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WO2024054919A1 - Modulateurs des récepteurs nmda spiro-lactames et leurs utilisations - Google Patents

Modulateurs des récepteurs nmda spiro-lactames et leurs utilisations Download PDF

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WO2024054919A1
WO2024054919A1 PCT/US2023/073653 US2023073653W WO2024054919A1 WO 2024054919 A1 WO2024054919 A1 WO 2024054919A1 US 2023073653 W US2023073653 W US 2023073653W WO 2024054919 A1 WO2024054919 A1 WO 2024054919A1
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mmol
alkyl
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M. Amin Khan
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Tenacia Biotechnology Hong Kong Co Ltd
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Tenacia Biotechnology Hong Kong Co Ltd
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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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

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., Nature 1987, 329:395-396; Mayer et al., Trends in Pharmacol. Sci.1990, 11:254-260).
  • the NMDA receptor has been implicated during development in specifying neuronal architecture and synaptic connectivity, and may be involved in experience-dependent synaptic modifications.
  • 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).
  • 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.
  • NMDA receptor Activation of the NMDA receptor has been shown to be responsible for post-stroke convulsions, and, in certain models of epilepsy, activation of the NMDA receptor has been shown to be necessary for the generation of seizures.
  • Neuropsychiatric involvement of the NMDA receptor has also been recognized since blockage of the NMDA receptor Ca ++ channel by the animal anesthetic PCP (phencyclidine) produces a psychotic state in humans similar to schizophrenia (reviewed in Johnson, K. and Jones, S., 1990).
  • PCP phencyclidine
  • 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 effect a conformational change in the overall structure of the protein which is ultimately reflected in the channel opening, partially opening, partially closing, or closing.
  • R 91 is selected from the group consisting of H, C1-C6alkyl, phenyl, -C(O)-C1-C6alkyl, and -C(O)-O-C 1 -C 6 alkyl
  • R 96 is independently for each occurrence selected from the group consisting of H, C 1 -C 6 alkyl, cyano, hydroxyl, phenyl, and halogen
  • R 98 is methyl, ethyl or propyl, or R 8 and R 6 together with the carbons to which they are attached form a cyclopropyl, wherein cyclopropyl is optionally substituted with methyl
  • m is 1 or 2
  • R 93 is selected from the group consisting of H, C1-C6 alkyl, phenyl, -C(O)R 31 and -C(O)OR 32 ;
  • R 93 is selected from the group consisting of H, C1-C6 alkyl, phenyl
  • the present disclosure also provides a compound having the Formula IV or Formula V: or a pharmaceutically acceptable salt and/or a stereoisomer thereof, where: q is 1 or 2; R 11 is selected from the group consisting of H, -C 1 -C 6 alkyl, and -S-C 1- C 4 alkyl; R 22 is independently selected for each occurrence from the group consisting of H, -C1-C6 alkyl, and halogen; R 55 is independently selected for each occurrence from the group consisting of H, -C1-C6 alkyl, and halogen; R 66 is independently selected for each occurrence from the group consisting of H, -C1-C6 alkyl, and halogen; or R 55 and R 66 taken together with the adjacent carbons to which they are attached form a 3- membered carbocyclic ring which can be optionally substituted by one or two substituents independently selected from the group consisting of halogen, hydroxyl, -C1- C4 alkyl,
  • 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,
  • 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 modulate other protein targets and/or specific NMDA receptor subtype.
  • Such methods can include administering to the patient a pharmaceutically effective amount of a disclosed compound or pharmaceutically acceptable salts, stereoisomers, N-oxides, and hydrates thereof.
  • the method includes treating depression.
  • depression can include one or more of major depressive disorder, dysthymic disorder, psychotic depression, postpartum depression, seasonal affective disorder, bipolar disorder, mood disorder, and depression caused by a chronic medical condition.
  • the method can treat schizophrenia.
  • schizophrenia can be, for example, paranoid type schizophrenia, disorganized type schizophrenia, catatonic type schizophrenia, undifferentiated type schizophrenia, residual type schizophrenia, post-schizophrenic depression, or simple schizophrenia.
  • 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 C 1 -C 6 alkyl, C 1 -C 4 alkyl, and C 1 -C 3 alkyl, respectively.
  • Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2- methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 3-methyl-2-butyl, 2,2-dimethyl-1-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-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-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 C 1 -C 6 alkoxy and C2-C6 alkoxy, respectively.
  • Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, and isopropoxy.
  • haloalkyl refers to an alkyl group, in which one or more hydrogen atoms of the alkyl group are replaced with one or more independently selected halogens.
  • a haloalkyl group can have 1 to 10 carbon atoms (i.e., C 1- C 10 haloalkyl group), for example, 1 to 6 carbon atoms (i.e., C1-C 6 haloalkyl group).
  • haloalkyl groups include -CF 3 , -C 2 F 5 , -CHF 2 , -CH 2 F, -CCl 3 , -CHCl 2 , -CH 2 Cl, -CH 2 CH 2 Cl, -CHFCH 2 Cl, and - C2Cl5.
  • Perhaloalkyl groups i.e., alkyl groups where all of the hydrogen atoms are replaced with halogen atoms (e.g., -CF 3 and -C 2 F 5 ), are included within the definition of “haloalkyl.”
  • 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 C3-C6 cycloalkyl or C4-C6 cycloalkyl, respectively.
  • exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, cyclobutyl, and cyclopropyl.
  • cyano refers to the substituent -CN.
  • heterocyclic ring refers to saturated or partially unsaturated 4- to 7-membered ring structures, 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.
  • heterocyclic rings include, but are not limited to, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl.
  • hydroxyl and hydroxyl refer to the substituent -OH.
  • 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, esters 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, an ester, or an N-oxide thereof.
  • a compound can refer to a pharmaceutically acceptable salt, or a hydrate, an ester or an N-oxide of a stereoisomer of the compound and/or an isotopically-labelled compound.
  • the term “moiety,” as used herein, 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.
  • 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.
  • 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. See, for example, Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.
  • 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 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 examples 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 O, 17 O, 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 e.g., those labeled with 3 H and 14 C) can be useful in compound and/or substrate tissue distribution assays.
  • Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes can be particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence can be preferred in some circumstances.
  • 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 Biologics standards.
  • 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 administration.
  • Pharmaceutical acceptable carriers 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.
  • the compositions also can include stabilizers and preservatives.
  • pharmaceutical 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 terms “individual,” “patient,” and “subject,” as used herein, are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and more preferably, humans.
  • 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.
  • terapéuticaally 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.
  • pharmaceutically acceptable 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 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-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pect
  • salts include anions of the compounds of the present disclosure compounded with a suitable cation such as Na + , NH4 + , and NW4 + (where W can be a C1-4 alkyl group), and the like.
  • a suitable cation such as Na + , NH4 + , and NW4 + (where W can be a C1-4 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 pharmaceutically acceptable compound.
  • Compounds included in the present 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, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis
  • Compounds included in the present 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.
  • Compounds included in the present 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.
  • the compound is amorphous.
  • the compound is a single polymorph.
  • the compound is a mixture of polymorphs.
  • the compound is in a crystalline form.
  • prodrug refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound.
  • the transformation can occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and/or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit into the intestine, blood, or liver).
  • Prodrugs are well known in the art (see e.g., see Rautio, Kumpulainen et al., Nature Reviews Drug Discovery 2008, 7, 255).
  • a prodrug can be an ester formed by the replacement of the hydrogen atom of the carboxylic acid group with a group such as (C 1 -C 8 )alkyl, (C 2 -C 12 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C1-C6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C 1 -C 6 )alkanoyloxy)ethyl (C 1 -C 6 )alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1-C6)alkanoyl, ⁇ -amino(C1-C4)alkanoyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ -aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C 1 -C 6 )
  • a prodrug can be formed, for example, by creation of an amide or carbamate, an N-acyloxyalkyl derivative, an (oxodioxolenyl) methyl derivative, an N-Mannich base, imine or enamine.
  • a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine. See, for example, Simpl ⁇ cio, et al., Molecules 2008, 13, 519 and references therein.
  • 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.
  • C1-6 alkyl is specifically intended to individually disclose C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 - C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.
  • phrases “optionally substituted with 1-5 substituents” is specifically intended to individually disclose a chemical group that can include 0, 1, 2, 3, 4, 5, 0-5, 0-4, 0-3, 0-2, 0-1, 1-5, 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5, 3-4, and 4-5 substituents.
  • the use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present disclosure and does not pose a limitation on the scope of the disclosure unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present disclosure.
  • variable is defined as found elsewhere in the disclosure unless understood to be different from the context.
  • definition of each variable and/or substituent for example, C 1 -C 6 alkyl, R 2 , R b , w and the like, when it occurs more than once in any structure or compound, can be independent of its definition elsewhere in the same structure or compound. Definitions of the variables and/or substituents in formulae and/or compounds herein encompass multiple chemical groups.
  • the present disclosure includes embodiments where, for example, i) the definition of a variable and/or substituent is a single chemical group selected from those chemical groups set forth herein, ii) the definition is a collection of two or more of the chemical groups selected from those set forth herein, and iii) the compound is defined by a combination of variables and/or substituents in which the variables and/or substituents are defined by (i) or (ii).
  • Various aspects of the disclosure are set forth herein under headings and/or in sections for clarity; however, it is understood that all aspects, embodiments, or features of the disclosure described in one particular section are not to be limited to that particular section but rather can apply to any aspect, embodiment, or feature of the present disclosure.
  • Compounds Disclosed compounds include a compound having the formula: or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein: X is selected from the group consisting of NR 1 , N, O, and CR 2 R 2 ; Y is NR 1 or CR 2 R 2 ; Z is NR 1 or CR 2 R 2 ; wherein two of X, Y, and Z is CR 2 R 2 ; is a double bond when X is N and a single bond when X is NR 1 , O or CR 2 R 2 ; p is 1, 2 or 3; R 1 is selected from the group consisting of H, -C1-C6 alkyl, -C(O)-C1-C6 alkyl, and - C(O)-O-C1-C6 alkyl; R 2 is independently selected for each occurrence from the group consisting of H, -C 1 -C 6 alkyl, and halogen; R 5 is independently selected for each occurrence from the
  • X can be NR 1 and Y and Z can be CR 2 R 2 .
  • Z can be NR 1 and X and Y can be CR 2 R 2 .
  • Y can be NR 1 and X and Z can be CR 2 R 2 .
  • p can be 1.
  • R 2 , R 5 , and R 6 can be H.
  • one or two of R 5 can be fluoro.
  • R 1 can be H.
  • R 1 can be -C(O)-O-C1-C6 alkyl.
  • R 1 can be -C(O)-O-tert-butyl.
  • R 1 can be -C(O)-C 1 -C 6 alkyl, where C 1 -C 6 alkyl, can be optionally substituted as described herein.
  • R 1 can be selected from the group consisting of: where R a and R b are as described herein.
  • R a and R b can be H.
  • R 1 can be -C 1 -C 6 alkyl optionally substituted by one, two or three substituents independently selected from the group consisting of –C(O)NR a R b , hydroxyl, - SH, and halogen.
  • R 1 can be selected from the group consisting of: where R a and R b are as defined herein.
  • R a and R b can be H.
  • X is N, and Y and Z can be CR 2 R 2 .
  • R 2 and R 6 can be H.
  • R 5 can be -S-C1-C4 alkyl, for example, R 5 can be –S-CH3.
  • a compound disclosed herein can be represented by Formula II: where R 3 is as defined herein.
  • X can be O
  • Y and Z can be CR 2 R 2 .
  • R 2 , R 5 , and R 6 can be H.
  • a compound disclosed herein can be represented by Formula III: where R 3 is as defined herein.
  • R 3 can be H.
  • R 3 can be -C 1 -C 6 alkyl, optionally substituted as described herein.
  • R 3 can be selected from the group consisting of: where R 65 is -C 1 -C 4 alkoxy; and R a and R b are each independently selected for each occurrence from the group consisting of H and -C1-C6 alkyl.
  • R 65 can be methoxy.
  • R 1 and/or R 3 and/or R 33 and/or R 91 and/or R 93 independently can be an amino acid or a derivative of an amino acid, for example, an alpha “amino amide” represented by H2N-CH(amino acid side chain)-C(O)NH2.
  • 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, for example, in Formula (I), (II), (III), (IV), (V) or (VI).
  • the carboxylic acid of the amino acid or the amide group of an amino amide 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, for example, in Formula (I), (II), (III), (IV), (V) or (VI), 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 and/or R 33 and/or R 91 and/or R 93 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 compound of the disclosure can be represented by: or a pharmaceutically acceptable salt and/or a stereoisomer thereof, where R 1 can be can be H, -C1-C4 alkoxy, or halogen; and R a and R b can be each independently for each occurrence selected from the group consisting of H and -C1-C6 alkyl.
  • R 1 can be ; R 3 can be ; R 65 can be H or -C 1 -C 4 alkoxy; and R a and R b each can be H.
  • R 1 can be ; and R 3
  • a compound of the disclosure can be represented by:
  • the present disclosure also provides a compound having the Formula IV or Formula V: or a pharmaceutically acceptable salt and/or a stereoisomer thereof, where: q is 1 or 2; R 11 is selected from the group consisting of H, -C 1 -C 6 alkyl, and -S-C 1- C 4 alkyl; R 22 is independently selected for each occurrence from the group consisting of H, -C1-C6 alkyl, and halogen; R 55 is independently selected for each occurrence from the group consisting of H, -C1-C6 alkyl, and halogen; R 66 is independently selected for each occurrence from the group consisting of H, -C1-C6 alkyl, and halogen; or R 55 and R 66 taken together with the adjacent carbons to which they are attached form a 3- membered carbocyclic ring which can be optionally substituted by one or two substituents independently selected from the group consisting of halogen, hydroxyl, -C1
  • Disclosed compounds include a compound having the formula: or a pharmaceutically acceptable salt and/or a stereoisomer thereof, where: R 91 is selected from the group consisting of H, C 1 -C 6 alkyl, phenyl, -C(O)-C 1 -C 6 alkyl, and -C(O)-O-C1-C6 alkyl; R 96 is independently for each occurrence selected from the group consisting of H, C 1 - C6alkyl, cyano, hydroxyl, phenyl, and halogen; R 98 is methyl, ethyl or propyl, or R 8 and R 6 together with the carbons to which they are attached form a cyclopropyl, wherein cyclopropyl is optionally substituted with methyl; m is 1 or 2; R 93 is selected from the group consisting of H, C1-C6 alkyl, phenyl, -C(O)R 31 and - C(O)OR 32
  • R 98 can be methyl.
  • m can be 1.
  • R 96 for each occurrence can be H.
  • R 91 can be -C(O)-O-C1-C6 alkyl.
  • R 91 can be tert- butyloxycarbonyl.
  • R 91 can be -C(O)-C 1 -C 6 alkyl.
  • R 91 can be selected from the group consisting of: where R a and R b can be independently for each occurrence selected from the group consisting of H and -C1-C4alkyl.
  • R 91 can be C 1 -C 6 alkyl.
  • R 91 can be methyl, ethyl, n-propyl, or isopropyl (
  • R 93 can be selected from the group consisting of: O where R a and R b can be independently for each occurrence selected from the group consisting of H and -C1-C4alkyl.
  • R 93 can be a benzyl group optionally substituted by one, two or three substituents each independently selected from methyl, methoxy, CF 3 , hydroxyl and halogen.
  • R 93 can be para-methoxybenzyl.
  • a disclosed compound can be selected from the compounds in the Examples described herein and/or in Tables 1 and 2, and includes a stereoisomer and/or a pharmaceutically acceptable salt thereof.
  • the compounds of the present disclosure and formulations thereof can have a plurality of chiral centers. Each chiral center can be independently R, S, or any mixture of R and S.
  • a chiral center can have an R:S ratio of between about 100:0 and about 50:50, 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 characteristics relative to racemic formulations of a disclosed compound or mixture of compounds.
  • depicted chemical structures 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.
  • the disclosed compounds can provide for efficient cation channel opening at the NMDA receptor, for example, 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 can be used to regulate (turn on or turn off) the NMDA receptor through action as an agonist or antagonist.
  • the compounds described herein may bind to or associate with specific NMDA receptor subtypes. For example, a disclosed compound may bind to one NMDA receptor subtype and not another.
  • a disclosed compound can bind to one, or more than one NMDA receptor subtype, and/or can have substantially less (or substantial no) binding activity to certain other NMDA receptor subtypes.
  • a disclosed compound e.g., compound A
  • a disclosed compound binds to NR2A with substantially no binding to NR2D.
  • a disclosed compound e.g., compound B
  • 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 10-fold or greater than the activity of existing NMDA receptor modulators.
  • the disclosed compounds can exhibit a high therapeutic index.
  • a disclosed compound can 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.
  • Compositions in other aspects, a pharmaceutical formulation or a pharmaceutical composition including a disclosed compound and a pharmaceutically acceptable excipient is provided.
  • a pharmaceutical composition includes a racemic mixture of one or more of the disclosed compounds or a mixture of stereoisomers between a racemic mixture and a pure enantiomer (i.e., a varied composition of stereoisomeric compounds 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 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
  • compositions of the disclosure can be suitable for delivery to the eye, i.e., ocularly.
  • Related methods can include administering a pharmaceutically 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 can vary according to factors such as the disease state, age, sex, and weight of the individual. Dosage regimens can be adjusted to provide the optimum therapeutic response.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • 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.
  • a coating such as lecithin
  • surfactants 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/or 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.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG).
  • PLG polylactic, polyglycolic copolymers
  • 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 other required ingredients from those enumerated above.
  • a sterile powders for the preparation of sterile injectable solutions, 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 disclosed compound can be formulated with one or more additional compounds that enhance the solubility of the compound.
  • the condition can be a mental condition.
  • a mental illness can be treated.
  • a nervous system condition can be treated.
  • a condition that affects the central nervous system, the peripheral nervous system, and/or the eye can be treated.
  • neurodegenerative diseases can 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
  • methods of treating a memory disorder associated with aging schizophrenia, special learning disorders, seizures, post-stroke convulsions, brain ischemia, hypoglycemia, cardiac arrest, epilepsy, Lewy body dementia, migraine, AIDS dementia, Huntington’s chorea, Parkinson’s disease, early stage Alzheimer’s disease, and Alzheimer’s disease are contemplated.
  • 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 can be treated using the methods and compositions described herein.
  • psychotic disorders such as schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders, and psychotic disorders with delusions or hallucinations can also be treated using the compositions described herein.
  • Paranoid schizophrenia can be characterized where delusions or auditory hallucinations are present, but thought disorder, disorganized behavior, or affective flattening are not. Delusions can be persecutory and/or grandiose, but in addition to these, other themes such as ashamedy, religiosity, or somatization can also be present.
  • Disorganized type schizophrenia can be characterized where thought disorder and flat affect are present together.
  • Catatonic type schizophrenia can be characterized where the patient can be almost immobile or exhibit agitated, purposeless movement.
  • Symptoms can include catatonic stupor and waxy flexibility.
  • Undifferentiated type schizophrenia can be characterized where psychotic symptoms are present but the criteria for paranoid, disorganized, or catatonic types have not been met.
  • Residual type schizophrenia can be characterized where positive symptoms are present at a low intensity only.
  • Post-schizophrenic depression can be characterized where a depressive episode arises in the aftermath of a schizophrenic illness where some low-level schizophrenic symptoms can still be present.
  • Simple schizophrenia can 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 can 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 can 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 neurodevelopmental disorder related to synaptic dysfunction in a patient in need thereof, where the methods generally include administering to the patient a therapeutically effective amount of a disclosed compound, or a pharmaceutical composition including a disclosed compound.
  • 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).
  • methods are provided for treating neuropathic pain.
  • the neuropathic pain can be acute or chronic.
  • the neuropathic pain can 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.
  • methods for enhancing pain relief and for providing analgesia to a patient are also provided. Further methods of the disclosure can include a method of treating autism in a patient need thereof, including administering a therapeutically effective amount of a disclosed compound to the patient.
  • a method for reducing the symptoms of autism in a patient in need thereof includes administering a therapeutically effective amount of a disclosed compound to the patient.
  • the disclosed compound can 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 can be measured relative to the incidence in the untreated individual or an untreated individual(s).
  • a method of modulating an autism target gene expression in a cell where the method includes contacting a cell with an effective amount of a compound described herein.
  • the autism gene expression can 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 is provided, where the method includes administering to the patient an effective amount of a disclosed compound.
  • a method of treating Alzheimer’s disease, or treatment of memory loss that accompanies early stage Alzheimer’s disease, in a patient in need thereof is provided, where the method includes administering a compound described herein.
  • Also provided herein is a method of modulating an Alzheimer’s amyloid protein e.g., beta amyloid peptide, e.g., the isoform A ⁇ 1-42
  • Such methods can include contacting the protein with an effective amount of a disclosed compound.
  • a disclosed compound can 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 can provide neuroprotective properties to a Alzheimer’s patient in need thereof, for example, can 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 pharmaceutically effective amount of a disclosed compound to a patient in need thereof.
  • a method of treating depression in a patient in need thereof includes administering a compound described herein.
  • the treatment can 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 these methods 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.
  • 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, and headaches, among others.
  • anxiety or any of the symptoms thereof can be treated by administering a compound as described herein to a patient in need thereof.
  • a method of treating depression in a treatment resistant patient where the method includes a) optionally identifying the patient as treatment resistant; and b) administering a therapeutically effective dose of a disclosed compound to the patient.
  • a compound described herein can be used for acute care of a patient.
  • a disclosed compound can be administered to a patient to treat a particular episode (e.g., a severe episode) of a condition described herein.
  • combination therapies including a disclosed compound in combination with one or more other active agents.
  • a disclosed compound can be combined with one or more antidepressants, such as tricyclic antidepressants, MAO-I’s, SSRI’s, double and triple uptake inhibitors, and/or anxiolytic drugs.
  • Exemplary drugs that can be used in combination with a disclosed 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 disclosed compound can 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 disclosed compound and one or more of the above therapeutics can be used for treatment of any suitable condition and are not limited to use as antidepressants or antipsychotics.
  • AIDS is acquired immune deficiency syndrome
  • Boc and BOC are tert-butoxycarbonyl
  • Boc2O is di-tert-butyl dicarbonate
  • Bn is benzyl
  • BOM-Cl is benzyloxymethyl chloride
  • CAN is ceric ammonium nitrate
  • Cbz is carboxybenzyl
  • DCM is dichloromethane
  • DIAD is diisopropyl azodicarboxylate
  • DIPEA is N,N-diisopropylethylamine
  • DMAP is 4-dimethylaminopyridine
  • DMF is N,N-dimethylformamide
  • DMSO is dimethyl sulfoxide
  • EDC and EDCI are 1-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride
  • reaction mixture After consumption of the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with CH 2 Cl 2 (2 x 50 mL). The combined organic layer was washed with brine solution (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude compound which was purified by silica gel column chromatography eluting with 6% MeOH/ CH2Cl2 to afford a racemic mixture of AA-1 and AA-2 (1.5 g, 50%) as an off white solid. The racemic mixture was separated by chiral HPLC purification.
  • reaction mixture was brought to RT and stirred for 16 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with 1 N HCl solution (10 mL) and extracted with 10% MeOH/ CH 2 Cl 2 (2 x 10 mL). The combined organic layer was washed with cold water (10 mL) and saturated brine solution (10 mL). The separated organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 10% MeOH/ CH2Cl2 to obtain compound 11 as a racemic mixture (600 mg, 44%) as off white solid.
  • reaction mixture was stirred at RT for 3 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with 5% MeOH/ CH 2 Cl 2 (2 x 50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Obtained crude material was purified by silica gel column chromatography eluting with 3% MeOH/ CH 2 Cl 2 to afford racemic AG-1 and G-2 (500 mg) as off white solid. The racemic mixture was separated by chiral HPLC purification.
  • reaction mixture was brought to RT and stirred for 3 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (10 mL) and extracted with 10% MeOH-DCM solvent mixture (2x15 mL). The separated organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 3% to 10% MeOH/ CH2Cl2 to obtain compound 11 ( 800 mg, racemic). LCMS (ESI): m/z 477.4 [M + +1].
  • AH-1 1 H-NMR: (500 MHz, DMSO-d 6 ): ⁇ 7.82 (s, 1H), 3.73-3.56 (m, 2H), 3.30-2.98 (m, 4H), 1.76-1.63 (m, 4H), 1.38 (s, 9H).
  • UPLC 99.27%.
  • AH-2 1 H-NMR: (500 MHz, DMSO-d6): ⁇ 7.82 (s, 1H), 3.73-3.56 (m, 2H), 3.30-2.98 (m, 4H), 1.76-1.63 (m, 4H), 1.38 (s, 9H).
  • AI-1 6-(L-threonyl)-2,6-diazaspiro[3.5]nonan-1-one
  • AI-2 6-(L-threonyl)-2,6-diazaspiro[3.5]nonan-1-one
  • reaction mixture was brought to RT and stirred for 16 h. After completion of starting material (by TLC), the reaction mass was diluted with CH2Cl2 (20 ml) and washed with 1 N HCl solution (10 mL), water and saturated NaHCO 3 solution (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain crude which was purified by column chromatography eluting with 30% EtOAc/ hexanes to afford compound 2 (5 g, 79%) as light yellow syrup.
  • reaction mixture was diluted with water (200 mL) and EtOAc (200 mL) and the organic layer was separated. The aqueous layer was acidified with 1N HCl (pH ⁇ 2) and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (1 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford compound 1 (34 g, 96%) as white solid.
  • reaction mixture was warmed to RT and stirred for 16 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2x50 mL). The separated organic layer was washed with water (50 mL) and brine solution (50 mL). The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 40% EtOAc/ hexanes to obtain compound 5 ( 300 mg, 32%) as thick syrup.
  • reaction mixture was diluted with water (50 mL) and extracted with 10% MeOH/ CH 2 Cl 2 (2x100 mL). Combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford compound racemic 4 (600 mg, 15%) as white solid.
  • reaction mixture was brought to RT and stirred for 3 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2x10 mL). The separated organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 40% EtOAc/ hexanes to obtain compound 6 ( 1.4 g, crude) as syrup.
  • reaction mixture was brought to RT and stirred for 3 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with DCM (10 mL), water (10 mL) and extracted with EtOAc (2x10 mL). Aqueous layer was further washed with 10% MeOH/ CH2Cl2 (2x10 mL). Combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 5% MeOH/ CH2Cl2 to afford racemic AS-1 and AS-2 (250 mg, 25%) as white solid. The racemic mixture was separated by chiral HPLC purification and obtained 60 mg of AS-1 and 50 mg of AS-2.
  • reaction mixture was brought to RT and stirred for 16 h. After consumption of the starting material (by TLC), the reaction was quenched with aqueous NH4Cl solution (20 mL) and extracted with EtOAc (2 x 30 mL). The separated organic layer was washed with water (20 mL) and brine solution (20 mL). The separated organic layer was dried over Na2SO4 and concentrated to afford crude which was purified by column chromatography eluting with 10% EtOAc/ hexanes to afford compound 3 (6.5 g, 51%) as brown syrup.
  • reaction mixture was diluted with water (50 mL) and extracted with 10% MeOH/ CH 2 Cl 2 (2x100 mL). Separated organic layer was washed with citric acid, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 5% MeOH/ DCM to obtain compound 6 ( 3.5 g, 65%) as white solid.
  • reaction mixture was quenched with 1N HCl solution (20 mL) and extracted with 10% MeOH/ CH 2 Cl 2 (2 x100 mL). Separated organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 5% MeOH/ CH2Cl2 to afford compound 7 (800 mg, 24%) as off white solid.
  • reaction mixture was portioned between CH 2 Cl 2 (50 mL) and water (50 mL). Separated organic layer was washed with 1 N HCl solution and brine solution. Organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 5% MeOH/ CH2Cl2to obtain racemic compound 4 ( 420 mg, 28%) as an off white solid.
  • Example AX Synthesis of methyl piperidine-4-carboxylate hydrochloride (1): To a stirred suspension of piperidine-4-carboxylic acid (SM1) (5 g, 38.7 mmol) in methanol (50 mL) was added thionyl chloride (9.4 mL, 127.7 mmol) dropwise at 0 °C. Then temperature was raised to RT and the reaction was stirred for 24 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure. Crude material was triturated twice with diethyl ether and dried under vacuum to afford crude compound 1.HCl salt (6.8 g, 86%) as white solid.
  • SM1 piperidine-4-carboxylic acid
  • thionyl chloride 9.4 mL, 127.7 mmol
  • reaction mixture After consumption of the starting material (by TLC), the reaction mixture was diluted with water (20 mL) and CH2Cl2 (20 mL). The organic layer was washed with saturated brine solution (50 mL). The separated organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 6% MeOH/ CH2Cl2 to obtain compound 5 ( 80 mg, 60%) as a white solid.
  • reaction mixture was stirred at RT for 16 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 6-10% MeOH/ CH2Cl2 to afford compound 9 (8 g, 44%) as light yellow syrup.
  • Example MM Synthesis of 2-(4-methoxybenzyl)-7-oxa-2-azaspiro[3.5]nonan-1-one (MM): To a solution of tetrahydro-2H-pyran-4-carboxylic acid (SM) (1 g, 7.69 mmol) in CH2Cl2 (5 mL) were added oxalyl chloride (1.3 mL, 15.3 mmol) and catalytic amount of DMF (0.1 mL) at 0 °C under nitrogen atmosphere. Then temperature was raised to RT and stirred for 2 h. After consumption of the starting material (by TLC), volatiles were concentrated under reduced pressure.
  • SM tetrahydro-2H-pyran-4-carboxylic acid
  • oxalyl chloride 1.3 mL, 15.3 mmol
  • catalytic amount of DMF 0.1 mL
  • Example MN Synthesis of methyl 4-((benzyloxy)methyl)tetrahydro-2H-pyran-4-carboxylate (1): To a stirring solution of DIPEA (15.1 mL, 104.1 mmol) in THF (50 mL) was added n- BuLi (65 mL, 104.1 mmol) at -78 °C under nitrogen atmosphere and allowed to stir for 45 minutes. Then, methyl tetrahydro-2H-pyran-4-carboxylate (SM-1) (10 g, 69.4 mmol) was added at -78 °C and allowed to stir 15 minutes.
  • DIPEA 15.1 mL, 104.1 mmol
  • THF 50 mL
  • n- BuLi 65 mL, 104.1 mmol
  • SM-1 methyl tetrahydro-2H-pyran-4-carboxylate
  • reaction mixture was heated to 80 °C and stirred for 3 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure and the crude was diluted with water (100 mL) and extracted with Et 2 O (3 x 100 mL). Separated aqueous layer was acidified using citric acid solution and extracted with CH2Cl2 (2 x 100 mL). Combined organic layer was washed with brine solution, dried over Na 2 SO 4 and concentrated to afford compound 2 (14 g, 74%) as off white solid.
  • reaction mixture was diluted with water (50 mL) and extracted with CH 2 Cl 2 (2 x 100 mL). Separated organic layer was washed with brine solution and citric acid, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting with 2% MeOH/ CH2Cl2 to obtain compound 4 ( 3.5 g, 72%) as off white solid.
  • Reaction mixture was brought to room temperature and stirred for 16 h. After consumption of the starting material (by TLC), the reaction was quenched with aqueous NH4Cl (50 mL) and extracted with EtOAc (2 x 200 mL). Organic layer was dried over Na2SO4 and concentrated to obtain crude was purified by column chromatography by eluting 20% EtOAc/n-hexane to afford mixture of ZCO & ZCP (3.5 g) and mixture of ZCQ & ZCR (300 mg) as a yellow syrup. Mixture of ZCO & ZCP (1 g) was purified by chiral preparative HPLC to afford ZCO (177 mg) as an off-white solid and ZCP (205 mg) as a white solid.
  • ZCS, ZCT Synthesis of ZCS, ZCT, ZDA, ZDB, ZDI, ZDJ, ZDQ, ZDR: Synthesis of 2-(4-methoxybenzyl)-7-methyl-1-oxo-6-phenyl-2,5-diazaspiro[3.4]octane-7- carbonitrile (ZCS, ZCT): To a mixture of ZCK & ZCL (1.2 g, 2.6 mmol) in CH2Cl2 (4 mL) was added TFA (2 mL, 26 mmol) at room temperature and stirred for 6 h. After consumption of the starting material (by TLC), volatiles were evaporated and co-distilled with Et2O under reduced pressure.
  • Chiral HPLC 99.07%.
  • reaction mixture was diluted with EtOAc (50 mL) and washed with aqueous NaHCO3 (3 x 100 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure.
  • the crude (800 mg) was purified by chiral preparative HPLC to afford ZDQ (190 mg) as white solid and ZDR (170 mg) as a white solid.
  • Chiral HPLC 100.00%.
  • Chiral HPLC 100.00%.
  • the PEL assay measures the acquisition of positive (hedonic) 50-kHz ultrasonic vocalizations (USVs) to a social stimulus, heterospecific rough and tumble play stimulation.
  • Heterospecific rough-and-tumble play stimulation was administered by the experimenter's right hand.
  • test compound or vehicle negative control (0.5% sodium carboxymethyl cellulose in 0.9% sterile saline vehicle)
  • animals received 3 min of heterospecific rough-and-tumble play that consisted of alternating 15 sec blocks of heterospecific play and 15 sec of no-stimulation.
  • test compounds act to facilitate NMDAR activation in NMDAR2A, NMDAR2B, NMDAR2C or NMDAR2D expressing HEK cell membranes as measured by increases in [ 3 H]MK-801 binding.
  • 300 ⁇ g of NMDAR expressing HEK cell membrane extract protein was preincubated for 15 minutes at 25° C in the presence of saturating concentrations of glutamate (50 ⁇ M) and varying concentrations of test compound (1x10 -15 M – 1x10 -7 M), or 1 mM glycine.
  • % maximal [ 3 H]MK-801 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 EC 50 and % maximal activity were then obtained from the best fit curve of the % maximal [ 3 H]MK-801 binding data modelled using the GraphPad program and the log(agonist) vs. response(three parameters) algorithm.
  • E. PLASMA STABILITY Plasma stability of disclosed compounds was investigated. The following table indicates the percent of compound remaining after 60 minutes.
  • F. PHARMACOKINETICS 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 (Tmax, Cmax and AUClast) are plasma values. An “ND” indicates that the measurement was not done.

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Abstract

Sont divulgués des composés ayant une puissance accrue dans la modulation de l'activité des récepteurs NMDA. De tels composés peuvent être utiles dans le traitement d'états tels que la dépression et des troubles associés. Sont divulguées également des formulations disponibles par voie orale et d'autres formes d'administration pharmaceutiquement acceptables des composés, notamment des formulations intraveineuses.
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WO2018026763A1 (fr) * 2016-08-01 2018-02-08 Aptinyx Inc. Modulateurs spiro-lactames des récepteurs nmda et leurs utilisations
WO2019152678A1 (fr) * 2018-01-31 2019-08-08 Aptinyx Inc. Modulateurs des récepteurs nmda spiro-lactames et leurs utilisations
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WO2018026763A1 (fr) * 2016-08-01 2018-02-08 Aptinyx Inc. Modulateurs spiro-lactames des récepteurs nmda et leurs utilisations
WO2019152678A1 (fr) * 2018-01-31 2019-08-08 Aptinyx Inc. Modulateurs des récepteurs nmda spiro-lactames et leurs utilisations
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