WO2019169165A1 - Kétamine et composés apparentés à la kétamine destinés au traitement de troubles neurologiques - Google Patents

Kétamine et composés apparentés à la kétamine destinés au traitement de troubles neurologiques Download PDF

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Publication number
WO2019169165A1
WO2019169165A1 PCT/US2019/020105 US2019020105W WO2019169165A1 WO 2019169165 A1 WO2019169165 A1 WO 2019169165A1 US 2019020105 W US2019020105 W US 2019020105W WO 2019169165 A1 WO2019169165 A1 WO 2019169165A1
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Prior art keywords
disorder
formula
pain
ketamine
disorders
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PCT/US2019/020105
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English (en)
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Mark Eben Massari
Laurent Gomez
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Novocine Therapeutics, Llc
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Publication of WO2019169165A1 publication Critical patent/WO2019169165A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • 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

Definitions

  • the present invention relates to ketamine and certain ketamine-related compounds and derivatives of such compounds, pharmaceutical compositions containing the compounds, methods of making the compounds and use of the compounds in various methods, including the treatment of one or more disorders, including but not limited to neurological disorders, psychotic disorders, dementia and other conditions and diseases.
  • compositions comprising the chemical entities, methods of making the chemical entities and the use of the chemical entities in various methods, including the treatment of one or more disorders, including but not limited to neurological disorders, psychotic disorders, pain disorders, dementia, major depressive disorders, suicidal ideation, cognitive impairment associated with various neurological disorders and other conditions and diseases.
  • disorders including but not limited to neurological disorders, psychotic disorders, pain disorders, dementia, major depressive disorders, suicidal ideation, cognitive impairment associated with various neurological disorders and other conditions and diseases.
  • the term“about” or“approximately” means within an acceptable range for a particular value as determined by one skilled in the art, and may depend in part on how the value is measured or determined, e.g., the limitations of the measurement system or technique.
  • “about” can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% or less on either side of a given value.
  • the term“about” can mean within an order of magnitude, within 5 fold, or within 2 fold on either side of a value. Numerical quantities given herein are approximate unless stated otherwise, meaning that the term“about” or“approximately” can be inferred when not expressly stated.
  • a group of items linked with the conjunction“and” should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as“and/or” unless expressly stated otherwise.
  • a group of items linked with the conjunction“or” should not be read as requiring mutual exclusivity among that group, but rather should also be read as“and/or” unless expressly stated otherwise.
  • items, elements or components of the invention may be described or claimed in the singular, the plural is contemplated to be within the scope thereof, unless limitation to the singular is explicitly stated.
  • alkyl refers to a fully saturated aliphatic hydrocarbon group.
  • the alkyl moiety may be a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain.
  • alkyl groups include, but are not limited to, methyl (Me, which also may be structurally depicted by the symbol,“*** «*”) ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, fer/-butyl (tBu), pentyl, isopentyl, /er/-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
  • Alkyl groups may be optionally substituted with one or more substituents including, but not limited to, hydroxyl, alkoxy, thioalkoxy, amino, and amino
  • alkenyl refers to optionally substituted unsaturated aliphatic moieties having at least one carbon-carbon double bond and including E and Z isomers of said alkenyl moiety.
  • alkenyl radicals include ethenyl, propenyl, butenyl, l,4-butadienyl, cyclopentenyl, cyclohexenyl and the like.
  • alkynyl refers to an optionally substituted unsaturated aliphatic moieties having at least one carbon-carbon triple bond and includes straight and branched chain alkynyl groups.
  • alkynyl radicals include ethynyl, propynyl, butynyl and the like.
  • haloalkyl refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain optionally substituting hydrogens with halogens.
  • haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, - CH2CH2F, -CH2CH2CI, -CH2CF2CF3 and other groups that in light of the ordinary skill in the art and the teachings provided herein, would be considered equivalent to any one of the foregoing examples.
  • alkoxy includes a straight chain or branched alkyl group with an oxygen atom linking the alkyl group to the rest of the molecule.
  • Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, /-butoxy, pentoxy and so on.
  • “Aminoalkyl,”“thioalkyl,” and “sulfonylalkyl” are analogous to alkoxy, replacing the terminal oxygen atom of alkoxy with, respectively, NH (or NR), S, and SO2.
  • haloalkoxy refers to alkoxy groups optionally substituting hydrogens with halogens.
  • haloalkoxy groups include, but are not limited to, -OCF3, -OCH2CF3, -OCH2CHF2, -OCH2CH2CI, -OCH2CF2CF3, -OCH(CH 3 )CHF 2 and other groups that in light of the ordinary skill in the art and the teachings provided herein, would be considered equivalent to any one of the foregoing examples.
  • amino refers to the -NH2 group.
  • alkylamino refers to the -NRR’ group, where R and R’ are independently selected from hydrogen (however, R and R’ cannot both be hydrogen), alkyl, and aryl groups; or R and R’, taken together, can form a cyclic ring system.
  • amino groups include, but are not limited to, -NH(CH 3 ), -N(CH 3 ) 2 , -NPhenyl(CH 3 ), -NHPhenyl, -N(CH 2 CH 3 )(CH 3 ), and the like.
  • cyano refers to the group -CN.
  • aryl refers to a monocyclic, or fused or spiro polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon), having from 3 to 12 ring atoms per ring (carbon atoms in aryl groups are sp2 hybridized).
  • aryl groups include the following moieties:
  • aryloxy refers to a group having the formula, -O-R, wherein R is an aryl group.
  • cycloalkyl refers to a saturated or partially saturated carbocycle, such as monocyclic, fused polycyclic, bridged monocyclic, bridged polycyclic, spirocyclic, or spiro polycyclic carbocycle having from 3 to 12 ring atoms per carbocycle.
  • cycloalkyl is qualified by a specific characterization, such as monocyclic, fused polycyclic, bridged polycyclic, spirocyclic, and spiro polycyclic, then such term cycloalkyl refers only to the carbocycle so characterized.
  • Illustrative examples of cycloalkyl groups include the following entities, in the form of properly bonded moieties:
  • A“heterocycloalkyl” refers to a monocyclic, or fused, bridged, or spiro polycyclic ring structure that is saturated or partially saturated and has from 3 to 12 ring atoms per ring structure selected from carbon atoms and up to three heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the ring structure may optionally contain up to two oxo groups on carbon or sulfur ring members.
  • Illustrative entities, in the form of properly bonded moieties include:
  • heteroaryl refers to a monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle.
  • heteroaryl groups include the following entities, in the form of properly bonded moieties:
  • halogen represents chlorine, fluorine, bromine or iodine.
  • halo represents chloro, fluoro, bromo or iodo.
  • heteroatom refers to, for example, O (oxygen), S (sulfur), or N (nitrogen).
  • substituted means that the specified group or moiety bears one or more substituents. Where the term“substituted” is used to describe a structural system, unless specified otherwise, the substitution is meant to occur at any valency-allowed position on the system. The term “unsubstituted” means that the specified group bears no substituents.
  • any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms.
  • compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof, are considered within the scope of the formula.
  • any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof.
  • certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers.
  • a“compound” refers to any one of: (a) the actually recited form of such compound; and (b) any of the forms of such compound in the medium in which the compound is being considered when named.
  • reference herein to a compound such as R- COOH encompasses reference to any one of, for example, R-COOH(s), R-COOH(sol), and R-COO-(sol).
  • R-COOH(s) refers to the solid compound, as it could be for example in a tablet or some other solid pharmaceutical composition or preparation
  • R- COOH(sol) refers to the undissociated form of the compound in a solvent
  • R-COO-(sol) refers to the dissociated form of the compound in a solvent, such as the dissociated form of the compound in an aqueous environment, whether such dissociated form derives from R-COOH, from a salt thereof, or from any other entity that yields R-COO- upon dissociation in the medium being considered.
  • the term“chemical entity” collectively refers to a compound, along with the derivatives of the compound, including salts, chelates, solvates, conformers, non- covalent complexes, metabolites, and prodrugs.
  • the chemical entity is selected from the group consisting of compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I), and pharmaceutically acceptable metabolites of compounds of Formula (I).
  • an expression such as“exposing an entity to a compound of formula R-COOH” refers to the exposure of such entity to the form, or forms, of the compound R-COOH that exists, or exist, in the medium in which such exposure takes place.
  • an expression such as“reacting an entity with a compound of formula R- COOH” refers to the reacting of (a) such entity in the chemically relevant form, or forms, of such entity that exists, or exist, in the medium in which such reacting takes place, with (b) the chemically relevant form, or forms, of the compound R-COOH that exists, or exist, in the medium in which such reacting takes place.
  • a“zwitterionic” compound is encompassed herein by referring to a compound that is known to form a zwitterion, even if it is not explicitly named in its zwitterionic form.
  • Terms such as zwitterion, zwitterions, and their synonyms zwitterionic compound(s) are standard IUP AC-endorsed names that are well known and part of standard sets of defined scientific names.
  • the name zwitterion is assigned the name identification CHEBT27369 by the Chemical Entities of Biological lnterest (ChEBI) dictionary of molecular entities.
  • a zwitterion or zwitterionic compound is a neutral compound that has formal unit charges of opposite sign.
  • aminoethanoic acid (the amino acid glycine) has the formula H2NCH2COOH, and it exists in some media (in this case in neutral media) in the form of the zwitterion +H3NCH2COO-.
  • Zwitterions, zwitterionic compounds, inner salts, and dipolar ions in the known and well established meanings of these terms are within the scope of this invention, as would in any case be so appreciated by those of ordinary skill in the art.
  • Isotopes may be present in the compounds described. Each chemical element present in a compound either specifically or generically described herein may include any isotope of said element. Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, U C, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, 36 Cl, and 125 I, respectively.
  • C1-3 refers independently to embodiments that have one carbon member (Ci), embodiments that have two carbon members (C2), and embodiments that have three carbon members (C3).
  • Cn- m alkyl refers to an aliphatic chain, whether straight or branched, with the total number N of carbon members in the chain that satisfies n ⁇ N ⁇ m, with m > n.
  • any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed.
  • prodrug means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g ., a prodrug on being brought to physiological pH is converted to the compound of Formula (I)).
  • A“pharmaceutically acceptable prodrug” is a prodrug that is preferably non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in“Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985
  • A“metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula (I) or salt thereof.
  • the metabolite is in an isolated form outside the body.
  • composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation, or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of Formula (I) and a pharmaceutically acceptable excipient.
  • a variety of means for administering the compositions described herein to subjects are known to those of skill in the art.
  • Such methods can include, but are not limited to oral, parenteral, intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol, e.g. by intranasal or inhalation delivery), pulmonary, cutaneous, topical, injection, intralesionally, or intratumoral administration. Administration can be local or systemic. More particularly, chemical entities and compositions of the present disclosure are administered orally, intranasally, or intravenously.
  • compositions of the invention refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to an animal (e.g., human).
  • pharmaceutically acceptable may also mean approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals (e.g. mammals), and more particularly in humans.
  • A“pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluents to facilitate administration of an agent and that is compatible therewith.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • Suitable pharmaceutical carriers include those described in Remington: The Science and Practice of Pharmacy, 2l st Ed., Lippincott Williams & Wilkins (2005).
  • A“pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented by Formula (I) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, G.S. Paulekuhn et al., Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database, J. Med. Chem. 2007, 50, 6665-6672; Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 1977, 66, 1-19; Stahl and Wermuth (eds), Pharmaceutical Salts; Properties, Selection, and Use: 2nd Revised Edition, Wiley-YCS, Zurich, Switzerland (2011).
  • Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response.
  • a compound of Formula (I) may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • carrier refers to an adjuvant, vehicle, or excipients, with which the compound is administered.
  • the carrier is a solid carrier.
  • Suitable pharmaceutical carriers include those described in Remington: The Science and Practice of Pharmacy, 2l st Ed., Lippincott Williams & Wilkins (2005).
  • Dosage form is the form in which the dose is to be administered to the subject or patient.
  • the drug is generally administered as part of a formulation that includes nonmedical agents.
  • the dosage form has unique physical and pharmaceutical characteristics.
  • Dosage forms may be solid, liquid or gaseous.
  • “Dosage forms” may include for example, a capsule, tablet, caplet, gel caplet (gelcap), syrup, a liquid composition, a powder, a concentrated powder, a concentrated powder admixed with a liquid, a chewable form, a swallowable form, a dissolvable form, an effervescent, a granulated form, and an oral liquid solution.
  • the dosage form is a solid dosage form, and more specifically, comprises a tablet or capsule.
  • inactive ingredient refers to any inactive ingredient of a described composition.
  • inactive ingredient as used herein follows that of the U.S. Food and Drug Administration, as defined in 21 C.F.R. 201.3(b)(8), which is any component of a drug product other than the active ingredient.
  • the disclosure relates to compounds and chemical entities of Formula (I), Formula (II) and Formula (III) and their use in the disclosed methods.
  • Ri and R2 are each independently selected from the group consisting of:
  • -Ci-Csalkyl optionally substituted with one or more members, each independently selected from the group consisting of -Ci-xalkyl, -Ci-xalkoxy, -halo, -hydroxy, -amino, -guanidyl, -amidyl, urea, and -carboxyl; or optionally Ri and R2 taken together with the carbon to which they are attached can form an optionally substituted three, four, five, six or seven membered cycloakyl or heterocycloalkyl ring;
  • -C2-8alkenyl or -C2-8alkynyl each optionally substituted with one or more members, each independently selected from the group consisting of -halo, -hydroxy, -Ci-salkyl, -Ci-salkoxy, and amino; -(CH2)naryl, -(CH2)nheteroaryl, -(CH2)ncycloalkyl, or -(CH2)nheterocycloalkyl, each optionally substituted with one or more members, each independently selected from the group consisting of -halo, -hydroxy, -Ci- 4 alkyl, -Ci- 4 alkoxy, and amino, wherein n is independently an integer selected from 0, 1, 2, 3, and 4;
  • R3 is selected from the group consisting of H and Me
  • R 4 and R5 are each independently selected from the group consisting of -H and -Ci-salkyl.
  • starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product.
  • the variables are as defined above in reference to Formula (I), Formula (II) and Formula (III).
  • Reactions may be performed between -78 ° C and the reflux temperature of the solvent. Reactions may be heated employing conventional heating or microwave heating. Reactions may also be conducted in sealed pressure vessels above the normal reflux temperature of the solvent.
  • aryl-hydroxylimines can rearrange to the corresponding 2- aminocyclohexanones, such as Formula (IV), under thermal conditions using solvents such as Dowtherm A at temperatures ranging from 100-240 °C.
  • solvents such as Dowtherm A at temperatures ranging from 100-240 °C.
  • a subsequent protection of the amino group with B0C2O under basic conditions, such as K2CO3 or the like, in a solvent such as toluene, benzene, or the like, and at temperatures ranging from 30-110 °C affords the corresponding carbamate of Formula (V).
  • a base such as LDA, or the like
  • a silylating agent such as TMC1, or the like
  • solvent such as THF, or the like
  • hydroxyl amino-ketone of Formula (VIII) is protected with a suitable protecting group (PG) such as Cbz or Boc.
  • PG protecting group
  • Removal of the protecting group (PG) is accomplished by using methods known to one skilled in the art. For example, removal of the Cbz protecting group (PG) in a compound of Formula (X) is accomplished by using palladium on carbon, hydrogen under pressure, in a solvent such as MeOH or EtOAc, or the like. ETpon deprotection of the protecting group, a spontaneous intramolecular cyclization occurs to afford a compound of Formula (XI).
  • reaction mixtures were magnetically stirred at room temperature (rt) under nitrogen atmosphere. Where solutions were“dried,” they were generally dried over a drying agent such as Na2S0 4 or MgSCri. Where mixtures, solutions, and extracts were “concentrated,” they were typically concentrated on a rotary evaporator under reduced pressure.
  • Analytical LC/MS were obtained on a Waters 2695 Separations Unit, 2487 Dual Absorbance Detector, Micromass ZQ fitted with ESI Probe, or a Waters AcquityTM Ultra performance LC (UPLC) with PDA el and SQ detectors.
  • Preparative HPLC was performed on a Shimadzu SIL-10AP system using a Waters SunFireTM OBD 30 mm x 100 mm X 2.5 pm (particle size) C 18 column with a 15 minute gradient of 10-100% acetonitrile in water and 0.05% trifluoroacetic acid added as a modifier to both phases. Elution profiles were monitored by UV at 254 and 220 nm.
  • Nuclear magnetic resonance (NMR) spectra were obtained in a Varian 400MHz or Bruker 400MHz NMR. Samples were analyzed in either deuterated acetone ((CD 3 )2CO)), chloroform (CDCh), ethanol - /2 (CD3OD), or dimethyl sulfoxide-r/r, (DMSO-r/r,).
  • CDCh samples the residual central resonance peak at 7.26 for 'H was used for chemical shift assignment for 'H NMR spectra.
  • CD3OD the residual central resonance peak at 3.31 for 'H was used for chemical shift assignment and for DMSO-r/r, the residual central resonance peak at 2.50 ppm for 'H was used for chemical shift assignment.
  • the format of the 'H NMR data is: chemical shift in ppm downfield the tetramethylsilane reference (multiplicity, coupling constant Jin Hz, integration).
  • This compound can be prepared in the manner described in Nature , 2016, 533(7604), 481-486.
  • Benzyl chloroformate (2.0 equiv) is added dropwise to a stirred and cooled (0°C) mixture of 2- amino-2-(2-chlorophenyl)-6-hydroxycyclohexan-l-one (Intermediate 1, 1.0 equiv) and triethylamine (4 equiv) in dichloromethane (0.3 M). The resulting mixture is stirred at room temperature overnight. The reaction mixture is diluted with dichloromethane and washed with saturated aqueous NaHCCb water and brine. The mixture is dried (MgS04) then filtered and the solvent is evaporated under reduced pressure to give the desired compound.
  • This compound may be prepared in a manner analogous to that described in J. Org. Chem ., 2011, 76, 1621-1633 as follows.
  • This compound may be prepared in a manner analogous to that described in J. Org. Chem ., 1984, 49, 1208-1211 as follows.
  • This compound may be prepared in a manner analogous to that described in J. Org. Chem., 1984, 49, 1208-1211 as follows.
  • Examples 4-20 which correspond to the (5f?,8ai?) enantiomers, may each be prepared in a manner analogous to Example 1 with the appropriate starting materials and reagent substitutions.
  • the corresponding (5S,8aS) enantiomers of Example 1, 4-20 can be synthesized in a similar manner to that described using the appropriate starting materials and reagent substitutions.
  • Example _ 4 ; _ 3-(T3A > .5A > )-5-amino-5-('2-chloroDhenyl )-2-oxo-3.5.6.7.8.8a-hexahydro-2//- benzor b ⁇ G 1 41oxazin-3 -vDpropanamide
  • Example 6 _ (5/ ⁇ 8a/ ⁇ )-5-amino-5-(2-chlorophenyl )-3-f1uoro-3.5.6.7.8.8a-hexahydro-2//- benzor V ⁇ ⁇ 1 41oxazin-2-one
  • Example 9 (5/ ⁇ 8a/ -5-amino-5-(2-chlorophenyl )-3.3-difluoro3.5.6.7.8.8a-hexahydro2//- benzor V ⁇ ⁇ 1 41oxazin-2-one
  • Example 10 (5i?.8ai?)-5-amino-5-(2-chlorophenvO-3-phenyl-3.5.6.7.8.8a-hexahvdiO-2//- benzor V ⁇ ⁇ 1 41oxazin-2-one
  • Example 11 3-(Y3i?.5i?.8ai?)-5-amino-5-(2-chlorophenvD-2-oxo-3.5.6.7.8.8a-hexahvdiO-2//-
  • Example 13 (3i?.5i?.8ai?)-5-amino-5-(2-chloiOphenvO-3-(methoxymethvO-3.5.6.7.8.8a- hexahvdro- xazin-2-one
  • Example 15 (3i?.5i?.8ai?)-5-amino-5-(2-chloiOphenvO-3-(2-(methylthio)ethvO-3.5.6.7.8.8a- hexahvdro- 2-one
  • Example 17 l-(3-(Y3i?.5i?.8ai?)-5-amino-5-(2-chloiOphenvO-2-oxo-3.5.6.7.8.8a-hexahydiO-2//- benzor b ⁇ ⁇ 1 41oxazin-3 -vOpropyOguanidine
  • Example 19 (3i?.5i?.8ai?)-3-(Yl//-indol-2-vOmethvO-5-amino-5-(2-chloiOphenvO-3.5.6.7.8.8a- hexahydro- oxazin-2-one
  • Examples 21-32 which correspond to the (5i?,8ai?) enantiomers, may each be prepared in a manner analogous to Example 2 with the appropriate starting materials and reagent substitutions.
  • the corresponding (5S,8aS) enantiomers of Example 2 21-32 can be synthesized in a similar manner to that described using the appropriate starting materials and reagent substitutions.
  • Example 21 (5i?.8ai?)-8a-(2-chlorophenvD-5-hvdroxy-3.5.6.7.8.8a-hexahvdroquinoxalin-2ni7V one
  • Example_ 22 (5i?.8ai?)-8a-(2-chlorophenvO-3-fluoro-5-hvdroxv-3.5.6.7.8.8a- hexahydroquinoxalin-2( lip-one
  • Example 24 -8a-(2-chlorophenyl )-5-hydroxy-3 -(hydroxy ethyl )-3.5.6.7.8.8a-
  • Example 25 -8a-(2-chlorophenyl )-3 -(3 -(dimethyl ami no )propyl )-5-hydroxy-
  • Example 26 -8a-(2-chlorophenvD-5-hvdiOxy-3-(4-hvdiOxybenzvD-3.5.6.7.8.8a-
  • Example 27 _ (5/ ⁇ 8a/ ⁇ )-3-(.syc-butyl )-8a-(2-chlorophenyl )-5-hydroxy-3.5.6.7.8.8a- hexahydroquinoxalin- -one
  • Example _ 28 _ (3 V.5/ ⁇ 8a/ ⁇ )-8a-(2-chlorophenyl )-5-hydroxy-3-isopentyl-3.5.6.7.8.8a- hexahydroquinoxalin-2( l/f)-one
  • Example 29 (3 V.5/ ⁇ 8a/ ⁇ )-8a-(2-chlorophenyl )-5-hydroxy-3-(2-(methylthio)ethyl )-3.5.6.7.8.8a- hexahydroquinoxalin-2( l/f)-one
  • Example 30 (5/ ⁇ 8a/ ⁇ )-8a-(2-chlorophenyl )-5-hydroxy-3-(2-( ethylamino)ethyl )-3.5.6.7.8.8a- hexahydroquinoxalin-2 -one
  • Example 31 (5/ ⁇ 8a/ ⁇ )-8a-(2-chlorophenyl )-5-hydroxy-3-(3-methoxypropyl )-3.5.6.7.8.8a- hexahydroquinoxalin-2( liTVone
  • Example _ 32 _ (5/ ⁇ 8a/ ⁇ )-8a-(2-chlorophenyl )-3.3-difluoro-5-hvdroxy-3.5.6.7.8.8a- hexahydroquinoxalin- -one
  • Example _ 33 (5/ ⁇ 8a/ ⁇ )-8a-(2-chlorophenyl )-3-fluoro-5-hvdroxy-3-methyl-3.5.6.7.8.8a- hexahydroquinoxalin-2( liTVone
  • Example 35 _ ('5A > .8aA > )-8a-('2-chlorophenyl )-3-cyclopropyl-5-hydroxy-3.5.6.7.8.8a- hexahydroquinoxalin- -one
  • Examples 36-46 which correspond to the (8a R) enantiomers, may each be prepared in a manner analogous to Example 3 with the appropriate starting materials and reagent substitutions.
  • the corresponding (8a S) enantiomers of Example 3 36-46 can be synthesized in a similar manner to that described using the appropriate starting materials and reagent substitutions.
  • Example 36 (7?V8a-(2-chlorophenvO-l-methyl- hexahvdroquinoxalin-2n/f)-one
  • Example _ 38 _ -8a-(2-chlorophenyl)-3-(4-methoxyphenyl)-l -methyl-3.5.6.7.8.8a-
  • Example _ 40 _ (35 , .8ai?)-8a-(2-chlorophenyl)-l-methyl-3-(oxetan-3-yl)-3.5.6.7.8.8a- hexahydroquinoxalin-2
  • Example 41 (7?)-8a-(2-chloiOphenvO-E3.3-trimethyl-3.5.6.7.8.8a-hexahvdiOquinoxalin-2n/f)- one
  • Example 41 (8ai?)-8a-(2-chloiOphenvO-3-(3-hvdiOxybutan-2-vO-l-methyl-3.5.6.7.8.8a- hexahydroquinoxalin-2( liTVone
  • Example 43 (8ai?)-8a-(2-chloiOphenvO-3-(3-mercaptopiOpyO-E3-dimethyl-3.5.6.7.8.8a- hexahydroquinoxalin-2( l/f)-one
  • Example 45 imidazol-2-vOmethvO-8a-(2-chlorophenvO-l -methyl-3 5.6.7.8.8a-
  • Example 46 (7?)-8a-(2-chlorophenvO-3.3-difluoro-l -methyl-3 5.6.7.8.8a-hexahvdroquinoxalin-
  • Examples 47-58 which correspond to the (8a R) enantiomers, may each be prepared in a manner analogous to Example 3 where norketamine is used in place of ketamine, with the appropriate starting materials and reagent substitutions.
  • the corresponding (8a S) enantiomers of Example 3, 47-58 can be synthesized in a similar manner to that described using the appropriate starting materials and reagent substitutions.
  • Example 48 (8ai?)-8a-(2-chlorophenvn-3-fluoro-3.5.6.7.8.8a-hexahvdroquinoxalin-2 -one
  • Example 49 (8ai?)-8a-(2-chloiOphenvO-3-(4-methoxyphenvO-3.5.6.7.8.8a-hexahvdiOquinoxalin- 2( l/f)-one
  • Example 51 (3 V.8a/ ⁇ )-8a-(2-chlorophenyl )-3-(oxetan-3-yl )-3.5.6.7.8.8a-hexahydroquinoxalin-
  • Example 52 (7?)-8a-(2-chloiOphenvO-3.3-dimethyl-3.5.6.7.8.8a-hexahvdiOquinoxalin-2( liTVone
  • Example 54 (8ai?)-8a-(2-chlorophenvn-3-fluoro-3-(2-(methylamino)ethvn-3.5.6.7.8.8a- hexahydroquinoxalin-2( liTVone
  • Example _ 56 _ (2-chloiOphenvO-3-(pyridin-2-ylmet:hvO-3.5.6.7.8.8a-
  • Example 58 (/ ⁇ )-8a-(2-chlorophenyl )-3.3-difluoro-3.5.6.7.8.8a-hexahydroquinoxalin- -one
  • Chemical entities of the present invention are useful in methods (or in the manufacture of a medicament for use in such methods) of treating a disorder by administering to a subject in need thereof an effective amount of the chemical entity.
  • the chemical entities are also useful in methods (or in the manufacture of a medicament for use in such methods) of enhancing cognitive function by administering to a subject in need thereof an effective amount of the chemical entity.
  • One embodiment the present invention provides a method of treating a subject suffering from or diagnosed with a disorder, comprising administering to a subject in need of such treatment an effective amount of at least one chemical entity of the present invention.
  • Chemical entities of the present invention are also useful in enhancing neuronal plasticity - an essential property of the brain that can be augmented in healthy animals and impaired in numerous central nervous system (CNS) disorders. Without being limited by mechanism, such chemical entities can enhance long-term potentiation (LTP). Since its discovery in 1973, LTP has been considered the cellular substrate of learning and memory (Nicoll, 2017). LTP and long-term depression (LTD) are forms of synaptic plasticity which are highly regulated by activity-dependent changes in the ratio of N-methyl-D-a$partate (NMD A) subunits, specifically N-methyl-D-aspanate receptor subtype A (NR2A) and N-methyi-D- aspartate receptor subtype B (NR2B) subunits.
  • NMD A N-methyl-D-a$partate receptor subtype A
  • NR2A N-methyl-D-aspanate receptor subtype A
  • NR2B N-methyi-D- aspartate receptor subtype B
  • NMDA receptors gate the influx of calcium ions across the post-synaptic membrane.
  • This calcium influx activates calcium-dependent enzymes such as calmodulin-dependent protein kinase 11 (CaMKlI), which triggers its autophosphorylation at Thr286.
  • CaMKlI calmodulin-dependent protein kinase 11
  • This autophosphory 1 ation is very important as it al loves the enzyme to remain active once the calcium levels return to normal.
  • This pathway requires interplay between the NMDA receptor, CaMKII and a post-synaptic scaffolding protein (PSD-95 in particular) which brings these biochemical elements into proximity .
  • Thr2S6 autophosphorylation is instrumental in promoting the association of CaMKI I with the PSD by directly binding to the NMDA receptor.
  • Thr3G5/306 a secondary inhibitory autophosphorylation at Thr3G5/306 that has been suggested to regulate the association of CaMKII to the PSD. Interplay between these states can govern the availability of CaMKII to regulate synaptic plasticity in response to calcium influx during learning and memory ' activity.
  • the present invention provides a method of enhancing neuronal plasticity, comprising administering to a subject in need thereof an effective amount of a chemical entity of the present invention.
  • Chemical entities of the present invention are also useful as“agents” (also referred to as“augmenting agents”) to augment the efficiency of training protocols, which facilitate functional reorganization in targeted“domains” (or“functions”) in the brain.
  • Training protocols can be directed to rehabilitating or enhancing a cognitive or motor function.
  • the training protocol (cognitive or motor training) induces neuronal activity in specific brain regions and produces improved performance of a specific brain (cognitive or motor) function.
  • Chemical entities of the present invention act as“augmenting agents,” which shorten the time that methods of rehabilitating (or enhancing) a cognitive or motor function result in improved performance or a functional gain.
  • Such augmented training therefore comprises a specific training protocol for a particular brain function, such as that underlying declarative memory, performance of a fine motor skill, a specific locomotor function, language acquisition, executive function, etc., and a general administration of ketamine or ketamine-related compounds given prior to the training event.
  • Ketamine (a racemic mixture of the corresponding S- and R-enantiomers) s an NMDA receptor antagonist, with a wide range of effects in humans, including analgesia, anesthesia, hallucinations, dissociative effects, elevated blood pressure and bronchodi!ation. Ketamine is primarily used for the induction and maintenance of general anesthesia. Other uses include sedation intensive care, analgesia (particularly in emergency medicine) and treatment of hronchospasms. Ketamine has been shown in clinical studies to be effective in the treatment of several conditions, including the of treatment-resistant bipolar depression, major depressive disorder, neuropathic pain, and chronic pain, including complex regional pain syndrome (CRPS).
  • CRPS complex regional pain syndrome
  • ketamine and norketamine are considered to be responsible for the antinociceptive response in CRPS patients.
  • CNS central nervous system
  • ketamine treatment is associated with serious side effects due to the drug's anesthetic and dissociative properties and abuse potential.
  • HNK did not exhibit the addictive properties and locomotor and sensory deficits observed with ketamine, suggesting a more favorable side-effect profile for this metabolite.
  • ketamine metabolite has been shown to be active in animal models of depression.
  • (5)-norketamine exhibited antidepressant effects in both a mouse LPS- induced depression model as well as in a chronic social defeat stress (CSDS) model of depression (Yang et al., 2018).
  • CSDS chronic social defeat stress
  • Y-norketamine had no effect on locomotor activity and did not cause pre-pulse inhibition (PPI) defects in mice, suggesting a greater safety profile as compared to ketamine (Yang et al., 2018).
  • the present disclosure fulfills this need and provides additional advantages set forth herein.
  • Chemical entities of the present invention are useful in methods of treating a neurological disorder, comprising administering to a subject in need thereof an effective amount of a chemical entity of Formula (I).
  • the methods are directed to a cognitive deficit (“cognitive impairment”) or motor deficit (“motor impairment”) associated with (or“due to”) the neurological disorder.
  • a neurological disorder is any disorder of the body's nervous system. Neurological disorders can be categorized according to the primary location affected, the primary type of dysfunction involved, or the primary type of cause. The broadest division is between peripheral nervous system (PNS) disorders and central nervous system (CNS) disorders (such as mental and psychiatric disorders).
  • PNS peripheral nervous system
  • CNS central nervous system
  • Neurological disorders are well-known in the art, and include, but are not limited to, the following mental and psychiatric disorders: Neurodevelopmental (or“developmental” disorders), such as intellectual disability disorders (e.g., Rubinstein-Taybi syndrome, Down syndrome); communication disorders; autism- spectrum disorders; attention-deficit/hyperactivity disorders; specific learning, language, or reading (e.g., dyslexia) disorders; motor disorders; fetal alcohol spectrum disorders (FASD); and other neurodevelopmental disorders;
  • Neurodevelopmental or“developmental” disorders
  • intellectual disability disorders e.g., Rubinstein-Taybi syndrome, Down syndrome
  • communication disorders e.g., autism- spectrum disorders; attention-deficit/hyperactivity disorders; specific learning, language, or reading (e.g., dyslexia) disorders; motor disorders; fetal alcohol spectrum disorders (FASD); and other neurodevelopmental disorders
  • FASD fetal alcohol spectrum disorders
  • Schizophrenia spectrum and other psychotic disorders such as schizophrenia, schizotypal (personality) disorder, delusional disorder, and schizophreniform disorder, and other schizophrenia spectrum and psychotic disorders;
  • Bipolar and related disorders such as Bipolar I and II disorders, cyclothymic disorders, and other bipolar and related disorders;
  • Depressive disorders such as major depressive disorder, persistent depressive disorder (dysthymia), and other depressive disorders;
  • Anxiety disorders such as specific phobia, social anxiety disorder, panic disorder, generalized anxiety disorder (social phobia), posttraumatic stress disorder (PTSD), and other anxiety disorders;
  • Obsessive-compulsive and related disorders such as obsessive-compulsive disorder, body dysmorphic disorder, and other obsessive-compulsive and related disorders;
  • Dissociative disorders such as dissociative identity disorder, dissociative amnesia, and other dissociative disorders;
  • Disruptive, impulse-control, and conduct disorders such as conduct disorders, antisocial personality disorders, and other disruptive, impulse-control, and conduct disorders;
  • Trauma- and stressor-related disorders such as posttraumatic stress disorder, adjustment disorders, and other trauma- and stressor-related disorders;
  • Feeding and eating disorders such as anorexia, bulimia, and binge-eating disorder
  • Sleep-wake disorders such as insomnia, narcolepsy, parasomnias, and other sleep- wake disorders
  • Sexual disorders such as arousal disorders, desire disorders, substance medication- induced dysfunctions, and other sexual disorders;
  • Substance-related and addictive disorders such as those involving alcohol, drugs, stimulants, opioids, tobacco, and non-substance-related disorders; and other substance- related and addictive disorders; and Personality disorders, such as paranoid personality disorders, antisocial and borderline personality disorders, avoidance personality disorders, and other personality disorders; and in particular embodiments, the disorder is schizophrenia or an anxiety disorder.
  • the neurological disorder is an acquired disorder, in which the primary clinical feature is impaired cognition.
  • it is a disorder in which the primary cognitive deficit has not been present since birth or very early life and therefore represents a decline from a previously attained level of functioning.
  • Such disorders which may be referred to herein as“cognitive disorders” or“neurocognitive disorders” include one or more of the following:
  • Delirium such as substance-intoxication (or withdrawal) delirium, medication-induced delirium, and other forms of delirium;
  • Dementias and other cognitive impairments due to HIV infection or due to neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Lewy body disease, Pick’s disease, a prion disease (e.g., Creutzfeldt- Jakob disease), Amyotrophic lateral sclerosis (ALS), multiple sclerosis, frontotemporal lobar degeneration, and corticobasal degeneration; dementia due to a vascular disease (“vascular disease”); and other dementias and neurodegenerative diseases;
  • Age-associated cognitive deficits including age-associated memory impairment (AAMI), also referred to as age-related memory impairment (AMI)
  • AMDI age-related memory impairment
  • MCI Mild Cognitive Impairment
  • Trauma-dependent losses of cognitive function such as vascular diseases due to stroke (e.g., ischemic or hemorrhagic stroke) or ischemia; microvascular disease arising from diabetes or arthrosclerosis; traumatic brain injury (TBI), such as brain trauma, including subdural hematoma and brain tumor; head trauma (closed and penetrating); head injury; tumors, such as nervous system cancers, including cerebral tumors affecting the thalamic or temporal lobe; hypoxia, and viral infection (e.g., encephalitis); excitotoxicity; and seizures; and
  • Cognitive impairments due to chemotherapy such as post-chemotherapy cognitive impairments (PCCI); chemotherapy-induced cognitive dysfunction or impairments; chemo brain; or chemo fog.
  • PCCI post-chemotherapy cognitive impairments
  • Such acquired disorders are not necessarily limited to cognitive impairments.
  • trauma related disorders such as stroke, traumatic brain injury, head trauma, and head injury, may also include impairments in other neurological functions, such as impairments in motor functions.
  • Neurodevelopment disorders “Neurodevelopment disorders,”“Schizophrenia spectrum and other psychotic disorders,” Bipolar and related disorders,”“Depressive disorders,”“Anxiety disorders,” “Obsessive-compulsive and related disorders,” “Dissociative disorders,” “Disruptive, impulse-control, and conduct disorders,” “Trauma- and stressor-related disorders,”“Feeding and eating disorders,” “Sleep-wake disorders,”“Sexual disorders,” “Substance-related and addictive disorders,” Personality disorders,” “Delirium,” “Neurocognitive disorders,”“Delirium,”“Dementias,” and“Trauma” includes treatment of those mental disorders as described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5; 5 th ed., 2013, American Psychiatric Association). The skilled artisan will recognize that there are alternative nomenclatures and classification systems for mental disorders, and that these systems evolve with medical and scientific progress. Thus the terms described in this paragraph are intended to include like disorders that are described in other diagnostics (DS
  • the neurological disorder is a movement or motor disorder, a group that includes, but is not limited to: kinesias and akinetic-rigid syndromes, such as Parkinson's disease or corticobasal degeneration; Tourette's syndrome, epilepsy, muscular spasms, and disorders associated with muscular spasticity or weakness; dyskinesias, including tremors, such as rest tremor, postural tremor and intention tremor); chorea, such as that in Huntington's disease; myoclonus (including generalized myoclonus and focal myoclonus); tics (including simple tics, complex tics and symptomatic tics); dystonia; restless leg syndromes; Wilson's Disease; Hallerworden-Spatz disease; basal ganglia disorders; hyperkinetic, hypokinetic, and dyskinetic disorders; movement disorders induced by drugs; and other movement and motor disorders.
  • kinesias and akinetic-rigid syndromes such as Parkinson's disease or corticobasal
  • Psychosis refers to a clinical state characterized by delusions (false beliefs) and/or hallucinations (sensory misperceptions).
  • DSM-IYTR Diagnostic and Statistical manual of Mental Disorders
  • Bipolar disorder also known as manic-depressive illness, is manifested by recurrent episodes of mania/hypomania, depression, or a combination of both (mixed episode). Each of these stages may manifest in psychosis or give rise to a risk for the emergence of psychosis.
  • Schizophrenia is comprised of psychotic manifestations, often depressive elements, and disruption of the basic elements of an individual's personality structure.
  • This syndrome typically lasts over a more protracted period of time than the classic cyclic nature (recurrence) of bipolar disorder.
  • Other psychotic disorders include borderline personality, delusional disorder, brief reactive psychosis, schizoaffective disorder, schizophreniform disorder, psychotic major depression, psychosis due to substance abuse, and psychoses associated with medical conditions e.g., dementia, delirium, etc.
  • Classical antipsychotic agents e.g., haloperidol
  • haloperidol are moderately effective but fail to alleviate many of the associated symptoms, such as mood changes. In fact, such agents can increase a patient's level of depression.
  • Newer "atypical" antipsychotics can be slightly more effective (in schizophrenia or acute mania) but still fail to achieve a full remission (elimination of serious signs and symptoms) within the majority of patients treated.
  • these agents fail to treat core disturbances in depressed mood.
  • antidepressants treat downturns in mood (such as major depression) they must be used with great caution because of their potential for switching a bipolar patient's mood from depression to mania, or inducing a pattern of rapid- cycling mania/hypomania and depression.
  • antidepressants fail to treat the most prominent aspects of the illness.
  • antidepressant drugs are not effective for psychotic symptoms when used alone.
  • clinicians have sometimes found it necessary to try mood-stabilizers such as lithium, valproate or carbamazepine.
  • Olanzapine has also been a popular choice, as it is indicated for schizophrenia, acute mania, and bipolar maintenance. However it is not approved for either general psychosis or depression.
  • Major Depressive Disorder is defined as the presence of one of more major depressive episodes that are not better accounted for psychotic disorder or bipolar disorder.
  • a major depressive episode is characterized by meeting five or more of the following criteria during the same 2 week period which represent a change in functioning and include at least depressed/sad mood or loss of interest and pleasure, indifference or apathy, or irritability and is usually associated with a change in a number of neurovegetative functions, including sleep patterns, appetite and body weight, motor agitation or retardation, fatigue, impairment in concentration and decision making, feelings of shame or guilt, and thoughts of death or dying ( Diagnostic and Statistical Manual of Menial Disorders, 4 th Edition-TR, American Psychiatric Association, 2004; Harrison's Principles of Internal Medicine, 2000).
  • Symptoms of a depressive episode include depressed mood, markedly diminished interest or pleasure in all, or almost all, activities most of the day, 'weight loss 'when not dieting or weight gain, or decrease or increase in appetite nearly every day, insomnia or hypersomnia nearly ever) day, psychomotor agitation or retardation nearly every day. fatigue or loss of energy nearly every day, feelings of worthlessness or excessive or inappropriate guilt nearly every day, diminished ability to think or concentrate, or indecisiveness, nearly every day, recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide. Further, the symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. ⁇ Diagnostic and Statistical Manual of Mental Disorders, 4 th Edition-TR, American Psychiatric Association, 2004)
  • drugs used in the treatment of depression include, but are not limited to imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, tri ipr amine, maprotiline, amoxapine, trazodone, bupropion, chlornipramine, fluoxetine, citaiopram, escitaiopram, sertraline, paroxetine, tianeptine, nefazadone, venlafaxine, desvenlafaxine, duloxetine, reboxetine, rnirtazapine, phenelzine, tranylcypromine, and/or moclobemide.
  • these agents including, but not limited to, serotonin reuptake inhibitors are also used when depression and anxiety co-exist, such as in anxious depression.
  • treatment of treatment-resi stant depression includes augmentation strategies including treatment with pharmacological agents such as, antipsychotics (such as quetiapine, aripiprazole, olanzapine, risperidone, and the like), lithium, carbarn azepine, and triiodothyronine, and the like, adjunctive electroconvulsive therapy, adjunctive transcranial magnetic stimulation, and deep brain stimulation, etc.
  • antipsychotics such as quetiapine, aripiprazole, olanzapine, risperidone, and the like
  • lithium carbarn azepine
  • triiodothyronine and the like
  • adjunctive electroconvulsive therapy such as quetiapine, aripiprazole, olanzapine, risperidone, and the like
  • adjunctive electroconvulsive therapy such as quetiapine, aripiprazole,
  • ketamine has been shown to be efficacious in the treatment of depression (particularly in those who have not responded to other anti-depressant treatment). In patients with major depressive disorders, ketamine has additionally been shown to produce a rapid antidepressant effect, acting within two hours.
  • the S-ketamine enantiomer (or S-(+)-ketamine or esketamine) has higher potency or affinity for the NMDA reception and thus potentially allowing for lower dosages, and is available for medical use under the brand name KETANEST S.
  • Bipolar disorder which is also referred to as manic-depression, is a brain disorder that causes extreme shifts in a person's mood, thought, energy, behavior, and ability to function.
  • the symptoms of bipolar disorder can be are severe, and can result in emotional problems, poor job or school performance, and even suicide.
  • the name“bipolar” comes from the patients' mood swings, which can alternate between the“poles” of mania (highs) and depression (lows). These mood swings can be quite dramatic, from overly“high” and/or irritable to sad and hopeless, and then back again, often with periods of normal mood in between, and severe changes in energy and behavior go along with these changes in mood.
  • Bipolar disorder typically develops in late adolescence or early adulthood. However, some people have their first symptoms during childhood or late in life. This disorder is not always viewed as an illness, and people may suffer for years before proper diagnosis.
  • Bipolar disorder has been separated into two categories, Type I and Type II, and is typically diagnosed following the guidelines in the Diagnostic and Statistical Manual of Mental Disorders (DSM) Fourth Edition, 1994 (American Psychiatric Association, 1400 K Street NW, Suite 1101, Washington, D.C. 20005-2403 USA). The fourth edition of these guidelines, DSM- IV, identifies the diagnostic features of Bipolar I Disorder as follows:
  • Bipolar Disorder fDSM-IY p 350 This disorder is a clinical course that is characterized by the occurrence of one or more Manic Episodes or Mixed Episodes. Often individuals have also had one or more Major Depressive Episodes. Episodes of Substance-Induced Mood Disorder (due to the direct effects of a medication, or other somatic treatments for depression, a drug of abuse, or toxin exposure) or of Mood Disorder Due to a General Medical Condition do not count toward a diagnosis of Bipolar I Disorder. In addition, the episodes are not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform Disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified.
  • This disorder is a clinical course that is characterized by the occurrence of one or more Major Depressive Episodes accompanied by at least one Hypomanic Episode. Hypomanic Episodes should not be confused with the several days of euthymia that may follow remission of a Major Depressive Episode.
  • Episodes of Substance-Induced Mood Disorder due to the direct effects of a medication, or other somatic treatments for depression, a drug of abuse, or toxin exposure
  • Mood Disorder Due to a General Medical Condition do not count toward a diagnosis of Bipolar I Disorder.
  • the episodes are not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform Disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified.
  • Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful). In children and adolescents, the mood can be an irritable mood.
  • the symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism).
  • a substance e.g., a drug of abuse, a medication
  • a general medical condition e.g., hypothyroidism
  • the symptoms are not better accounted for by bereavement, i.e., after the loss of a loved one, the symptoms persist for longer than 2 months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.
  • Decreased need for sleep e.g., feels rested after only 3 hours of sleep.
  • the mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.
  • the symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatments) or a general medical condition (e.g., hyperthyroidism).
  • a substance e.g., a drug of abuse, a medication, or other treatments
  • a general medical condition e.g., hyperthyroidism
  • Manic-like episodes that are clearly caused by somatic antidepressant treatment should not count toward a diagnosis of Bipolar I Disorder.
  • the mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.
  • the symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism).
  • a substance e.g., a drug of abuse, a medication, or other treatment
  • a general medical condition e.g., hyperthyroidism
  • the episode is associated with an unequivocal change in functioning that is uncharacteristic of the person when not symptomatic.
  • the symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism).
  • a substance e.g., a drug of abuse, a medication, or other treatment
  • a general medical condition e.g., hyperthyroidism
  • Hypomanic-like episodes that are clearly caused by somatic antidepressant treatment should not count toward a diagnosis of Bipolar II Disorder.
  • Nociceptive pain is caused by damage to body tissue and usually described as a sharp, aching, or throbbing pain. This kind of pain can be due to benign pathology; or by tumors or cancer cells that are growing larger and crowding other body parts near the cancer site. Nociceptive pain may also be caused by cancer spreading to the bones, muscles, or joints, or that causes the blockage of an organ or blood vessels. Neuropathic pain occurs when there is actual nerve damage. Nerves connect the spinal cord to the rest of the body and allow the brain to communicate with the skin, muscles and internal organs. Nutritional imbalance, alcoholism, toxins, infections or auto-immunity can all damage this pathway and cause pain.
  • Neuropathic pain can also be caused by a cancer tumor pressing on a nerve or a group of nerves. People often describe this pain as a burning or heavy sensation, or numbness along the path of the affected nerve. The two types of pain are not necessarily mutually exclusive. Cancer pain for example can be nociceptive or neuropathic, or both.
  • the capacity to experience pain has a protective role, that is, it warns us of imminent or actual tissue damage and elicits coordinated reflex and behavioral responses to keep such damage to a minimum. If tissue damage is unavoidable, a set of excitability changes in the peripheral and central nervous system establish a profound but reversible pain hypersensitivity in the inflamed and surrounding tissue. This process assists wound repair because any contact with the damaged part is avoided until healing has occurred.
  • persistent pain syndromes offer no biological advantage and cause suffering and distress.
  • Such maladaptive pain typically results from damage to the nervous system— the peripheral nerve, the dorsal root ganglion or dorsal root, or the central nervous system— and is known as neuropathic pain.
  • Such syndromes comprise a complex combination of negative symptoms or sensory deficits, such as partial or complete loss of sensation, and positive symptoms that include dysaethesia, paraesthesia, and pain.
  • neuropathic pain Apart from trigeminal neuralgia, which responds well to carbamazepine, pharmacotherapy for neuropathic pain has been disappointing. Patients with neuropathic pain for example do not respond to non-steroidal anti-inflammatory drugs and resistance or insensitivity to opiates is common. Patients are usually treated empirically with tricyclic or serotonin and norepinephrine uptake inhibitors, antidepressants, and anticonvulsants that all have limited efficacy and undesirable side-effects. Neurosurgical lesions have a negligible role and functional neurosurgery, including dorsal column or brain stimulation, is controversial, although transcutaneous nerve stimulation may provide some relief.
  • Local anaesthetic blocks targeted at trigger points, peripheral nerves, plexi, dorsal roots, and the sympathetic nervous system have useful but short-lived effects; longer lasting blocks by phenol injection or cryotherapy risk irreversible functional impairment and have not been tested in placebo- controlled trials.
  • Chronic epidural administration of drugs such as clonidine, steroids, opioids, or midazolam is invasive, has side-effects, and the efficacy of these drugs has not been adequately assessed.
  • Pathological pain is characterized by extensive modification of the systems involved in pain signal transmission and modulation at the spinal level (primary sensory neurons and the spinal cord) and probably in the brain.
  • Chronic pain particularly of neuropathic origin, may also lead to tissue remodeling (plasticity). This may include, for instance, loss of spinal interneurons, abnormal rearrangement of central afferents of primary sensory neurons and glial cell activation and proliferation.
  • tissue remodeling plasticity
  • Gene-based techniques allow local or even cell-type-specific interventions to be used to correct the abnormal production of some of these proteins, modulate the activity of signal transduction pathways or overproduce various therapeutic secreted proteins. In fact, with these approaches, it may be possible to not‘only’ relieve established ongoing pain but to reverse the pathological situation underlying chronic pain (Meunier and Pohl; Gene Therapy (2009) 16, 476-482).
  • Fibromyalgia syndrome is a complex chronic condition that causes widespread muscular pain and profound fatigue. Other symptoms include impaired memory, depression, impaired concentration, irritable bladder, sleep disturbance, and headaches. This debilitating, chronic affliction affects 10 million Americans and there is no known cure for the disease. Many of the current treatments have only a partial or temporary effect on some of the symptoms.
  • the inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (Levine and Taiwo, 1994, Textbook of Pain, 45-56).
  • Arthritic pain is the most common inflammatory pain.
  • Rheumatoid disease is one of the commonest chronic inflammatory conditions in developed countries and rheumatoid arthritis is a common cause of disability. The exact aetiology of rheumatoid arthritis is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson, 1994, Textbook of Pain, 397-407).
  • Visceral pain is pain associated with the viscera, which encompass the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain.
  • GI gastrointestinal
  • BBD functional bowel disorder
  • IBD inflammatory bowel disease
  • GI disorders include a wide range of disease states that are currently only moderately controlled, including, in respect of FBD, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and, in respect of IBD, Crohn's disease, ileitis and ulcerative colitis, all of which regularly produce visceral pain.
  • Other types of visceral pain include the pain associated with dysmenorrhea, cystitis and pancreatitis and pelvic pain.
  • Pain Treatment There are many ways to treat pain. Treatment varies depending on the cause of pain. The main treatment options are as follows:
  • Tylenol® (Acetaminophen) is used to treat pain. Unlike several other medications for pain, Tylenol does not have anti-inflammatory effects. Often, however, in cases of chronic pain, no inflammation is at the site of the pain, and thus Tylenol may be an appropriate treatment choice. Tylenol is safe when used appropriately, but can be dangerous when used excessively. Also, Tylenol may cause unwanted effects when used with certain other medicaments.
  • Non-Steroidal Anti-Inflammatory Medications NSAIDs: The NSAIDs (such as Ibuprofen®, Motrin®, Aleve®, etc.) are most beneficial in cases of acute pain, or flare-ups in patients with chronic pain. NSAIDs are also excellent at treating inflammatory conditions including tendonitis, bursitis, and arthritis. In general, NSAID use is limited for patients with chronic pain because of concerns about the development to stomach problems. While the newer, so-called COX-2 inhibitors, such as Celebrex®, were designed to avoid this complication, caution should still be used when using these medications for long periods of time.
  • COX-2 inhibitors such as Celebrex®
  • Corticosteroids As with NSAIDs, corticosteroids are powerful anti-inflammatory medications, and best used for acute pain or for flare-ups of a chronic inflammatory problem. Corticosteroids can either be taken orally (such as Medrol®, Prednisone) or injected into the soft tissues or joints (cortisone injections).
  • Corticosteroids can either be taken orally (such as Medrol®, Prednisone) or injected into the soft tissues or joints (cortisone injections).
  • Narcotics should be considered if pain cannot be otherwise controlled. Many narcotics can be dangerous and addicting. While narcotic medications are useful for acute pain, they also have significant side effects. The short-acting types of these medications can lead to overuse and the development of tolerance. Long-acting options have fewer side effects, and better control of chronic pain. Narcotics can become addictive when they are used for lengthy times without gradual reduction in the dose, or if the medications are taken for reasons other than pain.
  • Anti-convulsant medications are the category of medications that work to relieve nerve pain. These medications alter the function of the nerve and the signals that are sent to the brain. The most commonly prescribed anticonvulsant medication for nerve pain is called Neurontin® (Gabapentin). Another option that has more recently emerged, specifically for the treatment of fibromyalgia, is called Lyrica® (Pregabalin).
  • Local Anesthetics Local anesthetics can provide temporary pain relief to an area. When used in the setting of chronic pain, local anesthetics are often applied as a topical patch to the area of pain. Lidoderm comes in a patch that is applied to the skin and decreases the sensitivity of this area.

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  • Engineering & Computer Science (AREA)
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Abstract

L'invention concerne des compositions chimiques de formule (I), de formule (II), et de formule (III) : des dérivés de tels composés, des compositions pharmaceutiques contenant lesdites compositions, des procédés de préparation desdites compositions, et leurs utilisations dans divers procédés, notamment pour le traitement d'un ou de plusieurs troubles, notamment des troubles neurologiques, des troubles psychotiques, des troubles liés à la douleur, la démence, un trouble dépressif majeur, une dépression résistante au traitement, une idéation suicidaire, une déficience cognitive associée à divers troubles neurologiques et d'autres affections et maladies.
PCT/US2019/020105 2018-02-28 2019-02-28 Kétamine et composés apparentés à la kétamine destinés au traitement de troubles neurologiques WO2019169165A1 (fr)

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CN112521357A (zh) * 2020-08-31 2021-03-19 深圳瑞健生物科技有限公司 一种长效低成瘾性hnk衍生物及其制备方法
WO2021145952A1 (fr) * 2020-01-13 2021-07-22 Astromedical Biotechnology, Ltd. Utilisation de kétamine dans le traitement de la cachexie
WO2022041174A1 (fr) * 2020-08-31 2022-03-03 深圳瑞健生物科技有限公司 Dérivé hnk à faible dépendance à action prolongée et son procédé de préparation
US11426367B2 (en) 2018-05-04 2022-08-30 Perception Neuroscience, Inc. Methods of treating substance abuse
US11980595B2 (en) 2018-02-15 2024-05-14 National University Corporation Chiba University Preventive or therapeutic agent and pharmaceutical composition for inflammatory diseases or bone diseases

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11980595B2 (en) 2018-02-15 2024-05-14 National University Corporation Chiba University Preventive or therapeutic agent and pharmaceutical composition for inflammatory diseases or bone diseases
US11426367B2 (en) 2018-05-04 2022-08-30 Perception Neuroscience, Inc. Methods of treating substance abuse
WO2021145952A1 (fr) * 2020-01-13 2021-07-22 Astromedical Biotechnology, Ltd. Utilisation de kétamine dans le traitement de la cachexie
US11400060B2 (en) 2020-01-13 2022-08-02 Astromedical Biotechnology, Ltd. Use of ketamine in the treatment of cachexia
CN112521357A (zh) * 2020-08-31 2021-03-19 深圳瑞健生物科技有限公司 一种长效低成瘾性hnk衍生物及其制备方法
WO2022041174A1 (fr) * 2020-08-31 2022-03-03 深圳瑞健生物科技有限公司 Dérivé hnk à faible dépendance à action prolongée et son procédé de préparation

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