisulfate, bitartrate, citrate, acid citrate, formate, fumarate, gentisinate, gluconate, glucuronate, glutamate, hydrochloride, hydrobromide, hydroiodide, isonicotinate, lactate, maleate, nitrate, pantothenate, phosphate, acid phosphate, saccharate, salicylate, succinate, sulfate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1 , 1 '-methylene-bis-(2-hydroxy- 3-naphthoate)] salts.
  • benzenesulfonate such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, and methoxybenzoate
  • bicarbonate bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1 ,4-dioate, calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, clavulanate, citrate, decanoate, dihydrochloride,
  • dihydrogenphosphate edetate, edislyate, estolate, esylate, ethylsuccinate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate, heptanoate, hexyne-1 ,6-dioate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, ⁇ - hydroxybutyrate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, metaphosphate, methane-sulfonate, methylsulfate, monohydrogenphosphate, mucate, napsylate, naphthalene-1 -sulfonate, naphthalene-2-sulfonate, nitrate, oleate, o
  • Salts of particular interest include acetate, citrate, phosphate, L(+) lactate, L(+) tartrate, succinate, benzenesulfonate, sulfonate, fumarate, hydrochloride, 4- toluenesulfonate and methylsulfate.
  • the terms "the present invention,” “compound of the invention” and “the present invention or pharmaceutically acceptable salts thereof” are defined to include all forms of the compound of the invention, including hydrates, solvates, isomers, crystalline and non-crystalline forms, isomorphs, polymorphs, metabolites, and prodrugs thereof.
  • the compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline.
  • the term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid.
  • a change from solid to liquid properties occurs which is characterized by a change of state, typically second order ('glass transition').
  • 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order ('melting point').
  • the compound of Formula I may exist in unsolvated and solvated form.
  • 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • 'hydrate' is employed when said solvent is water.
  • Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules.
  • channel hydrates the water molecules lie in lattice channels where they are next to other water molecules.
  • metal-ion coordinated hydrates the water molecules are bonded to the metal ion.
  • the complex When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
  • multi-component complexes other than salts and solvates
  • complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals.
  • the latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt.
  • Co-crystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together - see Chem Commun, 17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004).
  • references to compounds of Formula I include references to the compound itself, and its salts, solvates, multi-component complexes and liquid crystals of salts thereof.
  • the compounds of the invention include compounds of Formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of Formula I.
  • the invention also relates to prodrugs of the compounds of Formula I.
  • prodrugs of the compounds of Formula I.
  • certain derivatives of compounds of Formula I which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of Formula I having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as "prodrugs”.
  • Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association).
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of Formula I with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
  • prodrugs in accordance with the invention include the compound of Formula I which contains an alcohol functionality which is functionalized into a suitably metabolically labile group (ethers, esters, carbamates, acetals, ketals, etc.).
  • the compounds of Formula I may themselves act as prodrugs of other compounds of Formula I.
  • metabolites of compounds of Formula I that is, compounds formed in vivo upon administration of the drug.
  • the compound of the invention has asymmetric carbon atoms (see the compound of Formula la).
  • the carbon-carbon bonds of the compound of the invention can be depicted herein using a solid line ( ), a solid wedge ( "" ⁇ - ), or a dotted wedge ( 111 ).
  • the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g. specific enantiomers, racemic mixtures, etc.) at that carbon atom are included.
  • Stereoisomers of the invention include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers, rotational isomers, conformational isomers, and tautomers of the compound of the invention, including compounds exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs). Also included are acid additions or base addition salts wherein the counterion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine.
  • the first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts.
  • the second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
  • the present invention also includes isotopically-labeled compounds, which are identical to that recited in the invention above, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that may be incorporated into the compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to,
  • isotopically-labeled compounds of the invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detect ability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • Isotopically-labeled compounds of the invention may generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.
  • stereochemistry shown in Formula la is the absolute stereochemistry, or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the invention is a hydrochloride monohydrate salt of the compound of Formula I (or la, lb, Ic, or Id).
  • Another embodiment of the invention is a crystalline polymorph of a hydrochloride monohydrate salt of the compound of Formula la with X-ray diffraction 2- Theta reflections of about 8.3, 12.1 and 14.4.
  • Another embodiment of the invention is a crystalline polymorph of a hydrochloride monohydrate salt of the compound of Formula la with additional X-ray diffraction 2-Theta reflections of about 8.3.
  • Another embodiment of the invention is a crystalline polymorph of a hydrochloride monohydrate salt of the compound of Formula la with additional X-ray diffraction 2-Theta reflections of about 12.1 .
  • Another embodiment of the invention is a crystalline polymorph of a hydrochloride monohydrate salt of the compound of Formula la with additional X-ray diffraction 2-Theta reflections of about 14.4.
  • Another embodiment of the invention is an anhydrous fumarate salt of the compound of Formula I (or la, lb, lc, or Id).
  • Another embodiment of the invention is a crystalline polymorph of anhydrous fumarate salt of the compound of Formula la.
  • Another embodiment of the invention is a crystalline polymorph of anhydrous fumarate salt of the compound of Formula la with X-ray diffraction 2-Theta reflections of about 9.7, 10.9 and 15.9.
  • Another embodiment of the invention is a crystalline polymorph of anhydrous fumarate salt of the compound of Formula la with additional X-ray diffraction 2-Theta reflections of about 9.7.
  • Another embodiment of the invention is a crystalline polymorph of anhydrous fumarate salt of the compound of Formula la with additional X-ray diffraction 2-Theta reflections of about 10.9.
  • Another embodiment of the invention is a crystalline polymorph of anhydrous fumarate salt of the compound of Formula la with additional X-ray diffraction 2-Theta reflections of about 15.9.
  • a method for the treatment of a disease or condition selected from the group consisting of neurological and psychiatric disorders comprising administering to the mammal an effective amount of the compound of Formula I or pharmaceutically acceptable salt thereof.
  • Another embodiment provides for a method for the treatment of a neurological disorder, wherein the neurological disorder is migraine, epilepsy, Alzheimer's disease, Parkinson's disease, brain injury, stroke, cerebrovascular diseases, cerebral arteriosclerosis, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, brain hypoxia-ischemia, cognitive disorders, amnesia, senile dementia, HIV associated dementia, Alzheimer's disease, Huntington's disease, Lewy body dementia, vascular dementia, drug related dementia, tardive dyskinesia, myoclonus, dystonia, delirium, Pick's disease, Creutzfeldt-Jacob disease, HIV disease, Gilles de la Tourette's syndrome, epilepsy, muscular spasms and disorders associated with muscular spasticity or weakness, tremors, mild cognitive impairment); mental deficiency, spasticity, Down syndrome, fragile X syndrome, sleep disorders, hypersomnia, circadian rhythm sleep disorder, insomnia, parasomnia and sleep deprivation.
  • the neurological disorder is
  • psychiatric disorder is anxiety, acute stress disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, agoraphobia, obsessive-compulsive disorder, factitious disorder, acute hallucinatory mania, impulse control disorders, compulsive gambling, intermittent explosive disorder, mood disorders, bipolar I disorder, bipolar II disorder, mania, mixed affective state, major depression, chronic depression, seasonal depression, psychotic depression, seasonal depression, premenstrual syndrome (PMS) premenstrual dysphoric disorder (PDD), postpartum depression, psychomotor disorder, psychotic disorders, schizophrenia, schizoaffective disorder, schizophreniform, delusional disorder, drug dependence, narcotic dependence, alcoholism, amphetamine dependence, cocaine addiction, nicotine dependence, drug withdrawal syndrome, eating disorders, anorexia, bulimia, binge eating disorder, hyperphagia, obesity, compulsive eating disorders, pagophagi
  • a pharmaceutical composition comprising a compound of the Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • an atypical antipsychotic atypical antipsychotic
  • cholinesterase inhibitor dimebon or NMDA receptor antagonist.
  • the compound of the invention and the pharmaceutically acceptable salts thereof are useful for the treatment of a variety of neurological and psychiatric disorders, including: acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease,
  • acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease,
  • Huntington's Chorea amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug- induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine (including migraine headache), urinary incontinence, substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety (including generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder and obsessive compulsive disorder), mood disorders (including depression, mania, bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, and post-traumatic pain), tardive dyskines
  • the invention provides a method for treating a condition in a mammal, such as a human, selected from the conditions above, comprising administering a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof to the mammal.
  • the mammal may be a mammal in need of such treatment or prevention.
  • the phrase "therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that is effective to treat the condition of interest - i.e., the amount of active compound or pharmaceutical agent that is effective to elicit a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following:
  • preventing the disease for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;
  • inhibiting the disease for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting or slowing further development of the pathology and/or symptomatology); and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating a mammal.
  • treating also includes adjuvant and neo-adjuvant treatment of a subject.
  • Administration of the compound of the invention may be effected by any method that enables delivery of the compound to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular and infusion), topical, and rectal administration.
  • Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the dose and dosing regimen is adjusted in accordance with methods well- known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a patient in practicing the present invention.
  • dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values.
  • an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 25 mg/day to about 525 mg/day, preferably about 10 mg/day to about 250 mg/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for
  • ком ⁇ онент therapy refers to the administration of a compound of the invention together with an at least one additional pharmaceutical or medicinal agent, either sequentially or simultaneously.
  • the present invention may include the use of a combination of a beta amyloid production inhibitor compound as provided in Formula (I) and one or more additional pharmaceutically active agent(s). If a combination of active agents is administered, then they may be administered sequentially or simultaneously, in separate dosage forms or combined in a single dosage form. Accordingly, the present invention also includes pharmaceutical compositions comprising an amount of: (a) a first agent comprising a compound of Formula (I) or a pharmaceutically acceptable salt of the compound; (b) a second pharmaceutically active agent; and (c) a pharmaceutically acceptable carrier, vehicle or diluent.
  • a pharmaceutically active agents may be selected for use in conjunction with the compound of the present invention, depending on the disease, disorder, or condition to be treated.
  • Pharmaceutically active agents that may be used in combination with the compositions of the present invention include, without limitation:
  • acetylcholinesterase inhibitors such as donepezil hydrochloride (ARICEPT,
  • MEMAC physostigmine salicylate
  • ANTILIRIUM physostigmine sulfate
  • ESERINE physostigmine salicylate
  • MESTINON physostigmine sulfate
  • MYTELASE ambenonium
  • Debio 9902 also known as ZT-1 ; Debiopharm
  • rivastigmine EXELON
  • ladostigil NP-0361
  • galantamine hydrobromide RAZADYNE, RIMINYL, NIVALIN
  • tacrine COGNEX
  • tolserine, velnacrine maleate memoquin, huperzine A (HUP-A; NeuroHitech), phenserine, edrophonium (ENLON, TENSILON), and INM-176;
  • amyloid- ⁇ (or fragments thereof), such as ⁇ 1-15 conjugated to pan HLA DR- binding epitope (PADRE), ACC-001 (Elan/Wyeth), ACI-01 , ACI-24, AN-1792, Affitope AD-01 , CAD106, and V-950;
  • antibodies to amyloid- ⁇ such as ponezumab, solanezumab, bapineuzumab (also known as AAB-001 ), AAB-002 (Wyeth/Elan), ACI-01 - Ab7, BAN-2401 , intravenous Ig (GAMMAGARD), LY2062430 (humanized m266; Lilly), R1450 (Roche), ACU-5A5, huC091 , and those disclosed in International Patent
  • amyloid-lowering or -inhibiting agents including those that reduce amyloid production, accumulation and fibrillization
  • amyloid-lowering or -inhibiting agents such as dimebon, davunetide, eprodisate, leuprolide, SK-PC-B70M, celecoxib, lovastatin, anapsos, oxiracetam, pramiracetam, varenicline, nicergoline, colostrinin, bisnorcymserine (also known as BNC), NIC5-15 (Humanetics), E-2012 (Eisai), pioglitazone, clioquinol (also known as PBT1 ), PBT2 (Prana Biotechnology), flurbiprofen (ANSAID, FROBEN) and its f?-enantiomer tarenflurbil (FLURIZAN), nitroflurbiprofen, fenoprofen (FENOPRON, NALFON), ibupro
  • Modulators such as ELND-007; and RAGE (receptor for advanced glycation end- products) inhibitors, such as TTP488 (Transtech) and TTP4000 (Transtech), and those disclosed in US Patent No 7,285,293, including PTI-777;
  • alpha-adrenergic receptor agonists such as guanfacine (INTUNIV, TENEX), clonidine (CATAPRES), metaraminol (ARAMI NE), methyldopa (ALDOMET, DOPAMET, NOVOMEDOPA), tizanidine (ZANAFLEX), phenylephrine (also known as
  • neosynephrine methoxamine
  • cirazoline guanfacine
  • lofexidine lofexidine
  • xylazine modafinil
  • PROVIGIL modafinil
  • NUVIGIL armodafinil
  • beta-adrenergic receptor blocking agents such as carteolol, esmolol (BREVIBLOC), labetalol (NORMODYNE, TRANDATE), oxprenolol (LARACOR, TRASACOR), pindolol (VISKEN), propanolol (INDERAL), sotalol (BETAPACE,
  • PRENT PRENT
  • nadolol CORGARD
  • metoprolol tartrate LPRESSOR
  • metoprolol succinate TOPROL-XL
  • atenolol TENORMIN
  • butoxamine butoxamine
  • SR 59230A Sanofi
  • anticholinergics such as amitriptyline (ELAVIL, ENDEP), butriptyline, benztropine mesylate (COGENTIN), trihexyphenidyl (ARTANE), diphenhydramine (BENADRYL), orphenadrine (NORFLEX), hyoscyamine, atropine (ATROPEN), scopolamine (TRANSDERM-SCOP), scopolamine methylbromide (PARMINE), dicycloverine (BENTYL, BYCLOMINE, DIBENT, DILOMINE), tolterodine (DETROL), oxybutynin (DITROPAN, LYRINEL XL, OXYTROL), penthienate bromide, propantheline (PRO-BANTHINE), cyclizine, imipramine hydrochloride (TOFRANIL), imipramine maleate (SURMONTIL), lofepramine, desipramine (NORPRAMIN),
  • anticonvulsants such as carbamazepine (TEGRETOL, CARBATROL), oxcarbazepine (TRILEPTAL), phenytoin sodium (PHENYTEK), fosphenytoin
  • DEPAKENE valproate sodium
  • DEPACON 1 -benzyl-5-bromouracil
  • progabide beclamide
  • zonisamide TRERIEF, EXCEGRAN
  • CP-465022 retigabine
  • talampanel retigabine
  • primidone MYSOLINE
  • antipsychotics such as lurasidone (LATUDA, also known as SM-13496;
  • (x) calcium channel blockers such as lomerizine, ziconotide, nilvadipine
  • ESCOR NIVADIL
  • diperdipine diperdipine
  • amiodipine NORVASC, ISTIN, AMLODIN
  • felodipine PLENDIL
  • nicardipine CARDENE
  • nifedipine ADALAT, PROCARDIA
  • MEM 1003 and its parent compound nimodipine NIMOTOP
  • nisoldipine SULAR
  • nitrendipine lacidipine
  • LACIPIL lacidipine
  • MOTENS lercanidipine
  • ZANIDIP lifarizine, diltiazem
  • catechol O-methyltransferase (COMT) inhibitors such as nitecapone, tolcapone (TASMAR), entacapone (COMTAN), and tropolone;
  • central nervous system stimulants such as atomoxetine, reboxetine, yohimbine, caffeine, phenmetrazine, phendimetrazine, pemoline, fencamfamine
  • GLUCOENERGAN REACTIVAN
  • fenethylline CAPTAGON
  • pipradol METRAN
  • deanol also known as dimethylaminoethanol
  • DAYTRANA methylphenidate
  • RITALIN methylphenidate hydrochloride
  • dexmethylphenidate FOCALIN
  • amphetamine alone or in combination with other CNS stimulants, e.g. ADDERALL (amphetamine aspartate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate)), dextroamphetamine sulfate (DEXEDRINE,
  • DEXTROSTAT methamphetamine
  • DELTASONE prednisolone
  • PRELONE prednisolone
  • OLEDONE prednisolone acetate
  • ODT methylprednisolone
  • DEPO-MEDROL methylprednisolone acetate
  • A-METHAPRED SOLU-MEDROL
  • dopamine receptor agonists such as apomorphine (APOKYN)
  • PARLODEL bromocriptine
  • DOSTINEX cabergoline
  • dihydrexidine dihydrexidine
  • dihydroergocryptine dihydroergocryptine, fenoldopam (CORLOPAM), lisuride (DOPERGIN), terguride spergolide (PERMAX), piribedil (TRIVASTAL, TRASTAL), pramipexole (MIRAPEX), quinpirole, ropinirole (REQUIP), rotigotine (NEUPRO), SKF-82958 (GlaxoSmithKline), cariprazine, pardoprunox and sarizotan;
  • dopamine receptor antagonists such as chlorpromazine, fluphenazine, haloperidol, loxzpine, resperidone, thioridazine, thiothixene, trifluoperazine,
  • tetrabenazine NITOMAN, XENAZINE
  • 7-hydroxyamoxapine droperidol
  • INAPSINE DRIDOL, DROPLETAN
  • domperidone MOTILIUM
  • L-741742, L-745870, raclopride SB-27701 1A
  • SCH-23390 ecopipam
  • SKF-83566 metoclopramide
  • dopamine reuptake inhibitors such as bupropion, safinamide, nomifensine maleate (MERITAL), vanoxerine (also known as GBR-12909) and its decanoate ester DBL-583, and amineptine;
  • GABA gamma-amino-butyric acid
  • histamine 3 (H3) antagonists such as ciproxifan, tiprolisant, S-38093, irdabisant, pitolisant, GSK-239512, GSK-207040, JNJ-5207852, JNJ-17216498, HPP- 404, SAR-1 10894, trans-3-fluoro-3-(3-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutane carboxylic acid ethylamide and those disclosed in US Patent Publication Nos US2005- 0043354, US2005-0267095, US2005-0256135, US2008-0096955, US2007-1079175, and US2008-0176925; International Patent Publication Nos WO2006/136924,
  • (xix) immunomodulators such as glatiramer acetate (also known as copolymer-1 ; COPAXONE), MBP-8298 (synthetic myelin basic protein peptide), dimethyl fumarate, fingolimod (also known as FTY720), roquinimex (LINOMIDE), laquinimod (also known as ABR-215062 and SAIK-MS), ABT-874 (human anti-IL-12 antibody; Abbott), rituximab (RITUXAN), alemtuzumab (CAMPATH), daclizumab (ZENAPAX), and natalizumab (TYSABRI);
  • glatiramer acetate also known as copolymer-1 ; COPAXONE
  • MBP-8298 synthetic myelin basic protein peptide
  • dimethyl fumarate fingolimod
  • LINOMIDE roquinimex
  • laquinimod also known as ABR-215062 and SAIK-
  • immunosuppressants such as methotrexate (TREXALL, RHEUMATREX), mitoxantrone (NOVANTRONE), mycophenolate mofetil (CELLCEPT), mycophenolate sodium (MYFORTIC), azathioprine (AZASAN, IMURAN), mercaptopurine (PURI- NETHOL), cyclophosphamide (NEOSAR, CYTOXAN), chlorambucil (LEUKERAN), cladribine (LEUSTATIN, MYLINAX), alpha-fetoprotein, etanercept (ENBREL), and 4- benzyloxy-5-((5-undecyl-2H-pyrrol-2-ylidene)methyl)-2,2'-bi-1 H-pyrrole (also known as PNU-156804);
  • TREXALL methotrexate
  • RHEUMATREX mitoxantrone
  • NOVANTRONE mycophenolate mofetil
  • interferons including interferon beta-1 a (AVONEX, REBIF) and interferon beta-1 b (BETASERON, BETAFERON);
  • levodopa or its methyl or ethyl ester
  • a DOPA decarboxylase inhibitor e.g. carbidopa (SINEMET, CARBILEV, PARCOPA), benserazide (MADOPAR), omethyldopa, monofluromethyldopa, difluoromethyldopa, brocresine, or m-hydroxybenzylhydrazine
  • DOPA decarboxylase inhibitor e.g. carbidopa (SINEMET, CARBILEV, PARCOPA), benserazide (MADOPAR), omethyldopa, monofluromethyldopa, difluoromethyldopa, brocresine, or m-hydroxybenzylhydrazine
  • NMDA V-methyl-D-aspartate receptor antagonists
  • memantine NAMENDA, AXURA, EBIXA
  • amantadine SYMMETREL
  • acamprosate CAMPRAL
  • besonprodil ketamine (KETALAR)
  • delucemine dexanabinol
  • dexefaroxan V-methyl-D-aspartate receptor antagonists
  • MAO monoamine oxidase inhibitors
  • EMSAM selegiline
  • l-deprenyl ELDEPRYL
  • ZELAPAR ZELAPAR
  • dimethylselegilene brofaromine
  • NARDIL phenelzine
  • PARNATE tranylcypromine
  • neuroprotective drugs such as bosutinib, condoliase, airmoclomol, lamotrigine, perampanel, aniracetam, minaprime, viluzole 2,3,4,9-tetrahydro-1 H- carbazol-3-one oxime, desmoteplase, anatibant, astaxanthin, neuropeptide NAP (e.g.
  • AL-108 and AL-208; both Allon Therapeutics neurostrol, perampenel, ispronicline, bis(4-3-D-glucopyranosyloxybenzyl)-2-3-D-glucopyranosyl-2-isobutyltartrate (also known as dactylorhin B or DHB), formobactin, xaliproden (XAPRILA), lactacystin, dimeboline hydrochloride (DIMEBON), disufenton (CEROVIVE), arundic acid (ONO-2506,
  • PROGLIA, CEREACT citicoline
  • citicoline also known as cytidine 5'-diphosphocholine
  • edaravone RADICUT
  • AEOL-101 13 and AEOL-10150 both Aeolus Pharmaceuticals
  • AGY-94806 also known as SA-450 and Msc-1
  • granulocyte-colony stimulating factor also known as AX-200
  • BAY-38-7271 also known as KN-387271 ; Bayer AG
  • ancrod VIPRINEX, ARWIN
  • DP-b99 D-Pharm Ltd
  • HF-0220 (17 ⁇ -hydroxyepiandrosterone; Newron Pharmaceuticals
  • HF-0420 also known as oligotropin
  • pyridoxal 5'-phosphate also known as MC-1
  • microplasmin S-18986, piclozotan, NP031 1 12, tacrolimus, L- seryl-L-methionyl-L-alanyl-L-lys
  • ADNF-14 National Institutes of Health
  • stilbazulenyl nitrone SUN- N8075 (Daiichi Suntory Biomedical Research), and zonampanel;
  • nicotinic receptor agonists such as epibatidine, bupropion, CP-601927, varenicline, ABT-089 (Abbott), ABT-594, AZD-0328 (AstraZeneca), EVP-6124, R3487
  • norepinephrine noradrenaline
  • reuptake inhibitors such as atomoxetine (STRATTERA), doxepin (APONAL, ADAPIN, SINEQUAN), nortriptyline (AVENTYL,
  • PAMELOR NORTRILEN
  • amoxapine ASENDIN, DEMOLOX, MOXIDIL
  • reboxetine EDRONAX, VESTRA
  • viloxazine VIVALAN
  • maprotiline DEPRILEPT, LUDIOMIL, PSYMION
  • bupropion WELLBUTRIN
  • radaxafine phosphodiesterase (PDE) inhibitors, including (a) PDE1 inhibitors (e.g. vinpocetine (CAVINTON, CERACTIN, INTELECTOL) and those disclosed in US Patent No 6,235,742, (b) PDE2 inhibitors (e.g.
  • erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), BAY 60-7550, and those described in US Patent No. 6, 174,884), (c) PDE3 inhibitors (e.g. anagrelide, cilostazol, milrinone, olprinone, parogrelil, and pimobendan), (d) PDE4 inhibitors (e.g.
  • apremilast ibudilastroflumilast, rolipram, Ro 20-1724, ibudilast (KETAS), piclamilast (also known as RP73401 ), CDP840, cilomilast (ARIFLO), roflumilast, tofimilast, oglemilast (also known as GRC 3886), tetomilast (also known as OPC-6535), lirimifast, theophylline (UNIPHYL, THEOLAIR), arofylline (also known as LAS-31025), doxofylline, RPR-122818, or mesembrine), and (e) PDE5 inhibitors (e.g.
  • sildenafil VIAGRA, REVATIO
  • tadalafil CIALIS
  • vardenafil LEVITRA, VIVANZA
  • udenafil avanafil
  • dipyridamole PERSANTINE
  • PDE9 inhibitors e.g. BAY 73-6691 (Bayer AG) and those disclosed in US Patent Publication Nos
  • PDE10 inhibitor such as 2-[4-(1 -Methyl-4- pyridin-4-yl-1 H-pyrazol-3-yl)phenoxymethyl]quinoline, and SCH-1518291 ;
  • quinolines such as quinine (including its hydrochloride, dihydrochloride, sulfate, bisulfate and gluconate salts), chloroquine, thankoquine, hydroxychloroquine (PLAQUENIL), mefloquine (LARIAM), and amodiaquine (CAMOQUIN, FLAVOQUINE);
  • ⁇ -secretase inhibitors such as ASP-1702, SCH-745966, JNJ-715754, AMG-0683, AZ-12304146, BMS-782450, GSK-188909, NB-533, LY-2886721 , E-2609, HPP-854, (+)-phenserine tartrate (POSIPHEN), LSN-2434074 (also known as LY- 2434074), KMI-574, SCH-745966, Ac-rER (N 2 -acetyl-D-arginyl-L-arginine), loxistatin (also known as E64d), and CA074Me;
  • POSIPHEN (+)-phenserine tartrate
  • LSN-2434074 also known as LY- 2434074
  • KMI-574 SCH-745966
  • Ac-rER N 2 -acetyl-D-arginyl-L-arginine
  • loxistatin also known as E64d
  • ⁇ -secretase inhibitors and modulators such as BMS-708163 (Avagacest), WO20060430064 (Merck), DSP8658 (Dainippon), ITI-009, L-685458 (Merck), ELAN-G, ELAN-Z, 4-chloro-/V-[2-ethyl-1 (S)-(hydroxymethyl)butyl]benzenesulfonamide;
  • (xxxiii) serotonin (5-hydroxytryptamine) 1A (5-HT 1A ) receptor antagonists such as spiperone, /ei/o-pindolol, BMY 7378, NAD-299, S(-)-UH-301 , NAN 190, lecozotan;
  • (xxxvi) serotonin (5-hydroxytryptamine) 6 (5-HT 6 ) receptor antagonists such as A-964324, AVI-101 , AVN-21 1 , mianserin (TORVOL, BOLVIDON, NORVAL),
  • methiothepin also known as metitepine
  • ritanserin ALX-1 161 , ALX-1 175, MS-245, LY- 483518 (also known as SGS518; Lilly), MS-245, Ro 04-6790, Ro 43-68544, Ro 63-0563, Ro 65-7199, Ro 65-7674, SB-399885, SB-2141 1 1 , SB-258510, SB-271046, SB-357134, SB-699929, SB-271046, SB-742457 (GlaxoSmithKline), Lu AE58054 (Lundbeck A/S), and PRX-07034 (Epix);
  • ANAFRANIL duloxetine
  • CYMBALTA duloxetine
  • MALEXIL femoxetine
  • trophic factors such as nerve growth factor (NGF), basic fibroblast growth factor (bFGF; ERSOFERMIN), neurotrophin-3 (NT-3), cardiotrophin-1 , brain- derived neurotrophic factor (BDNF), neublastin, meteorin, and glial-derived neurotrophic factor (GDNF), and agents that stimulate production of trophic factors, such as propentofylline, idebenone, PYM50028 (COGANE; Phytopharm), and AIT-082
  • NGF nerve growth factor
  • bFGF basic fibroblast growth factor
  • ERSOFERMIN neurotrophin-3
  • cardiotrophin-1 a neurotrophic factor
  • BDNF brain- derived neurotrophic factor
  • GDNF glial-derived neurotrophic factor
  • agents that stimulate production of trophic factors such as propentofylline, idebenone, PYM50028 (COGANE; Phytopharm), and AIT-082
  • Glycine transporter-1 inhibitors such as paliflutine, ORG-25935, JNJ- 17305600, and ORG-26041 ;
  • AMPA-type glutamate receptor modulators such as perampanel, mibampator, selurampanel, GSK-729327, and N-((3S, 4S)-4-(4-(5-cyanothiophen-2-yl)phenoxy)
  • the compound of the invention can be given alone or as pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the invention provides a method for treating a condition selected from migraine, anxiety disorders, schizophrenia, and epilepsy.
  • exemplary anxiety disorders are generalized anxiety disorder, social anxiety disorder, panic disorder, post- traumatic stress disorder and obsessive-compulsive disorder.
  • the invention provides a method for treating depression selected from Major Depression, Chronic Depression (Dysthymia), Seasonal Depression (Seasonal Affective Disorder), Psychotic Depression, and Postpartum Depression.
  • the invention provides a method for treating a sleep disorder selected from insomnia and sleep deprivation.
  • the invention comprises methods of treating a condition in a mammal, such as a human, by administering an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, wherein the condition is selected from the group consisting of atherosclerotic cardiovascular diseases, cerebrovascular diseases and peripheral arterial diseases, to the mammal.
  • a mammal such as a human
  • the mammal is preferably a mammal in need of such treatment or prevention.
  • Other conditions that may be treated in accordance with the present invention include hypertension and angiogenesis.
  • the present invention provides methods of treating neurological and psychiatric disorders associated with glutamate dysfunction, comprising administering to a mammal, preferably a mammal in need thereof, an amount of a compound of the invention or a pharmaceutically acceptable salt thereof effective in treating such disorders.
  • Figure 2 is the observed X-ray powder diffraction pattern of (5R,7S)-1-(3- fluorophenyl)-8-[4-hydroxy-3-(5-methyl-1 H-pyrazol-1-yl)benzyl]-7-methyl-1 ,8- diazaspiro[4.5]dec-3-en-2-one, fumarate salt.
  • Step 1 Synthesis of benzyl 2-methyl-4-oxo-3,4-dihvdropyridine-1 (2/-/)- carboxylate (CD.
  • Triethylamine (92.6 g, 0.915 mol) was added to a solution of 4- methoxypyridine (1 .00 kg, 9.16 mol) in tetrahydrofuran (12 L), and the solution was cooled to minus 50 °C.
  • Benzyl chloroformate (1.58 kg, 9.26 mol) was added to the reaction mixture at minus 50 °C. A white precipitate formed; additional tetrahydrofuran (4 L) was added to the reaction mixture to assist in stirring.
  • the reaction mixture was kept at minus 50 °C to minus 10 °C for 1 hour and cooled to minus 78 °C.
  • a solution of methylmagnesium bromide in diethyl ether (3.0 M, 3.67 L, 1 1 mol) was added over 1 hour, while maintaining the reaction temperature at minus 78 °C.
  • the reaction mixture was then allowed to warm to room temperature and stirred for 2 hours. At this point, it was cooled to minus 10 °C and quenched with aqueous hydrochloric acid (2 N, 10 L). Ethyl acetate (15 L) was added, and the layers were separated.
  • Step 2 Synthesis of benzyl 2-methyl-4-oxopiperidine-1 -carboxylate (C2).
  • a solution of benzyl 2-methyl-4-oxo-3,4-dihydropyridine-1 (2H)-carboxylate (C1 ) (1 .40 kg, 5.71 mol) in acetic acid (7 L) was heated to 60 °C.
  • Zinc dust 1.5 kg, 22.9 mol was added portion-wise over 1 hour, and the reaction was maintained at 60 °C for an additional 2 hours.
  • the reaction mixture was filtered through Celite® using ethyl acetate, and the filtrate was concentrated to an oil. This oil was partitioned between ethyl acetate (10 L) and water (5 L).
  • Step 3 Isolation of benzyl (2S)-2-methyl-4-oxopiperidine-1 -carboxylate (C3).
  • Racemic benzyl 2-methyl-4-oxopiperidine-1-carboxylate (C2) (4.01 kg, 16.2 mol) was dissolved in methanol (80 L) and separated into its enantiomers via chromatography (six Chiralpak AD columns, each 5 cm x 10 cm, 20 ⁇ , 40 °C; Eluant: methanol; Feed rate 7.2 mL/minute; Eluant rate: 225 mL/minute).
  • the first-eluting enantiomer was the desired (2S) enantiomer, obtained as an amber oil.
  • Step 4 Synthesis of benzyl (2S,4S)-4-hydroxy-2-methyl-4- (trichloromethyl)piperidine-l-carboxylate (C5). Tetrahydrofuran (3.57 L), chloroform (0.86 L, 1 1 mol) and trimethylsilyl chloride (0.94 L, 7.4 mol) were combined in a reactor and the resulting solution was cooled to minus 65 °C. A solution of lithium
  • Acetic acid (0.23 L, 4.0 mol) and a solution of tetrabutylammonium fluoride (1 M in tetrahydrofuran, 3.84 L, 3.84 mol) were added to the crude benzyl (2S,4S)-2-methyl-4- (trichloromethyl)-4-[(trimethylsilyl)oxy]piperidine-1-carboxylate in 2-methyltetrahydrofuran (roughly 6 L), and the reaction mixture was held at room temperature for 30 minutes.
  • a solution of potassium carbonate (0.62 kg, 4.5 mol) in water (3.78 L) was added and then the layers were separated. The organic layer was washed three times with water (3 x 3.78 L), then concentrated via vacuum distillation.
  • Step 5 Synthesis of 1 -benzyl 4-methyl (2S,4ffl-4-r(3-ethoxy-3-oxopropanoyl)(3- fluorophenyl)aminol-2-methylpiperidine-1 ,4-dicarboxylate (C7).
  • Methanol (6.48 L) and benzyl (2S,4S)-4-hydroxy-2-methyl-4-(trichloromethyl)piperidine-1 -carboxylate (C5) (1 .30 kg, 3.54 mol) were combined in a reactor and the resulting slurry was cooled to zero °C.
  • reaction mixture was held at zero °C until the reaction was deemed complete by HPLC analysis; this required periodic charging of additional ethyl 3-chloro-3-oxopropanoate (275 g total, 1 .83 mol).
  • 1 M Aqueous hydrochloric acid (6 L) was charged at a slow controlled rate while maintaining the internal temperature below 5 °C.
  • the layers were separated and then the organic layer was washed with 1 M aqueous hydrochloric acid and with aqueous sodium chloride solution.
  • the organic layer was concentrated via vacuum distillation and then 2- methyltetrahydrofuran was added and vacuum distillation was continued to remove residual water.
  • the concentrated solution was diluted with 2-methyltetrahydrofuran to an approximate volume of 1 1 L; this solution was used directly in the following reaction.
  • Step 6 Synthesis of benzyl (5R7SV1 -(3-fluorophenylV7-methyl-2.4-dioxo-1.8- diazaspiror4.51decane-8-carboxylate (C9).
  • the solution of 1 -benzyl 4-methyl (2S,4f?)-4- [(3-ethoxy-3-oxopropanoyl)(3-fluorophenyl)amino]-2-methylpiperidine-1 ,4-dicarboxylate (C7) in 2-methyltetrahydrofuran from the previous step was divided into two equal portions, and each was carried on as follows.
  • the solution was charged into a reactor and diluted with additional 2-methyltetrahydrofuran (5.5 L); a solution of sodium ethoxide in ethanol (20%, 0.76 L, 2.0 mol) was added at a slow controlled rate while maintaining the temperature at 15 °C to 25 °C. The solution was held at 20 °C for 4 hours. A solution of citric acid (0.42 kg, 2.0 mol) in water (2.5 L) was added, followed by addition of 1 M aqueous hydrogen chloride (2.0 L, 2.0 mol) and then the aqueous layer was removed.
  • the resulting solution (3.25 kg) was divided into two equal portions for purification of the product, and each was processed as follows.
  • the solution was concentrated to a residue of approximately 900 g, dissolved in 1 :1 ethyl acetate/heptane (2 L), and pumped through a column of silica gel (330 g) using 1 :1 ethyl acetate/heptane (6 L) as eluant.
  • Mixed fractions were evaporated under reduced pressure to yield a dark residue (777 g), which was dissolved in 2-methyltetrahydrofuran (3.1 L) and treated with heptane in 500 ml_ portions.
  • Step 7 Synthesis of (5R7S)-1 -(3-fluorophenyl)-7-methyl-1 ,8-diazaspiror4.5ldec- 3-en-2-one, hydrochloride salt (PP. 2-Methyltetrahydrofuran (4.04) and ethanol (4.04 L) were charged into a reactor, followed by benzyl (5f?,7S)-1-(3-fluorophenyl)-7-methyl-2,4- dioxo-1 ,8-diazaspiro[4.5]decane-8-carboxylate (C9) (0.50 kg, 1.23 mol).
  • Methanesulfonyl chloride (0.17 L, 2.2 mol) was added at a slow controlled rate while maintaining the temperature at 10 °C ⁇ 3 °C, and the reaction mixture was then held at 10 °C ⁇ 3 °C for 20 minutes, at which time the reaction was deemed complete by HPLC analysis.
  • 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (0.67 L, 4.4 mol) was charged and the reaction mixture was held at 10 °C ⁇ 3 °C for 20 minutes, at which time the reaction was deemed complete by HPLC analysis.
  • the reaction mixture was washed with aqueous hydrochloric acid (1 M, 2 x 4 L) and with aqueous sodium chloride solution.
  • dichloromethane (3 x 2.5 L).
  • the product-rich organic layer was concentrated via vacuum distillation and then ethyl acetate was added and vacuum distillation was continued to remove dichloromethane, to a final volume of approximately 4 L.
  • a solution of hydrogen chloride in ethyl acetate was prepared by adding acetyl chloride (0.14 L, 2.0 mol) to a mixture of ethyl acetate (1.0 L) and methanol (0.10 L, 2.5 mol). This hydrogen chloride solution in ethyl acetate was added at a slow controlled rate to the product solution in ethyl acetate; the reaction mixture was held at room temperature for 2 hours and then heated to 50 °C for 1 hour.
  • Step 1 Synthesis of 1 -(5-bromo-2-methoxyphenyl)-5-methyl-1 H-pyrazole (C14). Boron trifluoride-tetrahydrofuran complex (777 g, 5.55 mol) was slowly added to a solution of 5-bromo-2-methoxyaniline (799.8 g, 3.96 mol) in 2-methyltetrahydrofuran (5.3 L), and the mixture was filtered through Celite®. The filtrate was brought to a volume of 9 L with additional 2-methyltetrahydrofuran.
  • tert-butyl nitrite (433 g, 4.20 mol) was dissolved in 2-methyltetrahydrofuran (8.0 L); the volume was then adjusted to 9 L by addition of 2-methyltetrahydrofuran.
  • the two solutions were pumped by two Ismatec syringe pumps, both of which had been calibrated to deliver 15 mL/minute of 2-methyltetrahydrofuran, into a T-mixer connected to a 240 ml_ polytetrafluoroethylene (PTFE) coil for diazonium salt formation.
  • PTFE polytetrafluoroethylene
  • the syringe pumps were started simultaneously, and the material was passed through the coil into a two-stage continuous flow stirred-tank reactor, where the 5-bromo-2-methoxybenzenediazonium tetrafluoroborate product (C12) was continuously extracted into water, using a water pump with a flow rate of 20 to 22.5 mL/minute.
  • the aqueous layer was continuously separated in a stand pipe decanter, and then quenched into a jacketed 20 L reactor containing a mixture of tin(ll) chloride dihydrate (2.28 kg, 12.0 mol), 2- methyltetrahydrofuran (4 L) and water (4 L) at zero °C.
  • Dichlorophenylborane (0.51 kg, 3.2 mol) was added at a slow controlled rate to a solution of 1 -(5-bromo-2-methoxyphenyl)-5-methyl-1 H-pyrazole (C14) (0.57 kg, 2.13 mol) in toluene (5.73 L), while maintaining the temperature at 20 °C ⁇ 10 °C.
  • the reaction mixture was heated to 95 °C ⁇ 5 °C and held at this temperature for 3 hours, at which time the reaction was deemed complete by HPLC analysis.
  • Aqueous sodium hydroxide solution (1 N, 9.4 L, 9.4 mol) was added at a slow controlled rate while maintaining the temperature at 20 °C ⁇ 10 °C, and the reaction mixture was stirred for 30 minutes.
  • the organic layer was extracted with 1 N aqueous sodium hydroxide (2.6 L, 2.6 mol).
  • Concentrated aqueous hydrogen chloride (37%) was added to the combined aqueous layers at a slow controlled rate, while maintaining the temperature at 20 °C ⁇ 5 °C, until a pH of 9-10 was achieved.
  • the resulting solid was collected by filtration, washed with water (2.86 L) and dried under a stream of nitrogen.
  • Step 3 Synthesis of 4-hydroxy-3-(5-methyl-1 /- -pyrazol-1 -yl)benzaldehyde (P2).
  • 4-Bromo-2-(5-methyl-1 H-pyrazol-1 -yl)phenol (C15) (1 17.7 g, 464.9 mmol) was dissolved in tetrahydrofuran (1.18 L) and cooled in a dry ice/acetone bath.
  • the resulting slurry was treated drop-wise with methyllithium (3.0 M in 1 ,2-dimethoxyethane, 232.5 ml_, 697.4 mmol) over 35 minutes, while maintaining the reaction temperature below minus 55 °C.
  • Sodium triacetoxyborohydride (91 .2 g, 430 mmol) was added in one portion, and the reaction mixture was allowed to stir for 18 hours. At this point, aqueous hydrochloric acid (1 M, 800 ml_, 800 mmol) was added, providing a solution of pH approximately 4. The pH was adjusted to approximately 8 using aqueous sodium hydroxide solution (1 M, then a 50% solution). The aqueous layer was extracted with ethyl acetate (2 x 800 ml_), and the combined organic layers were washed with water (2 x 800 ml_), then with saturated aqueous sodium chloride solution (300 ml_).
  • hydrochloride salt had formed that were appropriate for Single Crystal X-ray Diffraction analysis.
  • the absolute configuration of the title product was established via X-ray crystallography.
  • Data collection was performed on a Bruker AXS SMART-APEX II diffractometer at room temperature with graphite-monochromated MoK a -radiation.
  • the diffractometer is equipped with a CCD area detector and controlled using APEX II software (see Apex 2 v 2008 4.0 control software, Bruker AXS Inc., Madison, Wl 2007).
  • Intensities were integrated (see Bruker SAINT v7.56A integration software, Bruker AXS Inc., Madison, Wl 2007) from three series of exposures, in which each exposure covered 0.3° in ⁇ over 30 seconds.
  • SHELXL-97 Program for crystal structure refinement, G. M. Sheldrick, University of Gottingen, Germany, 1997, release 97-2) based on 1 1716 unique reflections. It was found that the asymmetric unit contained two ion pairs of (5f?,7S)-1 -(3-fluorophenyl)-8- [4-hydroxy-3-(5-methyl-1 /-/-pyrazol-1-yl)benzyl]-7-methyl-1 ,8-diazaspiro[4.5]dec-3-en-2- one, hydrochloride salt (1 ). At this stage it was found that there was some small amount of residual electron density in the structure. This was refined as two water molecules with full occupancy.
  • This structure therefore represents the monohydrate of (5f?,7S)-1- (3-fluorophenyl)-8-[4-hydroxy-3-(5-methyl-1 H-pyrazol-1 -yl)benzyl]-7-methyl-1 ,8- diazaspiro[4.5]dec-3-en-2-one, hydrochloride salt (1 ). All non-hydrogen atoms were found and refined using anisotropic displacement parameters.
  • the hydrogen atoms on nitrogen and oxygen were initially found from a Fourier difference map.
  • the O-H bond lengths in the water molecules were restrained to 0.9 A, while the other O/N-H bonds were subsequently refined freely. All remaining hydrogen atoms on carbon were fixed geometrically.
  • the final refinement included isotropic displacement parameters for all H atoms.
  • the calculated powder pattern was generated from the single crystal data using Mercury version 2.3 software (Cambridge Crystallographic Data Centre).
  • preliminary peak assignments on the PXRD pattern calculated from the crystal structure were conducted using a Threshold value of 0.25 and a Width value of 0.3.
  • the output of automated assignments was visually checked to ensure validity and adjustments manually made if necessary. Additionally, peaks were manually assigned within spectra if appropriate (see Table 2).
  • compositions disclosed herein may be delivered by a route such as oral, dermal, transdermal, intrabronchial, intranasal, intravenous, intramuscular, subcutaneous, parenteral, intraperitoneal, intranasal, vaginal, rectal, or by sustained release.
  • a pharmaceutically effective amount of the compound(s) may vary depending on the specific compound(s), mode of delivery, severity of the condition being treated, and any other active ingredients used in the formulation or the selected regimen.
  • the dosing regimen may be adjusted to provide the optimal therapeutic response. Several divided doses may be delivered daily or a single daily dose may be delivered.
  • the dosage to be used in the treatment or prevention of a specific cognitive deficit or other condition may be subjectively determined by the attending physician.
  • the variables involved include the specific cognitive deficit and the size, age and response pattern of the patient.
  • a starting dose of about 25 mg per day with gradual increase in the daily dose to about 525 mg per day may provide the desired dosage level in the human.
  • the dose may however, be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
  • the compound may be administered to a subject by any desirable route, taking into consideration the specific condition for which it has been selected.
  • subject any suitable mammal, including humans, domestic animals (e.g., canines and felines), and livestock, which have been recognized as having or at risk of having one or more of the conditions for which modulation of beta amyloid levels is desirable.
  • the compound of the invention is useful for treatment and/or prevention of a number of human and veterinary conditions.
  • prevention encompasses prevention of symptoms in a subject who has been identified as at risk for the condition, but has not yet been diagnosed with same and/or who has not yet presented any symptoms thereof.
  • the compound of the invention may be delivered or administered by any suitable route of delivery, e.g., orally, intravenous, subcutaneous, intramuscular, sublingual, intracranial, epidural, intratracheal, rectal, vaginal, among others.
  • the compound may be delivered orally or by a suitable parenteral.
  • the compound may be formulated in combination with conventional pharmaceutical carriers that are physiologically compatible.
  • the compound of the invention may be mixed with other active agents.
  • Suitable physiologically compatible carriers may be readily selected by one of skill in the art.
  • suitable solid carriers include, among others, one or more substances which may also act as lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material.
  • the carrier is a finely divided solid, which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets may contain up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, starch, sugars (including, e.g., lactose and sucrose), calcium phosphate, cellulose (including, e.g., microcrystalline cellulose, methyl cellulose, sodium carboxymethyl cellulose), kaolin, magnesium stearate, talc, dextrin, gelatin, polyvinylpyrrolidine, low melting waxes, and ion exchange resins.
  • Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
  • the active ingredient may be dissolved or suspended in a
  • liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
  • the liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers,
  • liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g. cellulose derivatives, such as, sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
  • the carrier may also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • additives customarily employed in the preparation of pharmaceutical compositions such as, for example, sweeteners or other flavoring agents, coloring agents, preservatives, and antioxidants, e.g., vitamin E, ascorbic acid, BHT and BHA.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions, may be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions may also be administered intravenously. Oral administration may be either liquid or solid composition form.
  • the pharmaceutical composition may be in unit dosage form, e.g. as tablets or capsules.
  • the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
  • the unit dosage forms may be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the unit dosage form may be, for example, a capsule or tablet itself, or it may be the appropriate number of any such compositions in package form.
  • sustained delivery devices may be desirable, in order to avoid the necessity for the patient to take medications on a daily basis.
  • sustained delivery is defined as delaying the release of an active agent, i.e., a claimed compound, until after placement in a delivery environment, followed by a sustained release of the agent at a later time.
  • suitable sustained delivery devices include, e.g., hydrogels (see, e.g., US Patent Nos. 5,266,325; 4,959,217; 5,292,515), an osmotic pump, such as described by Alza (US Patent No. 4,295,987 and US Patent No. 5,273,752) or Merck (European Patent No.
  • hydrophobic membrane materials such as ethylenemethacrylate (EMA) and ethylenevinylacetate (EVA); bioresorbable polymer systems (see, e.g., International Patent Publication No. WO 98/44964, Bioxide and Cellomeda; US Patent No. 5,756, 127 and US Patent No. 5,854,388); other
  • bioresorbable implant devices have been described as being composed of, for example, polyesters, polyanhydrides, or lactic acid/glycolic acid copolymers (see, e.g., US Patent No. 5,817,343 (Alkermes Inc.)).
  • the compound of the invention may be formulated as described herein.
  • the claimed compound has utility for the prevention and treatment of AD by virtue of their ability to reduce beta amyloid production.
  • Cellular, cell- free and in vivo screening methods to detect inhibitors of beta amyloid production are known in the art (for example International Patent Publication No. WO 98/22493, European Patent No. 0 652 009, US Patent No. 5,703,129 and US Patent No.
  • the claimed compound has utility for the prevention and/or treatment of disorders involving beta amyloid production including cerebrovascular diseases.
  • the compound of the invention has also been shown to inhibit beta amyloid production employing the cellular assays described below.
  • the compound of the invention is an inhibitor of beta amyloid production.
  • the compound of the invention has been shown to exhibit specific inhibition with respect to protease activity.
  • the claimed compounds are useful for treatment and prevention of a variety of conditions in which modulation of beta amyloid levels provides a therapeutic benefit.
  • Such conditions include, for example, amyloid angiopathy, cerebral amyloid angiopathy, systemic amyloidosis, Alzheimer's Disease (AD), hereditary cerebral hemorrhage with
  • amyloidosis of the Dutch type inclusion body myositis, Down's syndrome, among others.
  • the compound of the invention may be utilized in generating reagents useful in diagnosis of conditions associated with abnormal levels of beta amyloid.
  • the compound of the invention may be used to generate antibodies which would be useful in a variety of diagnostic assays.
  • Methods for generating monoclonal, polyclonal, recombinant, and synthetic antibodies or fragments thereof are well known to those of skill in the art. See, e.g., E. Mark and Padlin, "Humanization of Monoclonal Antibodies", Chapter 4, The Handbook of Experimental Pharmacology, Vol. 1 13, The Pharmacology of Monoclonal Antibodies, Springer-Verlag (June, 1994); Kohler and
  • suitable diagnostic formats including, e.g., radioimmunoassays and enzyme-linked
  • ELISAs immunosorbent assays
  • Beta-Secretase is one of the enzymes involved in the generation of the Amyloid Beta peptide found in the Amyloid plaques of Alzheimer's patients. This assay measures the inhibition of the beta-Secretase enzyme as it cleaves a non-native peptide substrate.
  • the fluorescent tagged synthetic substrate, Biotin-GLTNIKTEEISEISY A EVEFR- C[oregon green]KK-OH can be efficiently cleaved by the beta-Secretase enzyme and is therefore useful to assay beta-secretase activity in the presence or absence of inhibitory compounds.
  • the histidine tagged BACE1 enzyme was affinity purified material from conditioned media of CHO-K1 cells that had been transfected to express soluble, truncated BACE enzyme (BACE1 deltaTM96His).
  • ELISA Assay The following assay measures BACE inhibition as a decrease in soluble Amyloid Precursor Protein (sAPP). H4 cells were stably transfected with wild type APP which is the substrate for BACE. Cleavage of APP by BACE results in the secretion of sAPP into the media. Inhibition of BACE enzyme prevents the formation and secretion of sAPP.
  • sAPP soluble Amyloid Precursor Protein
  • the neuroglioma cell line H4 cells are grown in Dulbecco's Modified Eagle
  • DMEM DMEM
  • FBS fetal bovine serum
  • 200mM L-Glutamine 200mM L-Glutamine
  • 50mg/ml Geneticin 50mg/ml.
  • Cells are plated over night in tissue culture treated 384 well plates from Falcon at a cell density of 4,500 cells/well in 50uL of media. The next day media is removed, cells are washed once with phosphate buffered saline after which 25uL media is placed in all wells. 2.5uL of a 10x compound dose response curve is added to the cells. The final compound top dose is at 30uM with 1 % DMSO and compounds are diluted by half log 1 1 times. Compounds are allowed to incubate with cells overnight in a 37°C incubator.
  • the coated plates are blocked with 1 % BSA in PBS/TWEEN 20 (0.05%) for an hour and then washed 3 times with PBS/Tween.
  • 10uL of media from the treated cells is transferred to the washed plates and incubated at ambient temperature for an hour and then washed again.
  • a 10ul aliquot of a 1 :1000 dilution of antibody 192 from Elan Pharmaceuticals which recognizes the BACE cleavage site of sAPP is added and incubated for an hour.
  • the plates are washed and then incubated with 10ul of a 1 :1000 dilution of anti-rabbit, HRP tagged antibody from Pierce.
  • liver microsomes 0.3-10 mg microsomal protein/ml
  • substrates (1 .0 ⁇ )
  • MgCI 2 3.3 mM
  • NADPH 1.3 mM
  • Reactions were commenced with the addition of NADPH and shaken in a water bath open to the air at 37°C.
  • T 5 0 and at five time points ranging to 40 min aliquots (50 ml) were removed and added to termination mixtures containing internal standards as listed in Table 1.
  • Such assays may include radioimmunoassays and enzyme-linked immunosorbent assay (ELISA), among others. See, e.g., P.D.

Abstract

La présente invention concerne un composé et des sels pharmaceutiquement admis de ce composé, lequel composé présente la structure (I) définie dans la spécification. L'invention concerne également des compositions pharmaceutiques, des traitements, des procédés de synthèse, et des intermédiaires. Le composé représenté par la formule (I) convient comme inhibiteur de bêta-sécrétases utilisable dans le cadre d'un traitement contre la maladie d'Alzheimer et d'autres troubles neurodégénératifs et/ou neurologiques.
PCT/IB2012/052722 2011-06-13 2012-05-30 Lactames convenant comme inhibiteurs des bêta-sécrétases WO2012172449A1 (fr)

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