WO2019152685A1 - Spiro-lactame modulateur des récepteurs nmda et leurs procédés d'utilisation - Google Patents

Spiro-lactame modulateur des récepteurs nmda et leurs procédés d'utilisation Download PDF

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WO2019152685A1
WO2019152685A1 PCT/US2019/016107 US2019016107W WO2019152685A1 WO 2019152685 A1 WO2019152685 A1 WO 2019152685A1 US 2019016107 W US2019016107 W US 2019016107W WO 2019152685 A1 WO2019152685 A1 WO 2019152685A1
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group
alkyl
phenyl
compound
optionally substituted
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PCT/US2019/016107
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English (en)
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M. Amin Khan
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Aptinyx Inc.
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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
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • NMDA N-methyl-d-aspartate
  • the NMDA receptor controls the flow of both divalent and monovalent ions into the postsynaptic neural cell through a receptor associated channel (Foster et al,
  • NMDA receptor has been implicated during development in specifying neuronal architecture and synaptic connectivity, and may be involved in experience-dependent synaptic
  • NMDA receptors are also thought to be involved in long term potentiation and central nervous system disorders.
  • the NMDA receptor plays a major role in the synaptic plasticity that underlies many higher cognitive functions, such as memory acquisition, retention and learning, as well as in certain cognitive pathways and in the perception of pain (Collingridge et al. , The NMDA Receptor, Oxford University Press, 1994). In addition, certain properties of NMDA receptors suggest that they may be involved in the information-processing in the brain that underlies consciousness itself.
  • the NMDA receptor has drawn particular interest since it appears to be involved in a broad spectrum of CNS disorders. For instance, during brain ischemia caused by stroke or traumatic injury, excessive amounts of the excitatory amino acid glutamate are released from damaged or oxygen deprived neurons. This excess glutamate binds to the NMDA receptors which opens their ligand-gated ion channels; in turn the calcium influx produces a high level of intracellular calcium which activates a biochemical cascade resulting in protein degradation and cell death. This phenomenon, known as excitotoxicity, is also thought to be responsible for the neurological damage associated with other disorders ranging from hypoglycemia and cardiac arrest to epilepsy.
  • NMDA receptors have also been implicated in certain types of spatial learning.
  • the NMDA receptor is believed to consist of several protein chains embedded in the postsynaptic membrane.
  • the first two types of subunits discovered so far form a large extracellular region, which probably contains most of the allosteric binding sites, several transmembrane regions looped and folded so as to form a pore or channel, which is permeable to Ca ++ , and a carboxyl terminal region.
  • the opening and closing of the channel is regulated by the binding of various ligands to domains (allosteric sites) of the protein residing on the extracellular surface.
  • the binding of the ligands is thought to affect a conformational change in the overall structure of the protein which is ultimately reflected in the channel opening, partially opening, partially closing, or closing.
  • the present disclosure includes compounds that can be NMDA modulators. More specifically, the present disclosure provides a compound represented by Formula I:
  • X is selected from the group consisting of O, S, NR a and CR P R P ;
  • R 1 is -S(0) w -Ci-C 6 alkyl, wherein w is 0, 1 or 2;
  • R 3 is selected from the group consisting of H, -Ci-C 6 alkyl, -C(0)-R 31 , -C(0)-0-R 32 , phenyl, and -CFF-phenyl, wherein Ci-C 6 alkyl is optionally substituted by one, two or three substitutents each independently selected from R s , and each phenyl is optionally substituted by one, two or three substituents each independently selected from R T ;
  • R 6 is independently, for each occurrence, selected from the group consisting of H, -Ci- Q,alkyl, and halogen, wherein C
  • R 31 is selected from the group consisting of H, -Ci-Cealkyl, -C3-C6cycloalkyl, and phenyl, wherein Ci-C 6 alkyl is optionally substituted by one, two or three substitutents each independently selected from R s , and phenyl and C3-C 6 cycloalkyl are optionally substituted by one, two or three substituents each independently selected from R T ;
  • R 32 is selected from the group consisting of -Ci-Cealkyl, -C3-C6cycloalkyl, and phenyl, wherein Ci-C 6 alkyl is optionally substituted by one, two or three substitutents each independently selected from R s , and phenyl and C3-C 6 cycloalkyl are optionally substituted by one, two or three substituents each independently selected from R T ;
  • R s is independently, for each occurrence, selected from the group consisting of - C(0)NR a R b , -NR a R b , hydroxyl, -SH, and halogen;
  • R T is independently, for each occurrence, selected from the group consisting of - C(0)NR a R b , -NR a R b , -Ci_C4alkyl, -Ci-C 4 alkoxy, hydroxyl, and halogen;
  • R a and R b are each independently for each occurrence selected from the group consisting of H, -Ci-C3alkyl, phenyl and -CFU-phenyl; or R a and R b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each Ci- C 3 alkyl and phenyl is optionally substituted by one, two or three substituents each
  • R p is independently, for each occurrence, selected from the group consisting of H, - CCkH, hydroxyl, halogen, -NR a R b , phenyl, -Ci-Cealkoxy, and -Ci-Cealkyl, wherein each phenyl, Ci-Cealkoxy and Ci-Cealkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen and hydroxyl.
  • X is NR a or CR P R P ;
  • R 1 is selected from the group consisting of H, -Ci-Cealkyl, -C(0)-Ci-C 6 alkyl, -C(0)-0- Ci-C 6 alkyl, -Ci-C 6 alkylene-C 3 -C 6 cycloalkyl, and phenyl, wherein Ci-Cealkyl is optionally substituted by one, two or three substitutents each independently selected from R s , and phenyl and C 3 -C 6 cycloalkyl are optionally substituted by one, two or three substituents each independently selected from R T ;
  • R 3 is selected from the group consisting of H, -Ci-Cealkyl, -C(0)-R 31 , -C(0)-0-R 32 , phenyl, and -CFF-phenyl, wherein C
  • R 6 is independently, for each occurrence, selected from the group consisting of H, -Ci- Cealkyl, and halogen, wherein C
  • R 31 is selected from the group consisting of H, -Ci-Cealkyl, -C 3 -C 6 cycloalkyl, and phenyl, wherein C
  • R 32 is selected from the group consisting of -Ci-C 6 alkyl, -C3-C6cycloalkyl, and phenyl, wherein Ci-C 6 alkyl is optionally substituted by one, two or three substitutents each
  • R s independently selected from R s , and phenyl and C3-C 6 cycloalkyl are optionally substituted by one, two or three substituents each independently selected from R T ;
  • R s is independently, for each occurrence, selected from the group consisting of - C(0)NR a R b , -NR a R b , hydroxyl, -SH, and halogen;
  • R T is independently, for each occurrence, selected from the group consisting of - C(0)NR a R b , -NR a R b , -Ci_C 4 alkyl, -Ci-C 4 alkoxy, hydroxyl, and halogen;
  • R a and R b are each independently, for each occurrence, selected from the group consisting of H, -Ci-C3alkyl, phenyl, and -CH2-phenyl; or R a and R b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each Ci- C3alkyl, phenyl, and CFF-phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, Ci-C3alkyl, and halogen; and
  • R p is independently, for each occurrence, selected from the group consisting of H, - C0 2 H, hydroxyl, halogen, -NR a R b , phenyl, -Ci-Cealkoxy, and -Ci-Cealkyl; wherein each phenyl, Ci-Cealkoxy and Ci-Cealkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen and hydroxyl.
  • R 1 is selected from the group consisting of H, -Ci-Cealkyl, -C(0)-Ci-C 6 alkyl, and - C(0)-0-Ci-C 6 alkyl, wherein Ci-C 6 alkyl is optionally substituted by one, two or three substitutents each independently selected from R s ;
  • R 3 is selected from the group consisting of H, -Ci-Cealkyl, and -CFF-phenyl, wherein Ci-C 6 alkyl is optionally substituted by one, two or three substitutents each independently selected from R s , and phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of -C(0)NR a R b , -NR a R b , -Ci-C 4 alkoxy, -Ci_ C 4 alkyl, hydroxyl, and halogen;
  • R 6 is independently, for each occurrence, selected from the group consisting of H, -Ci- C 6 alkyl, and halogen, wherein Ci-C 6 alkyl is optionally substituted by one, two or three substitutents each independently selected from R s ;
  • R s is independently, for each occurrence, selected from the group consisting of -C(0)NR a R b , -NR a R b , hydroxyl, and halogen;
  • R a and R b are each independently, for each occurrence, selected from the group consisting of H, -Ci-C3alkyl, phenyl, and -CH 2 -phenyl; or R a and R b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each - C 3 alkyl, phenyl, and benzyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, Ci-C 3 alkyl, and halogen.
  • compositions comprising a disclosed compound, and a pharmaceutically acceptable excipient.
  • Such compositions can be suitable for administration to a patient orally, parenterally, topically, intravaginally, intrarectally, sublingually, ocularly, transdermally, or nasally.
  • Such methods may comprise administering to a patient a therapeutically effective amount of a disclosed compound, or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof, or a pharmaceutical composition including a disclosed compound, or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof.
  • a method of this disclosure includes treating depression. In some embodiments, a method of this disclosure includes treating schizophrenia. In certain embodiments, a method of this disclosure includes treating Alzheimer’s disease. In various embodiments, a method of this disclosure includes treating attention deficit disorder. In some embodiments, a method of this disclosure includes treating anxiety. In certain embodiments, a method of this disclosure includes treating a migraine. In various embodiments, a method of this disclosure includes treating neuropathic pain. In some embodiments, a method of this disclosure includes treating traumatic brain injury. In certain embodiments, a method of this disclosure includes treating a neurodevelopment disorder related to a synaptic dysfunction. In various embodiments, a method of this disclosure includes treating a cognitive impairment disorder.
  • Such methods may comprise administering to a patient a therapeutically effective amount of a disclosed compound, or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof, or a pharmaceutical composition including a disclosed compound, or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof.
  • This disclosure is generally directed to compounds that are capable of modulating NMDA receptors, for example, NMDA receptor antagonists, agonists, or partial agonists, and compositions and/or methods of using the disclosed compounds.
  • compounds described herein bind to NMDA receptors expressing certain NR2 subtypes.
  • the compounds described herein bind to one NR2 subtype and not another. It is appreciated that disclosed compounds may bind to another protein target and/or another NMDA receptor type. It is appreciated that the disclosed compounds may modulate other protein targets and/or specific NMDA receptor subtype.
  • alkyl refers to a saturated straight-chain or branched hydrocarbon, such as a straight-chain or branched group of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as -Ce alkyl, C 1 -C 4 alkyl, and C 1 -C 3 alkyl, respectively.
  • “Ci- Q, alkyl” refers to a straight-chain or branched saturated hydrocarbon containing 1-6 carbon atoms.
  • Ci-C 6 alkyl group examples include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, ieri-butyl, isopentyl, and neopentyl.
  • “Ci-C 4 alkyl” refers to a straight-chain or branched saturated hydrocarbon containing 1-4 carbon atoms.
  • Examples of a C 1 -C 4 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl and ieri-butyl.
  • Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl- 1 -propyl, 2- methyl-2-propyl, 2-methyl- l-butyl, 3 -methyl- 1 -butyl, 3-methyl-2-butyl, 2,2-dimethyl- l-propyl, 2-methyl- 1 -pentyl, 3-methyl- 1 -pentyl, 4-methyl- 1 -pentyl, 2-methyl-2-pentyl, 3-methyl-2- pentyl, 4-methyl-2-pentyl, 2,2-dimethyl- l-butyl, 3,3-dimethyl-l-butyl, 2-ethyl- l-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl.
  • alkoxy refers to an alkyl group attached to an oxygen atom (alkyl-O-).
  • Alkoxy groups can have 1-6 or 2-6 carbon atoms and are referred to herein as Ci- C 6 alkoxy and C2-C6 alkoxy, respectively.
  • Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, and isopropoxy.
  • alkylene refers to a divalent alkyl group or a diradical of an alkyl group, which is a linking group capable of forming a covalent bond with two other moieties. Accordingly, it should be understood that a“divalent” group is a linking group capable of linking two other moieties.
  • exemplary alkylene groups include -CH2-, -CH2CH2-, - C(CH 3 ) 2 CH 2 -, and -CH 2 C(H)(CH 3 )CH 2 -.
  • cyano refers to the radical -CN.
  • carbocyclic ring refers to a hydrocarbon ring system in which all the ring atoms are carbon.
  • exemplary carbocyclic rings including cycloalkyls and phenyl.
  • cycloalkyl refers to a monocyclic saturated or partially unsaturated hydrocarbon ring system, for example, having 3-6 or 4-6 carbon atoms in its ring system, referred to herein as C 3 -C 6 cycloalkyl or C 4 -C 6 cycloalkyl, respectively.
  • exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, cyclobutyl, and cyclopropyl.
  • halo and“halogen,” as used herein, refer to F, Cl, Br, or I.
  • heteroatom refers to an atom of any element other than carbon or hydrogen and includes, for example, nitrogen (N), oxygen (O), silicon (Si), sulfur (S), phosphorus (P), and selenium (Se).
  • heterocyclic ring is art-recognized and refer to saturated or partially unsaturated 4- to 8-membered ring systems, for example, 3- to 7- or 3- to 6- membered ring systems, whose ring system include one, two or three heteroatoms, such as nitrogen, oxygen, and/or sulfur.
  • a heterocyclic ring can be fused to one or more phenyl, partially unsaturated, or saturated rings. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl.
  • amino acid includes any one of the following alpha amino acids: isoleucine, alanine, leucine, asparagine, lysine, aspartate, methionine, cysteine, phenylalanine, glutamate, threonine, glutamine, tryptophan, glycine, valine, proline, arginine, serine, histidine, and tyrosine.
  • An amino acid also can include other art-recognized amino acids such as beta amino acids.
  • compound refers to the compound itself and its pharmaceutically acceptable salts, hydrates, and N-oxides including its various stereoisomers and its isotopically-labelled forms, unless otherwise understood from the context of the description or expressly limited to one particular form of the compound, i.e., the compound itself, a specific stereoisomer and/or isotopically-labelled compound, or a pharmaceutically acceptable salt, a hydrate, or an N-oxide thereof. It should be understood that a compound can refer to a pharmaceutically acceptable salt, or a hydrate, or an N-oxide of a stereoisomer of the compound and/or an isotopically-labelled compound.
  • moiety refers to a portion of a compound or molecule.
  • the compounds of the disclosure can contain one or more chiral centers and/or double bonds and therefore, can exist as stereoisomers, such as geometric isomers, and enantiomers or diastereomers.
  • stereoisomers when used herein, consists of all geometric isomers, enantiomers and/or diastereomers of the compound.
  • the compound depicted without such chirality at that and other chiral centers of the compound are within the scope of the present disclosure, i.e., the compound depicted in two-dimensions with“flat” or“straight” bonds rather than in three dimensions, for example, with solid or dashed wedge bonds.
  • Stereospecific compounds may be designated by the symbols“R” or“S,” depending on the configuration of substituents around the stereogenic carbon atom.
  • the present disclosure encompasses all the various stereoisomers of these compounds and mixtures thereof.
  • Mixtures of enantiomers or diastereomers can be designated“( ⁇ )” in nomenclature, but a skilled artisan will recognize that a structure can denote a chiral center implicitly. It is understood that graphical depictions of chemical structures, e.g., generic chemical structures, encompass all stereoisomeric forms of the specified compounds, unless indicated otherwise.
  • Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns, or (4) kinetic resolution using stereoselective chemical or enzymatic reagents.
  • Racemic mixtures also can be resolved into their component enantiomers by well-known methods, such as chiral-phase gas chromatography or crystallizing the compound in a chiral solvent.
  • Stereoselective syntheses a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art.
  • Stereoselective syntheses encompass both enantio- and diastereoselective transformations.
  • Geometric isomers resulting from the arrangement of substituents around a carbon- carbon double bond or arrangement of substituents around a cycloalkyl or heterocyclic ring, can also exist in the compounds of the present disclosure.
  • the symbol . denotes a bond that may be a single, double or triple bond as described herein.
  • Substituents around a carbon- carbon double bond are designated as being in the“Z’ or“£” configuration, where the terms “Z’ and“E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the“E” and“Z” isomers.
  • Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or“trans,” where“cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
  • the arrangement of substituents around a carbocyclic ring can also be designated as“cis” or“trans.”
  • the term “cis” represents substituents on the same side of the plane of the ring and the term“trans” represents substituents on opposite sides of the plane of the ring.
  • Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated“cis/trans.”
  • the disclosure also embraces isotopically-labeled compounds which are identical to those compounds recited herein, except 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 can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H (“D”), 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • a compound described herein can have one or more H atoms replaced with deuterium.
  • Certain isotopically-labeled compounds can be useful in compound and/or substrate tissue distribution assays. Tritiated (/. ⁇ ? ., 3 H) and carbon- 14 (/. ⁇ ? ., 14 C) isotopes can be particularly preferred for their ease of preparation and
  • Isotopically-labeled compounds can generally be prepared by following procedures analogous to those disclosed herein, for example, in the Examples section, by substituting an isotopically- labeled reagent for a non-isotopically-labeled reagent.
  • phrases“pharmaceutically acceptable” and“pharmacologically acceptable,” as used herein, refer to compounds, molecular entities, compositions, materials, and/or dosage forms that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate.
  • preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologies standards.
  • phrases“pharmaceutically acceptable carrier” and“pharmaceutically acceptable excipient,” as used herein, refer to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical
  • compositions can include phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents.
  • emulsions e.g., such as an oil/water or water/oil emulsions
  • the compositions also can include stabilizers and preservatives.
  • composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • the pharmaceutical compositions can also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • the compounds described in the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, for example, domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • the mammal treated in the methods described in the disclosure is preferably a mammal in which treatment, for example, of pain or depression, is desired.
  • treating includes any effect, for example, lessening, reducing, modulating, ameliorating, or eliminating, that results in the improvement of the condition, disease, disorder, and the like, including one or more symptoms thereof. Treating can be curing, improving, or at least partially ameliorating the disorder.
  • disorder refers to and is used interchangeably with, the terms“disease,” “condition,” or“illness,” unless otherwise indicated.
  • modulation refers to and includes antagonism (e.g., inhibition), agonism, partial antagonism, and/or partial agonism.
  • therapeutically effective amount refers to the amount of a compound (e.g., a disclosed compound) that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the compounds described in the disclosure can be administered in therapeutically effective amounts to treat a disease.
  • a therapeutically effective amount of a compound can be the quantity required to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in lessening of a symptom of a disease such as depression.
  • salt refers to any salt of an acidic or a basic group that may be present in a compound of the present disclosure, which salt is compatible with pharmaceutical administration ⁇
  • salts of the compounds of the present disclosure may be derived from inorganic or organic acids and bases.
  • salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate,
  • flucoheptanoate glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy ethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like.
  • salts include anions of the compounds of the present disclosure compounded with a suitable cation such as Na + , NH 4 + , and NW 4 + (where W can be a Ci_ 4 alkyl group), and the like.
  • a suitable cation such as Na + , NH 4 + , and NW 4 + (where W can be a Ci_ 4 alkyl group), and the like.
  • salts of the compounds of the present disclosure can be pharmaceutically acceptable.
  • salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a
  • compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesul I
  • compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • compositions that include a basic or acidic moiety can also form pharmaceutically acceptable salts with various amino acids.
  • the compounds of the disclosure can contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.
  • the compounds disclosed herein can exist in a solvated form as well as an unsolvated form with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms.
  • compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present disclosure that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present disclosure that consist essentially of, or consist of, the recited processing steps.
  • an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.
  • compositions of the present disclosure and/or in methods of the present disclosure, unless otherwise understood from the context.
  • embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments can be variously combined or separated without parting from the present teachings and disclosure(s).
  • all features described and depicted herein can be applicable to all aspects of the disclosure(s) described and depicted herein.
  • the term“about” refers to a ⁇ 10% variation from the nominal value unless otherwise indicated or inferred from the context.
  • molecular weight is provided and not an absolute value, for example, of a polymer, then the molecular weight should be understood to be an average molecule weight, unless otherwise stated or understood from the context.
  • substituents are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges.
  • the term“Ci -6 alkyl” is specifically intended to individually disclose Ci, C 2 , C 3 , C 4 , C 5 , C 6 , Ci-C 6 , C 1 -C 5 , C 1 -C 4 , Ci- C 3 , Ci-C 2 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 alkyl.
  • an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,
  • variable is defined as found elsewhere in the disclosure unless understood to be different from the context.
  • definition of each variable, substituent, substitution, expression and the like, for example, C i -C 6 alkyl, R 2 , R b , w and the like, when it occurs more than once in any structure or compound, is intended to be independent of its definition elsewhere in the same structure or compound.
  • Disclosed compounds include a compound represented by Formula I:
  • X is selected from the group consisting of O, S, NR a and CR P R P ;
  • R 1 is -S(0) w -Ci-C 6 alkyl, wherein w is 0, 1 or 2;
  • R 3 is selected from the group consisting of H, -Ci-C 6 alkyl, -C(0)-R 31 , -C(0)-0-R 32 , phenyl, and -CFF-phenyl, wherein Ci-C 6 alkyl is optionally substituted by one, two or three substitutents each independently selected from R s , and each phenyl is optionally substituted by one, two or three substituents each independently selected from R T ;
  • R 6 is independently, for each occurrence, selected from the group consisting of H, -Ci- C 6 alkyl, and halogen, wherein Ci-C 6 alkyl is optionally substituted by one, two or three substitutents each independently selected from R s ;
  • R 31 is selected from the group consisting of H, -Ci-C 6 alkyl, -C3-C6cycloalkyl, and phenyl, wherein Ci-C 6 alkyl is optionally substituted by one, two or three substitutents each independently selected from R s , and phenyl and C3-C 6 cycloalkyl are optionally substituted by one, two or three substituents each independently selected from R T ;
  • R 32 is selected from the group consisting of -Ci-Cealkyl, -C3-C6cycloalkyl, and phenyl, wherein Ci-C 6 alkyl is optionally substituted by one, two or three substitutents each independently selected from R s , and phenyl and C3-C 6 cycloalkyl are optionally substituted by one, two or three substituents each independently selected from R T ;
  • R s is independently, for each occurrence, selected from the group consisting of - C(0)NR a R b , -NR a R b , hydroxyl, -SH, and halogen;
  • R T is independently, for each occurrence, selected from the group consisting of - C(0)NR a R b , -NR a R b , -Ci_C4alkyl, -Ci-C 4 alkoxy, hydroxyl, and halogen;
  • R a and R b are each independently for each occurrence selected from the group consisting of H, -Ci-C3alkyl, phenyl and -CH2-phenyl; or R a and R b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each Ci- C3alkyl and phenyl is optionally substituted by one, two or three substituents each
  • R p is independently, for each occurrence, selected from the group consisting of H, - CCkH, hydroxyl, halogen, -NR a R b , phenyl, -Ci-Cealkoxy, and -Ci-Cealkyl; wherein each phenyl, Ci-Cealkoxy and Ci-Cealkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen and hydroxyl.
  • X can be O or S. In certain embodiments, X can be O.
  • w is 2.
  • R 1 can be -S(0) w -Ci-C 3 alkyl.
  • R 1 can be -S(0) 2 -Ci-C 3 alkyl.
  • R 1 can be - S(0) 2 -CH 3 .
  • R 3 can be H. In some embodiments, R 3 can be -Ci-C 6 alkyl, wherein -Q, alkyl can be optionally substituted by one, two or three substituents each independently selected from the group consisting of -C(0)NR a R b , -NR a R b , hydroxyl, -SH, and halogen. In various embodiments, R 3 can be selected from the group consisting of methyl, ethyl, and isobutyl. In some embodiments, R 3 can be methyl, optionally substituted by - C(0)NR a R b . For example, R 3 can be -CH 2 C(0)NH 2 , -CH 2 C(0)NHCH 3 , or -
  • R 3 can be ethyl, optionally substituted by - C(0)NR a R b , such as -C(0)NH 2 , -C(0)NHCH 3 , or -C(0)N(CH 3 ) 2 , and/or hydroxyl.
  • R 3 can be selected from the group consisting of:
  • R a and R b can be each independently, for each occurrence, selected from the group consisting of H and -Ci-C 6 alkyl, for example, methyl or ethyl such that the moieties containing these variables can be -C(0)NH 2 , -C(0)NHCH 3 , -C(0)(CH 3 ) 2 , -C(0)NHCH 2 CH 3 , or - C(0)(CH 2 CH 3 ) 2 .
  • R 3 can be any organic compound
  • R 66 is independently, for each occurrence, -Ci-C 4 alkoxy; and n is 1, 2, or 3. In certain embodiments, n is 1. In various embodiments, n is 2. In particular embodiments, n is 3. In some embodiments, R 66 is, for each occurrence, methoxy.
  • R a and R b can be H. In certain embodiments, one of R a and R b can be H, and the other of R a and R b can be -Ci-C 4 alkyl, for example, methyl or ethyl. In particular embodiments, each of R a and R b can be -Ci-C 4 alkyl, for example, methyl or ethyl.
  • R 6 can be independently, for each occurrence, selected from the group consisting of H and halogen. In some embodiments, one R 6 can be H and the other R 6 can be a halogen. In certain embodiments, each R 6 can be a halogen. In particular embodiments, the halogen is fluoro (F).
  • X is NR a or CR P R P ;
  • R 1 is selected from the group consisting of H, -Ci-C 6 alkyl, -C(0)-Ci-C 6 alkyl, -C(0)-0- Ci-Cealkyl, -Ci-C6alkylene-C3-C6cycloalkyl, and phenyl, wherein Ci-C 6 alkyl is optionally substituted by one, two or three substitutents each independently selected from R s , and phenyl and C3-C 6 cycloalkyl are optionally substituted by one, two or three substituents each independently selected from R T ;
  • R 3 is selected from the group consisting of H, -Ci-Cealkyl, -C(0)-R 31 , -C(0)-0-R 32 , phenyl, and -CFF-phenyl, wherein Ci-C 6 alkyl is optionally substituted by one, two or three substitutents each independently selected from R s , and each phenyl is optionally substituted by one, two or three substituents each independently selected from R T ;
  • R 6 is independently, for each occurrence, selected from the group consisting of H, -Ci- Q,alkyl, and halogen, wherein C
  • R 31 is selected from the group consisting of H, -Ci-Cealkyl, -C3-C6cycloalkyl, and phenyl, wherein Ci-C 6 alkyl is optionally substituted by one, two or three substitutents each independently selected from R s , and phenyl and C3-C 6 cycloalkyl are optionally substituted by one, two or three substituents each independently selected from R T ;
  • R 32 is selected from the group consisting of -Ci-Cealkyl, -C3-C6cycloalkyl, and phenyl, wherein Ci-C 6 alkyl is optionally substituted by one, two or three substitutents each independently selected from R s , and phenyl and C3-C 6 cycloalkyl are optionally substituted by one, two or three substituents each independently selected from R T ;
  • R s is independently, for each occurrence, selected from the group consisting of - C(0)NR a R b , -NR a R b , hydroxyl, -SH, and halogen;
  • R T is independently, for each occurrence, selected from the group consisting of - C(0)NR a R b , -NR a R b , -Ci_C4alkyl, -Ci-C 4 alkoxy, hydroxyl, and halogen;
  • R a and R b are each independently, for each occurrence, selected from the group consisting of H, -Ci-C ⁇ alkyl, phenyl, and -CH2-phenyl; or R a and R b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each Ci- alkyl, phenyl, and CH2-phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, Ci-C ⁇ alkyl, and halogen; and
  • R p is independently, for each occurrence, selected from the group consisting of H, - CO2H, hydroxyl, halogen, -NR a R b , phenyl, -Ci_C 6 alkoxy, and -Ci_C 6 alkyl; wherein each phenyl, Ci_C 6 alkoxy and Ci_C 6 alkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen and hydroxyl.
  • X is NR a , where R a is selected from the group consisting of H and -Ci-Csalkyl. In some embodiments, X is NH. In certain embodiments, X is CR P R P , where RP is independently, for each occurrence, selected from the group consisting of H and -Ci- Cealkyl. In particular embodiments, X is CH2.
  • R 1 can be H. In some embodiments, R 1 can be -Ci-C 6 alkyl, optionally substituted by one, two or three substitutents each independently selected from the group consisting of -C(0)NR a R b , -NR a R b , hydroxyl, -SH, and halogen. In certain embodiments, R 1 can be H. In some embodiments, R 1 can be -Ci-C 6 alkyl, optionally substituted by one, two or three substitutents each independently selected from the group consisting of -C(0)NR a R b , -NR a R b , hydroxyl, -SH, and halogen. In certain embodiments, R 1 can be H. In some embodiments, R 1 can be -Ci-C 6 alkyl, optionally substituted by one, two or three substitutents each independently selected from the group consisting of -C(0)NR a R b , -NR a R b , hydroxyl,
  • R 1 can be selected from the group consisting of methyl, ethyl, and isobutyl.
  • R 3 can be H. In some embodiments, R 3 can be -Ci-C 6 alkyl, wherein Ci-C 6 alkyl can be optionally substituted by one, two or three substituents each independently selected from -C(0)NR a R b , -NR a R b , hydroxyl, -SH, and halogen. In various embodiments, R 3 can be selected from the group consisting of methyl, ethyl, and isobutyl. In some embodiments, R 3 can be methyl, optionally substituted by -C(0)NR a R b .
  • R 3 can be -CH 2 C(0)NH 2 , -CH 2 C(0)NHCH 3 , or -CH 2 C(0)(CH 3 ) 2 .
  • R 3 can be ethyl, optionally substituted by -C(0)NR a R b and/or hydroxyl.
  • R 3 can be selected from the group consisting of:
  • R a and R b can be each independently, for each occurrence, selected from the group consisting of H and -Ci-C 6 alkyl, for example, methyl or ethyl such that the moieties containing these variables can be -C(0)NH 2 , -C(0)NHCH 3 , -C(0)(CH 3 ) 2 , -C(0)NHCH 2 CH 3 , or - C(0)(CH 2 CH 3 ) 2 .
  • R 3 can be any organic compound
  • R 66 is independently, for each occurrence, -Ci-C 4 alkoxy; and n is 1, 2, or 3. In certain embodiments, n is 1. In various embodiments, n is 2. In particular embodiments, n is 3. In some embodiments, R 66 is, for each occurrence, methoxy.
  • R a and R b can be H. In certain embodiments, one of R a and R b can be H, and the other of R a and R b can be -Ci-C 4 alkyl, for example, methyl or ethyl. In particular embodiments, each of R a and R b can be -Ci-C 4 alkyl, for example, methyl or ethyl.
  • R 6 can be independently, for each occurrence, selected from the group consisting of H and halogen. In some embodiments, one R 6 can be H and the other R 6 can be a halogen. In certain embodiments, each R 6 can be a halogen. In particular embodiments, the halogen is fluoro (F).
  • R 1 is selected from the group consisting of H, -Ci-Cealkyl, -C(0)-Ci-C 6 alkyl, and - C(0)-0-Ci-C 6 alkyl, wherein Ci-C 6 alkyl is optionally substituted by one, two or three substitutents each independently selected from R s ;
  • R 3 is selected from the group consisting of H, -Ci-C 6 alkyl, and -CH 2 -phenyl, wherein Ci-C 6 alkyl is optionally substituted by one, two or three substitutents each independently selected from R s , and phenyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of -C(0)NR a R b , -NR a R b , -Ci-C 4 alkoxy, -Ci_ C 4 alkyl, hydroxyl, and halogen;
  • R 6 is independently, for each occurrence, selected from the group consisting of H, -Ci- C 6 alkyl, and halogen, wherein Ci-C 6 alkyl is optionally substituted by one, two or three substitutents each independently selected from R s ;
  • R s is independently, for each occurrence, selected from the group consisting of -C(0)NR a R b , -NR a R b , hydroxyl, and halogen;
  • R a and R b are each independently, for each occurrence, selected from the group consisting of H, -Ci-C 3 alkyl, phenyl, and -CH2-phenyl; or R a and R b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein each Ci- C 3 alkyl, phenyl, and benzyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, Ci-C 3 alkyl, and halogen.
  • R 1 can be H. In some embodiments, R 1 can be -Ci-C 6 alkyl optionally substituted by one, two or three substitutents each independently selected from the group consisting of -C(0)NR a R b , -NR a R b , hydroxyl, -SH, and halogen. In certain embodiments, R 1 can be H. In some embodiments, R 1 can be -Ci-C 6 alkyl optionally substituted by one, two or three substitutents each independently selected from the group consisting of -C(0)NR a R b , -NR a R b , hydroxyl, -SH, and halogen. In certain embodiments, R 1 can be H. In some embodiments, R 1 can be -Ci-C 6 alkyl optionally substituted by one, two or three substitutents each independently selected from the group consisting of -C(0)NR a R b , -NR a R b , hydroxyl, -SH,
  • R 1 can be selected from the group consisting of methyl, ethyl, and isobutyl.
  • R 3 can be H. In some embodiments, R 3 can be -Ci-C 6 alkyl, wherein Ci-C 6 alkyl can be optionally substituted by one, two or three substituents each independently selected from -C(0)NR a R b , -NR a R b , hydroxyl, -SH, and halogen. In various embodiments, R 3 can be selected from the group consisting of methyl, ethyl, and isobutyl. In some embodiments, R 3 can be methyl, optionally substituted by -C(0)NR a R b .
  • R 3 can be -CH 2 C(0)NH 2 , -CH 2 C(0)NHCH 3 , or -CH 2 C(0)(CH 3 ) 2 .
  • R 3 can be ethyl, optionally substituted by -C(0)NR a R b and/or hydroxyl.
  • R 3 can be selected from the group consisting of:
  • R a and R b can be each independently, for each occurrence, selected from the group consisting of H and -Ci-C 6 alkyl, for example, methyl or ethyl such that the moieties containing these variables can be -C(0)NH 2 , -C(0)NHCH 3 , -C(0)(CH 3 ) 2 , -C(0)NHCH 2 CH 3 , or - C(0)(CH 2 CH 3 ) 2 .
  • R 3 can be any organic compound
  • R 66 is independently, for each occurrence, -Ci-C 4 alkoxy; and n is 1, 2, or 3. In certain embodiments, n is 1. In various embodiments, n is 2. In particular embodiments, n is 3. In some embodiments, R 66 is, for each occurrence, methoxy.
  • R a and R b can be H. In certain embodiments, one of R a and R b can be H, and the other of R a and R b can be -Ci-C 4 alkyl, for example, methyl or ethyl. In particular embodiments, each of R a and R b can be -Ci-C 4 alkyl, for example, methyl or ethyl.
  • R 6 can be independently, for each occurrence, selected from the group consisting of H and halogen. In some embodiments, one R 6 can be H and the other R 6 can be a halogen. In certain embodiments, each R 6 can be a halogen. In particular embodiments, the halogen is fluoro (F).
  • R 1 and/or R 3 independently can be an amino acid or a derivative of an amino acid, for example, an alpha “amino amide” represented by H 2 N-CH(amino acid side chain)-C(0)NH 2 .
  • the nitrogen atom of the amino group of the amino acid or the amino acid derivative is a ring nitrogen in a chemical formula described herein.
  • the carboxylic acid of the amino acid or the amide group of an amino amide (amino acid derivative) is not within the ring structure, i.e., not a ring atom.
  • the carboxylic acid group of the amino acid or the amino acid derivative forms an amide bond with a ring nitrogen in a chemical formula disclosed herein, thereby providing an amino amide, where the amino group of the amino amide is not within the ring structure, i.e., not a ring atom.
  • R 1 and/or R 3 independently can be an alpha amino acid, an alpha amino acid derivative, and/or another amino acid or amino acid derivative such as a beta amino acid or a beta amino acid derivative, for example, a beta amino amide.
  • a disclosed compound is selected from the Examples described herein, for example, Examples AA to EN and/or depicted in Table 1, and includes
  • a disclosed compound is selected from the group consisting of:
  • the present disclosure also includes a compound having the formula:
  • the compounds of the present disclosure and formulations thereof may have a plurality of chiral centers.
  • Each chiral center may be independently R, S, or any mixture of R and S.
  • a chiral center may have an R:S ratio of between about 100:0 and about 50:50 (“racemate”), between about 100:0 and about 75:25, between about 100:0 and about 85:15, between about 100:0 and about 90:10, between about 100:0 and about 95:5, between about 100:0 and about 98:2, between about 100:0 and about 99:1, between about 0:100 and 50:50, between about 0: 100 and about 25:75, between about 0:100 and about 15:85, between about 0:100 and about 10:90, between about 0:100 and about 5:95, between about 0:100 and about 2:98, between about 0:100 and about 1:99, between about 75:25 and 25:75, and about 50:50.
  • Formulations of the disclosed compounds comprising a greater ratio of one or more isomers may possess enhanced therapeutic characteristic relative to racemic formulations of a disclosed compounds or mixture of compounds.
  • chemical formulas contain the descriptor“-(R)-“ or“-(S)-“ that is further attached to solid wedge or dashed wedge. This descriptor is intended to show a methine carbon (CH) that is attached to three other substituents and has either the indicated R or S configuration.
  • Disclosed compounds may provide for efficient cation channel opening at the NMDA receptor, e.g. may bind or associate with the glutamate site or glycine site or other modulatory site of the NMDA receptor to assist in opening the cation channel.
  • the disclosed compounds may be used to regulate (turn on or turn off) the NMDA receptor through action as an agonist or antagonist.
  • a disclosed compound may bind to a specific NMDA receptor subtypes.
  • a disclosed compound may bind to one NMDA subtype and not another.
  • a disclosed compound may bind to one, or more than one NMDA subtype, and/or may have substantially less (or substantial no) binding activity to certain other NMDA subtypes.
  • a disclosed compound e.g., compound A
  • a disclosed compound binds to NR2A with substantially no binding to NR2D.
  • a disclosed compound binds to NR2B and NR2D with substantially lower binding to NR2A and NR2C.
  • the compounds as described herein may bind to NMDA receptors.
  • a disclosed compound may bind to the NMDA receptor resulting in agonist- like activity (facilitation) over a certain dosing range and/or may bind to the NMDA receptor resulting in antagonist- like activity (inhibition) over a certain dosing range.
  • a disclosed compound may possess a potency that is lO-fold or greater than the activity of existing NMDA receptor modulators.
  • the disclosed compounds may exhibit a high therapeutic index.
  • a disclosed compound may have a therapeutic index of at least about 10:1, at least about 50:1, at least about 100:1, at least about 200:1, at least about 500:1, or at least about 1000:1.
  • a pharmaceutical formulation or a pharmaceutical composition including a disclosed compound and a pharmaceutically acceptable excipient is provided.
  • a pharmaceutical composition comprises a racemic mixture of one or more of the disclosed compounds.
  • a formulation can be prepared in any of a variety of forms for use such as for administering an active agent to a patient, who may be in need thereof, as are known in the pharmaceutical arts.
  • the pharmaceutical compositions of the present disclosure can be formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets (e.g., those targeted for buccal, sublingual, and/or systemic absorption), boluses, powders, granules, and pastes for application to the tongue; (2) parenteral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets (e.g., those targeted for buccal, sublingual, and/or systemic absorption), boluses, powders, granules, and pastes for application to the tongue; (2) parenteral
  • administration by, for example, subcutaneous, intramuscular, intraperitoneal, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical administration, for example, as a cream, ointment, or a controlled- release patch or spray applied to the skin; (4) intravaginal or intrarectal administration, for example, as a pessary, cream or foam; (5) sublingual administration; (6) ocular administration; (7) transdermal administration; or (8) nasal administration.
  • compositions of the disclosure can be suitable for delivery to the eye, i.e., ocularly.
  • Related methods can include administering a therapeutically effective amount of a disclosed compound or a pharmaceutical composition including a disclosed compound to a patient in need thereof, for example, to an eye of the patient, where
  • administering can be topically, subconjunctivally, subtenonly, intravitreally, retrobulbarly, peribulbarly, intracomerally, and/or systemically.
  • Amounts of a disclosed compound as described herein in a formulation may vary according to factors such as the disease state, age, sex, and weight of the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form as used herein 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.
  • compositions typically must be sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin.
  • the compounds can be administered in a time release formulation, for example in a composition which includes a slow release polymer.
  • the compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, poly anhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG). Many methods for the preparation of such formulations are generally known to those skilled in the art.
  • Sterile injectable solutions can be prepared by incorporating the compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • a compound can be formulated with one or more additional compounds that enhance the solubility of the compound.
  • Methods of this disclosure for treating a condition in a patient in need thereof generally include administering a therapeutically effective amount of a compound described herein or a composition including such a compound.
  • the condition may be a mental condition.
  • a mental illness may be treated.
  • a nervous system condition may be treated.
  • a condition that affects the central nervous system, the peripheral nervous system, and/or the eye may be treated.
  • neurodegenerative diseases may be treated.
  • the methods include administering a compound to treat patients suffering from autism, anxiety, depression, bipolar disorder, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, a psychotic disorder, a psychotic symptom, social withdrawal, obsessive-compulsive disorder (OCD), phobia, post-traumatic stress syndrome, a behavior disorder, an impulse control disorder, a substance abuse disorder (e.g., a withdrawal symptom, opiate addiction, nicotine addiction, and ethanol addition), a sleep disorder, a memory disorder (e.g., a deficit, loss, or reduced ability to make new memories), a learning disorder, urinary incontinence, multiple system atrophy, progressive supra-nuclear palsy, Friedrich's ataxia, Down’s syndrome, fragile X syndrome, tuberous sclerosis, olivio- ponto-cerebellar atrophy, cerebral palsy, drug-induced optic neuritis, ischemic retinopathy, diabetic retinopathy, glaucoma, dementia,
  • ADHD attention
  • the present disclosure provides methods of treating a cognitive impairment disorder, for example, a dysfunction in learning and/or memory such as that seen in age-related cognitive decline, Lewy body dementia, AIDS dementia, HIV dementia, vascular dementia, mild cognitive impairment in Huntington’s disease, Huntington’s disease dementia, mild cognitive impairment in Parkinson’s disease, Parkinson’s disease dementia, mild cognitive impairment in Alzheimer’s disease, Alzheimer’s dementia, frontotemporal dementia, cognitive impairment associated with schizophrenia (CIAS), and cognitive impairment associated with seizures, stroke, cerebral ischemia, hypoglycemia, cardiac arrest, migraine, multiple sclerosis, traumatic brain injury, and/or Down’s syndrome.
  • a cognitive impairment disorder for example, a dysfunction in learning and/or memory such as that seen in age-related cognitive decline, Lewy body dementia, AIDS dementia, HIV dementia, vascular dementia, mild cognitive impairment in Huntington’s disease, Huntington’s disease dementia, mild cognitive impairment in Parkinson’s disease, Parkinson’s disease dementia, mild cognitive impairment in Alzheimer’s disease, Alzheimer’s dementia, frontotemporal
  • methods for treating schizophrenia are provided.
  • paranoid type schizophrenia disorganized type schizophrenia (i.e., hebephrenic schizophrenia), catatonic type schizophrenia, undifferentiated type schizophrenia, residual type schizophrenia, post-schizophrenic depression, and simple schizophrenia
  • Psychitic disorders such as schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders, and psychotic disorders with delusions or hallucinations may also be treated using the compositions disclosed herein.
  • Paranoid schizophrenia may be characterized where delusions or auditory hallucinations are present, but thought disorder, disorganized behavior, or affective flattening are not.
  • Delusions may be persecutory and/or grandiose, but in addition to these, other themes such as ashamedy, religiosity, or somatization may also be present.
  • Disorganized type schizophrenia may be characterized where thought disorder and flat affect are present together.
  • Catatonic type schizophrenia may be characterized where the patient may be almost immobile or exhibit agitated, purposeless movement. Symptoms can include catatonic stupor and waxy flexibility.
  • Undifferentiated type schizophrenia may be characterized where psychotic symptoms are present but the criteria for paranoid, disorganized, or catatonic types have not been met.
  • Residual type schizophrenia may be characterized where positive symptoms are present at a low intensity only.
  • Post-schizophrenic depression may be characterized where a depressive episode arises in the aftermath of a schizophrenic illness where some low-level schizophrenic symptoms may still be present.
  • Simple schizophrenia may be characterized by insidious and progressive development of prominent negative symptoms with no history of psychotic episodes.
  • methods are provided for treating psychotic symptoms that may be present in other mental disorders, including, but not limited to, bipolar disorder, borderline personality disorder, drug intoxication, and drug-induced psychosis.
  • methods for treating delusions e.g., "non-bizarre" that may be present in, for example, delusional disorder are provided.
  • methods for treating social withdrawal in conditions including, but not limited to, social anxiety disorder, avoidant personality disorder, and schizotypal personality disorder are provided.
  • the disclosure provides methods for treating a
  • the neurodevelopmental disorder related to synaptic dysfunction can be Rett syndrome also known as cerebroatrophic hyperammonemia, MECP2 duplication syndrome (e.g., a MECP2 disorder), CDKL5 syndrome, fragile X syndrome (e.g., a FMR1 disorder), tuberous sclerosis (e.g., a TSC1 disorder and/or a TSC2 disorder), neurofibromatosis (e.g., a NF1 disorder), Angelman syndrome (e.g., a UBE3A disorder), the PTEN hamartoma tumor syndrome, Phelan-McDermid syndrome (e.g., a SHANK3 disorder), or infantile spasms.
  • Rett syndrome also known as cerebroatrophic hyperammonemia, MECP2 duplication syndrome (e.g., a MECP2 disorder), CDKL5 syndrome, fragile X syndrome (e.g., a FMR1 disorder), tuberous sclerosis (e.g., a T
  • the neurodevelopmental disorder can be caused by mutations in the neuroligin (e.g., a NLGN3 disorder and/or a NLGN2 disorder) and/or the neurexin (e.g., a NRXN1 disorder).
  • the neuroligin e.g., a NLGN3 disorder and/or a NLGN2 disorder
  • the neurexin e.g., a NRXN1 disorder
  • neuropathic pain may be acute or chronic.
  • the neuropathic pain may be associated with a condition such as herpes, HIV, traumatic nerve injury, stroke, post-ischemia, chronic back pain, post-herpetic neuralgia, fibromyalgia, reflex sympathetic dystrophy, complex regional pain syndrome, spinal cord injury, sciatica, phantom limb pain, diabetic neuropathy such as diabetic peripheral neuropathy (“DPN”), and cancer chemotherapeutic- induced neuropathic pain.
  • DPN diabetic peripheral neuropathy
  • Further methods include a method of treating autism and/or an autism spectrum disorder in a patient need thereof, comprising administering an effective amount of a compound to the patient.
  • a method for reducing the symptoms of autism in a patient in need thereof comprises administering an effective amount of a disclosed compound to the patient.
  • the compound may decrease the incidence of one or more symptoms of autism such as eye contact avoidance, failure to socialize, attention deficit, poor mood, hyperactivity, abnormal sound sensitivity, inappropriate speech, disrupted sleep, and perseveration. Such decreased incidence may be measured relative to the incidence in the untreated individual or an untreated individual(s).
  • Also provided herein is a method of modulating an autism target gene expression in a cell comprising contacting a cell with an effective amount of a compound described herein.
  • the autism gene expression may be for example, selected from ABAT, APOE, CHRNA4, GABRA5,GFAP, GRIN2A, PDYN, and PENK.
  • a method of modulating synaptic plasticity in a patient suffering from a synaptic plasticity related disorder comprising administering to the patient an effective amount of a compound.
  • a method of treating Alzheimer’s disease, or e.g., treatment of memory loss that e.g., accompanies early stage Alzheimer’s disease, in a patient in need thereof comprising administering a compound.
  • a method of modulating an Alzheimer’s amyloid protein e.g., beta amyloid peptide, e.g. the isoform Abi_ 42 ), in-vitro or in-vivo (e.g. in a cell) comprising contacting the protein with an effective amount of a compound is disclosed.
  • a compound may block the ability of such amyloid protein to inhibit long-term potentiation in hippocampal slices as well as apoptotic neuronal cell death.
  • a disclosed compound may provide neuroprotective properties to a Alzheimer’s patient in need thereof, for example, may provide a therapeutic effect on later stage Alzheimer’s -associated neuronal cell death.
  • the disclosed methods include treating a psychosis or a pseudobulbar affect (“PBA”) that is induced by another condition such as a stroke, amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease), multiple sclerosis, traumatic brain injury, Alzheimer’s disease, dementia, and/or Parkinson’s disease.
  • PBA pseudobulbar affect
  • Such methods include administration of a therapeutically effective amount of a disclosed compound to a patient in need thereof.
  • a method of treating depression includes administering a therapeutically effective amount of a compound described herein.
  • the treatment may relieve depression or a symptom of depression without affecting behavior or motor coordination and without inducing or promoting seizure activity.
  • Exemplary depression conditions that are expected to be treated according to this aspect include, but are not limited to, major depressive disorder, dysthymic disorder, psychotic depression, postpartum depression, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder (SAD), bipolar disorder (or manic depressive disorder), mood disorder, and depressions caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress, and post traumatic stress disorders.
  • SAD seasonal affective disorder
  • bipolar disorder or manic depressive disorder
  • mood disorder and depressions caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress, and post traumatic stress disorders.
  • patients suffering from any form of depression often experience anxiety.
  • Various symptoms associated with anxiety include fear, panic, heart palpitations, shortness of breath, fatigue, nausea
  • a method of treating depression in a treatment resistant patient comprising a) optionally identifying the patient as treatment resistant and b) administering an effective dose of a compound to said patient.
  • a compound described herein may be used for acute care of a patient.
  • a compound may be administered to a patient to treat a particular episode (e.g., a severe episode) of a condition disclosed herein.
  • combination therapies comprising a compound of the disclosure in combination with one or more other active agents.
  • a compound may be combined with one or more antidepressants, such as tricyclic antidepressants, MAO-I's, SSRI's, and double and triple uptake inhibitors and/or anxiolytic drugs.
  • Exemplary drugs that may be used in combination with a compound include Anafranil, Adapin, Aventyl, Elavil, Norpramin, Pamelor, Pertofrane, Sinequan, Surmontil, Tofranil, Vivactil, Parnate, Nardil, Marplan, Celexa, Lexapro, Luvox, Paxil, Prozac, Zoloft, Wellbutrin, Effexor, Remeron, Cymbalta, Desyrel (trazodone), and Ludiomill.
  • a compound may be combined with an antipsychotic medication.
  • Non-limiting examples of antipsychotics include butyrophenones, phenothiazines, thioxanthenes, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, iloperidone, zotepine, sertindole, lurasidone, and aripiprazole. It should be understood that combinations of a compound and one or more of the above therapeutics may be used for treatment of any suitable condition and are not limited to use as antidepressants or antipsychotics.
  • Ac is acetyl (-C(0)CH 3 ), AIDS is acquired immune deficiency syndrome, Boc and BOC are tert- butoxycarbonyl, Boo 2 0 is di-ieri-butyl dicarbonate, Bn is benzyl, BOM-C1 is benzyloxymethyl chloride, CAN is ceric ammonium nitrate, Cbz is carboxybenzyl, DCC is N,N'- dicyclohexylcarbodiimide, DCM is dichloromethane, DEA is diethylamine, DIAD is diisopropyl azodicarboxylate, DMAP is 4-dimethylaminopyridine, DMS is dimethyl sulfide, DIPEA is /V,/V-diisopropylethylamine, DMF is NN-di methyl formamide, DMSO is dimethyl sulfoxide, DTAD is die
  • EK & EL Mixture of EK & EL (1.2 g) was purified by chiral preparative HPLC purification to obtain EK (270 mg) as a hygroscopic white solid and EL (280 mg) as a hygroscopic white solid.
  • the DPM disintegrations per minute
  • the baseline value was determined from the best fit curve of the DPM values modeled using the GraphPad program and the log(agonist) vs. response(three parameters) algorithm was then subtracted from all points in the dataset.
  • the % maximal [ 3 H]MK-80l binding was then calculated relative to that of 1 mM glycine: all baseline subtracted DPM values were divided by the average value for 1 mM glycine.
  • the EC50 and % maximal activity were then obtained from the best fit curve of the % maximal [ 3 H]MK-80l binding data modelled using the GraphPad program and the log(agonist) vs. response( three parameters) algorithm.
  • Microsomal stability of disclosed compounds was investigated. The following table indicates the percent of compound remaining after 60 minutes.
  • Plasma stability of disclosed compounds was investigated. The following table indicates the percent of compound remaining after 60 minutes.
  • Sprague Dawley rats were dosed intravenously using a normal saline formulation containing 2 mg/kg of the compounds identified in the below table.
  • the table below summarizes the results of the IV pharmacokinetics.
  • Sprague Dawley rats were dosed per os (oral gavage) using a normal saline formulation containing 10 mg/kg of the compounds identified in the table below.
  • Plasma, brain, and CSF samples were analyzed at various time points over a 24 hour period.
  • the table below summarizes the results of the oral pharmacokinetics, where the first three values (T max , C max and AUCi ast ) are plasma values.

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Abstract

L'invention concerne des composés ayant une capacité à moduler l'activité des récepteurs NMDA. De tels composés peuvent être utilisés dans le traitement d'états pathologiques notamment la dépression et des troubles associés.
PCT/US2019/016107 2018-01-31 2019-01-31 Spiro-lactame modulateur des récepteurs nmda et leurs procédés d'utilisation WO2019152685A1 (fr)

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WO2021112987A1 (fr) * 2019-12-04 2021-06-10 Aptinyx Inc. Méthodes de traitement d'une déficience cognitive associée à une maladie neurodégénérative
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