EP4665344A1 - Lumatépérone et ses dérivés pour moduler le système nerveux - Google Patents

Lumatépérone et ses dérivés pour moduler le système nerveux

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Publication number
EP4665344A1
EP4665344A1 EP24715032.9A EP24715032A EP4665344A1 EP 4665344 A1 EP4665344 A1 EP 4665344A1 EP 24715032 A EP24715032 A EP 24715032A EP 4665344 A1 EP4665344 A1 EP 4665344A1
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EP
European Patent Office
Prior art keywords
compound
formula
brain
less
increased
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
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EP24715032.9A
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German (de)
English (en)
Inventor
Robert E. Davis
Gretchen Snyder
Sophie DUTHEIL
Peng Li
Emma LEHMANN
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Intra Cellular Therapies Inc
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Intra Cellular Therapies Inc
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Publication of EP4665344A1 publication Critical patent/EP4665344A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring 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

Definitions

  • FIELD [0001] The present disclosure relates to the use of lumateperone, related analogs thereof, and other octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalines, for enhancing neuritogenesis, enhancing neurite outgrowth, enhancing neural growth, neural connectivity, synaptic density, dendritic spine density, dendritic spine size, and excitatory neurotransmission, in the brain (e.g., in the prefrontal cortex).
  • SERT serotonin transporter
  • dopamine D2 receptors At dopamine D2 receptors, it has dual properties and acts as both a post-synaptic antagonist and a pre-synaptic partial agonist. It also stimulates phosphorylation of glutamatergic NMDA NR2B (GluN2B) receptors in a mesolimbic specific manner. It is believed that this regional selectivity in the brain areas thought to mediate the efficacy of antipsychotic drugs, together with the serotonergic, glutamatergic, and dopaminergic interactions, may result in antipsychotic efficacy for positive, negative, affective and cognitive symptoms associated with schizophrenia.
  • GluN2B glutamatergic NMDA NR2B
  • Lumateperone also exhibits serotonin reuptake inhibition, providing antidepressant activity for the treatment of schizoaffective disorder, co-morbid depression, and/or as a stand- alone treatment for bipolar depression or major depressive disorder. Lumateperone is also useful for the treatment of bipolar disorder and other psychiatric and neurodegenerative disorders, particularly behavioral disturbances associated with dementia, autism and other CNS diseases. These features may be able to improve the quality of life of patients with schizophrenia and enhance social function to allow them to more fully integrate into their families and their workplace. [0005] Lumateperone displays differential dose-dependent effects, selectively targeting the 5-HT2A receptor at low doses, while progressively interacting with the D2 receptor at higher doses.
  • Lumateperone has been approved in the United States for the treatment of schizophrenia and bipolar depression, and is in development as a treatment for schizophrenia, bipolar depression and agitation in dementia, including Alzheimer’s Disease.
  • Lumateperone and related compounds have been disclosed in U.S. Pat. No. 6,552,017; 7,071,186; 7,183,282; and U.S. RE39,680, for the treatment of disorders associated with 5-HT 2A receptor modulation such as anxiety, depression, psychosis, and schizophrenia.
  • U.S. 8,598,119, U.S. 9,616,061, and U.S. 10,117,867, each incorporated herein by reference, disclose the use of lumateperone for the treatment of depression, schizophrenia and sleep disorders.
  • U.S. 11,053,245 and U.S. 11,124,514, each incorporated herein by reference, disclose the use of lumateperone for the treatment of a combination of psychosis and depressive disorders as well as sleep, depressive and/or mood disorders in patients with psychosis or Parkinson's disease and for the treatment or prophylaxis of disorders associated with dementia, particularly behavioral or mood disturbances such as agitation, irritation, aggressive/assaultive behavior, anger, physical or emotional outbursts and psychosis and sleep disorders associated with dementia.
  • U.S. 8,648,077 discloses methods of preparing toluenesulfonic acid addition salt crystals of particular substituted heterocycle fused gamma- carbolines, e.g., toluenesulfonic acid addition salt of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a- hexahydro-1H-pyrido[3',4': 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1- butanone.
  • US 2021/0060009 discloses the use of lumateperone, and its deuterated analogs, for the acute treatment of anxiety and depression (e.g., for the treatment of acute anxiety and acute depression).
  • Conventional antidepressants often take weeks or months to achieve their full effects, so are generally not effective for acute treatment of depression. This delayed onset of action increases the risk for suicidal behavior.
  • ketamine is a selective NMDA receptor antagonist, acting through separate systems unrelated directly to the monoamines, and this is a major reason for its much more rapid antidepressant effect compared to the traditional antidepressants.
  • Ketamine directly antagonizes extrasynaptic glutamatergic NMDA receptors, which also indirectly results in activation of AMPA-type glutamate receptors.
  • the downstream effects involve the brain- derived neurotrophic factor (BDNF) and mTOR (e.g., mTORC1) kinase pathways (signal transduction pathways).
  • BDNF brain- derived neurotrophic factor
  • mTOR e.g., mTORC1
  • Lumateperone has been found to have very similar activity on NMDA/AMPA receptors and downstream BDNF and mTOR signaling as ketamine, and thus, it may provide a rapid antidepressant effect similar to that of ketamine. See, e.g., Dutheil et al., J. Neurosci., 43(5):863-877 (2023); Titulaer et al., Eur. Neuropsychopharm., 62:22-35 (2022). [0012] Serotonin, also known as 5-hydroxytryptamine (5-HT), is a neurotransmitter widely distributed in the brain.
  • 5-hydroxytryptamine 5-HT
  • 5-HT receptor agonists and selective serotonin reuptake inhibitors are widely used in psychiatry, finding use in the treatment of numerous mood disorders as well as in the treatment of psychosis.
  • strong 5-HT agonists tend to cause hallucinations, which is a dangerous side effect.
  • hallucinogenic psychedelic serotonin agonists such as LSD (D-lysergic acid diethylamide) and psilocybin (via its active metabolite psilocin) could be very effective in the treatment of numerous neuropsychiatric disorders, especially depression, but these drugs are not feasible in practice because of their hallucinogenic side effects.
  • Psilocybin is a serotonergic psychedelic derived from the hallucinogenic mushrooms of the genus Psilocybe. Psilocybin itself is inactive, but it is a pro-drug of the active compound psilocin, formed via a rapid enzymatic dephosphorylation: [0014] Psilocin is most prominently a strong agonist of the 5-HT2A receptor, with lesser activity at other serotonin receptors.
  • Psilocin has similar mind-altering effects to LSD (lysergic acid diethylamide), mescaline, ibogaine and DMT (N,N-dimethyltryptamine), including euphoria, visual and auditory hallucinations, changes in perception, distorted sense of time, and perceived spiritual experiences. In addition, it can cause nausea and panic attacks (e.g., “bad trips”). The effects can last for 2 to 6 hours. Psilocybin has been proposed to have great untapped therapeutic potential, such as in treating depression, but it has been hampered by the widespread classification of psilocin and psilocybin as controlled substances.
  • Psilocybin has recently been studied in mice for its effect of promoting the growth of dendritic spines in cells of the frontal cortex in mice.
  • Neurons communicate with each other primarily by transfer of signals across synapses.
  • Synapses are junctions between the cell membranes of two neurons (or between a neuron and a muscle cells) in which a signal is relayed by the release of neurotransmitter molecules on the presynaptic side of the synapse, and binding of those neurotransmitter molecules to receptors on the post-synaptic side of the synapse.
  • Dendrites Most neurons are arranged with a cell body having numerous short, branching extensions called dendrites, and a single long extension called an axon.
  • Dendrites have numerous smaller surface spikes called dendritic spines, at the ends of which are synapses connecting the nerve cell to other nerve cells. These dendritic synapses serve as a way for the neuron to receive messages from other neurons, while the axon is terminated by synapses that are used to transmit a message to other neurons (or muscle cells).
  • Dendrites and dendritic spines, as well as axons, are therefore essential to the ability of nerve cells to communicate with each other.
  • the vast majority of neurons are multipolar neurons, meaning that they have a cell body with numerous process extension, called neurites.
  • Dendrites and axons are both considered types of neurites.
  • the term neurite is often used because it can be difficult to distinguish between a growing axon and a growing dendrite, before cellular differentiation is complete.
  • the sprouting and subsequent growth of neurites is referred to as neuritogenesis (or neurite outgrowth), and this includes both the growth of dendrites and the growth of axons, particularly in an immature neuronal cell.
  • the initial sprouting of a neurite is a three-step process: first the original round shape of the cell is broken down to make a bud, then the bud is transformed into a neurite, then the neurite is transformed into an axon or dendrite.
  • Neuritogenesis can be studied using different qualitative or quantitative measures, such as based on histological or immunochemical staining of cell cultures. Measures can include cell size or length, total number of neurites per cell, length of the neurites (individually and/or in total for a neuron), the number of branch points on the neurites, the number of neurite roots, the number of neurite nodes, the total number of neurite extremities, and the total length of neurons with or without its branches.
  • Total neurite arborization can also be measured or estimated, such as, using a Sholl Analysis.
  • assay methods have been disclosed for neuritogenesis analysis, which may be used for testing the compounds disclosed herein. See, e.g., Li, S. et al., “Evaluation of Chemical Compounds that Inhibit Neurite Outgrowth in iPSC-derived Human Neurons,” Neurotoxicology 83:137-145 (2021); Li, Z. et al., “High-throughput neurite outgrowth assay using GFP-labeled iPSC-derived neurons,” Curr Protoc. 2(9):e542 (2022); Duchemin, C.
  • ketamine and psilocybin may exert their effects in part by promoting the growth of new dendritic spines, and from these, new synaptic connections, in the brain (so called “structural remodeling” or “synaptic plasticity” of the brain).
  • Such antidepressants have been suggested to operate, at least in part, by inducing transient increases in mTORC1 activity in the brain, resulting in increased synaptic spine density in the mPFC.
  • Neuroimaging studies have suggested improved functional connectivity in the right lateral PFC of patients with MDD after ketamine treatment.
  • Psilocybin is however a strong hallucinogen. It remains to be seen whether the hallucinogenic effects of psilocybin can be dissociated from the structural remodeling effect by modification of the psilocybin structure. This is particularly important for psychosis patients (e.g., schizophrenia or related disorders) who may otherwise be in need of therapies which provide neural structural remodeling, but for whom even mild hallucinogenic side effects could severely exacerbate the psychotic disorder. Similarly, patients with dementia are at an increased risk of severe adverse events resulting from drug-induced hallucination because of their reduced ability to recognize the side effects. There are many patients for whom hallucinogenic psychedelic therapy is contraindicated, so there is a need for drugs without hallucinogenic side effects.
  • hallucinogenic psychedelic therapy is contraindicated, so there is a need for drugs without hallucinogenic side effects.
  • lumateperone may have the same neural structural remodeling effect in the brain as psilocybin, but instead mediated via enhancement of mTOR signaling (whether psilocybin similarly has a direct or indirect effect on mTOR signaling is not yet known, but it is possible that psilocybin agonism of 5-HT2A receptors on prefrontal cortex neurons activates mTOR signaling).
  • lumateperone leads to FYN kinase- mediated phosphorylation of the GluN2B subunit of NMDA receptor and thereby enhanced NMDA-mediated neurotransmission in prefrontal neurons.
  • glutamate release is increased which enhances AMPA mediated currents, BDNF release, and mTORC1 activation.
  • Increased synaptogenesis has been associated with enhanced mTORC1 signaling in the PFC.
  • lumateperone may induce structural remodeling in the brain, such as enhancing neural growth, neural connectivity, synaptic density, dendritic spine density, dendritic spine size, and excitatory neurotransmission, such as in the medial prefrontal cortex region.
  • Analogs of lumateperone and other octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalines are expected to have similar properties.
  • the Gq-mediated signaling cascade is responsible for the hallucinogenic effects of the traditional psychedelics, and that ligands which are biased towards beta-arrestin recruitment may provide the therapeutic benefits of the psychedelics, such as antidepressant action, without hallucinogenic side effects.
  • the compounds disclosed in PCT/US2023/86562 are functionally biased towards 5-HT2A receptor beta-arrestin signaling. Many of the compounds disclosed are either partial or full agonists of beta-arrestin signaling, but either inactive or antagonistic of Gq signaling. Other of these compounds are antagonistic at both pathways but with a functional bias towards beta-arrestin signaling.
  • the present disclosure thus provides a method for enhancing neural growth, enhancing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and/or increasing excitatory neurotransmission, in the brain of a subject in need thereof, e.g., in the medial prefrontal cortex region of the brain, the method comprising administering an effective amount of lumateperone, related analogs thereof, deuterated analogs thereof, and other octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3- de]quinoxalines, in free, or pharmaceutically acceptable salt form, to the subject.
  • the enhanced neural growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and/or increased excitatory neurotransmission is characterized by or caused by enhanced neuritogenesis and/or enhanced neurite outgrowth (e.g., characterized by increases in the total number of neurites per neuron, the length of neurites (individually and/or in total for a neuron), the number of branch points on neurites, the number of neurite roots, the number of neurite nodes, the total number of neurite extremities, the total length of neurons (with or without branches), and total neurite arborization), and/or is characterized by or associated with changes in synaptic neurotransmitter receptor or neurotransmitter transporter density.
  • enhanced neuritogenesis and/or enhanced neurite outgrowth e.g., characterized by increases in the total number of neurites per neuron, the length of neurites (individually and/or in total for a neuron), the number of branch points on neurites
  • the present disclosure further provides a method for enhancing neuritogenesis and/or enhancing neurite outgrowth, in the brain of a subject in need thereof, e.g., in the medial prefrontal cortex region of the brain, the method comprising administering an effective amount of lumateperone, related analogs thereof, deuterated analogs thereof, and other octahydro-1H- pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalines, in free, or pharmaceutically acceptable salt form, to the subject.
  • the enhanced neuritogenesis and/or enhanced neurite outgrowth is characterized by increases in the total number of neurites per neuron, the length of neurites (individually and/or in total for a neuron), the number of branch points on neurites, the number of neurite roots, the number of neurite nodes, the total number of neurite extremities, the total length of neurons (with or without branches), and total neurite arborization.
  • the enhanced neuritogenesis and/or enhanced neurite outgrowth is also associated with changes in synaptic neurotransmitter receptor or neurotransmitter transporter density.
  • the present disclosure further provides a method for enhancing neural growth, enhancing neuritogenesis, enhancing neurite outgrowth, enhancing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and/or increasing excitatory neurotransmission, in a neural cell or neural tissue (e.g., a cell culture), in vitro or in vivo, the method comprising the step of contacting the neural cell or neural tissue with an effective amount of lumateperone, related analogs thereof, deuterated analogs thereof, and other octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalines, in free, or pharmaceutically acceptable salt form.
  • a neural cell or neural tissue e.g., a cell culture
  • the method comprising the step of contacting the neural cell or neural tissue with an effective amount of lumateperone, related analogs thereof, deuterated analogs thereof, and other octahydro-1H
  • the present disclosure provides a method for enhancing neural growth, enhancing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and/or increasing excitatory neurotransmission, in the brain of a subject in need thereof, e.g., in the prefrontal cortex region of the brain, the method comprising the step of administering an effective amount of a Compound of Formula I or a Compound of Formula II, as described herein below.
  • the present disclosure provides a method (Method 1) for enhancing neural growth, enhancing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and/or increasing excitatory neurotransmission, in the brain of a subject in need thereof, e.g., in the prefrontal cortex region of the brain, the method comprising the step of administering an effective amount of a Compound of Formula I (Compound I): wherein X is selected from -O-, -S-, -N(H), and -N(CH3)-, and Y is selected from -O-, -C(O)-, -CH(OH)-, and -CH(OCH 3 ); or a deuterated analog thereof, in free, or pharmaceutically acceptable salt form, to the subject.
  • a Compound of Formula I Compound I: wherein X is selected from -O-, -S-, -N(H), and -N(CH3)-, and Y is selected from
  • the present disclosure provides: Method 1, wherein in the Compound of Formula I, X is -O- or -S-; Method 1, wherein in the Compound of Formula I, X is -N(H) or -N(CH3)-; Method 1, wherein in the Compound of Formula I, X is -N(CH3)-; Method 1, or any of 1.1-1.3, wherein in the Compound of Formula I, Y is -O-; Method 1, or any of 1.1-1.3, wherein in the Compound of Formula I, Y is -C(O)-; Method 1, or any of 1.1-1.3, wherein in the Compound of Formula I, Y is -CH(OH)-; Method 1, or any of 1.1-1.6, wherein the Compound of Formula I is selected from the group consisting of: a deuterated analog Method 1, or any of 1.1-1.7, wherein the Compound of Formula I is selected from: r a deuterated analog Method 1,
  • D represents a hydrogen position with substantially greater than natural deuterium incorporation (i.e., substantially greater than 0.0156%), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90% or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%, in free or pharmaceutically acceptable salt form, e.g., tosylate salt form;
  • the method provides enhanced neural growth in the brain of the subject (e.g., in the prefrontal cortex region of the brain);
  • the method provides enhanced neural connectivity, in the brain of the subject (e.g., in the prefrontal cortex region of the brain);
  • the method provides increased synaptic density, in the brain of the subject (e.g., in the prefrontal cortex region of the brain);
  • the method provides increased dend
  • any foregoing method wherein the subject (e.g., patient) is under concurrent treatment with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine; 1.60. Any foregoing method, wherein the subject (e.g., patient) is not under concurrent treatment with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine; 1.61. Any foregoing method, wherein the subject (e.g., patient) is unresponsive to, or cannot be treated with ketamine (e.g., S-ketamine), e.g., because it is contraindicated in said subject (e.g., patient).
  • ketamine e.g., S-ketamine
  • the disclosure provides Compound of Formula I or a deuterated analog thereof, as hereinbefore described, in free or pharmaceutically acceptable salt form, for use in enhancing neural growth, enhancing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and/or increasing excitatory neurotransmission, in the brain of a subject in need thereof, e.g., in the prefrontal cortex region of the brain, e.g., for use in any of Methods 1, et seq.
  • the disclosure provides the use of Compound of Formula I or a deuterated analog thereof, as hereinbefore described, in free or pharmaceutically acceptable salt form, in the manufacture of a medicament for enhancing neural growth, enhancing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and/or increasing excitatory neurotransmission, in the brain of a subject in need thereof, e.g., in the medial prefrontal cortex region of the brain, e.g., for any of Methods 1, et seq.
  • the present disclosure provides: 2.1. Method 2, wherein in the Compound of Formula II X is S, S(O), or S(O)2; 2.2. Method 2, wherein in the Compound of Formula II, X is O; 2.3. Method 2, wherein in the Compound of Formula II, X CH 2 , CHR b , or C(R b ) 2 ; 2.4. Method 2.3, wherein R b is independently C1-6alkyl (e.g., methyl); 2.5. Method 2, wherein in the Compound of Formula II, X is CH2; 2.6. Method 2, wherein in the Compound of Formula II, X is NH; 2.7.
  • Method 2 or any of 2.1-2.96, wherein in the Compound of Formula II, n is 1 and Z is a bond; 2.104.
  • Method 2 or any of 2.1-2.104 wherein the Compound of Formula II is selected from the group consisting of: acceptable salt or form; 2.106.
  • Method 2 or any of 2.1-2.105, wherein the Compound of Formula II is: wherein the variables are defined as provided in any of the following embodiments: X Y m n Z A Method 2, or any of 2.1-2.107, wherein the Compound of Formula II is in free form; Method 2, or any of 2.1-2.107, wherein the Compound of Formula II is in salt form, e.g., pharmaceutically acceptable salt form; Method 2, or any of 2.1-2.107, wherein the Compound of Formula II is in acid addition salt form, for example, hydrochloric or toluenesulfonic acid salt form; Method 2, or any of 2.1-2.110, wherein the Compound of Formula II is in substantially pure diastereomeric form (i.e., substantially free from other diastereomers); Method 2 or any of 2.1-2.110, wherein the Compound of Formula II has a diastereomeric excess of greater than 70%, preferably greater than 80%, more preferably greater than 90% and most preferably greater than 95%; Method 2 or any of
  • any foregoing method wherein the subject (e.g., patient) is under concurrent treatment with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine; 2.198. Any foregoing method, wherein the subject (e.g., patient) is not under concurrent treatment with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine; 2.199. Any foregoing method, wherein the subject (e.g., patient) is unresponsive to, or cannot be treated with ketamine (e.g., S-ketamine), e.g., because it is contraindicated in said subject (e.g., patient).
  • ketamine e.g., S-ketamine
  • the disclosure provides Compound of Formula II, as hereinbefore described, in free or pharmaceutically acceptable salt form, for use in enhancing neural growth, enhancing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and/or increasing excitatory neurotransmission, in the brain of a subject in need thereof, e.g., in the prefrontal cortex region of the brain, e.g., for use in any of Methods 2, et seq.
  • the disclosure provides the use of Compound of Formula II, as hereinbefore described, in free or pharmaceutically acceptable salt form, in the manufacture of a medicament for enhancing neural growth, enhancing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and/or increasing excitatory neurotransmission, in the brain of a subject in need thereof, e.g., in the medial prefrontal cortex region of the brain, e.g., for any of Methods 2, et seq.
  • the present disclosure provides a method (Method 3) for enhancing neuritogenesis and/or neurite outgrowth in the brain of a subject in need thereof, e.g., in the prefrontal cortex region of the brain, the method comprising the step of administering an effective amount of a Compound of Formula I (Compound I): wherein X is selected from -O-, -S-, -N(H), and -N(CH 3 )-, and Y is selected from -O-, -C(O)-, -CH(OH)-, and -CH(OCH3); or a deuterated analog thereof, in free, or pharmaceutically acceptable salt form, to the subject.
  • a Compound of Formula I Compound I: wherein X is selected from -O-, -S-, -N(H), and -N(CH 3 )-, and Y is selected from -O-, -C(O)-, -CH(OH)-, and -
  • the present disclosure provides: 3.1. Method 3, wherein in the Compound of Formula I, X is -O- or -S-; 3.2. Method 3, wherein in the Compound of Formula I, X is -N(H) or -N(CH 3 )-; 3.3. Method 3, wherein in the Compound of Formula I, X is -N(CH3)-; 3.4. Method 3, or any of 3.1-3.3, wherein in the Compound of Formula I, Y is -O-; 3.5. Method 3, or any of 3.1-3.3, wherein in the Compound of Formula I, Y is -C(O)-; 3.6. Method 3, or any of 3.1-3.3, wherein in the Compound of Formula I, Y is -CH(OH)-; 3.7. Method 3, or any of 3.1-3.6, wherein the Compound of Formula I is selected from the group consisting of: ,
  • r a deuterated analog I is selected from: a deuterated analog I is selected from: r a deuterated analog Method 3, or any of 3.1-3.7, wherein the Compound of Formula I is: (lumateperone), or a deuterated analog thereof; wherein the Compound of Formula I or deuterated analog thereof is in the form of a free base; Method 3, or any of 3.1-3.11, wherein the Compound of Formula I or deuterated analog thereof is in the form of a pharmaceutically acceptable salt; Method 3.12, wherein the pharmaceutically acceptable salt is a toluenesulfonic acid addition salt (e.g., a mono-tosylate salt or a bis-tosylate salt); Method 3 or any of 3.1-3.13, wherein the Compound of Formula I or deuterated analog thereof is non-deuterated lumateperone, i.e., having the following structure: ; Method 3 or any of 3.1-3.14, wherein the Compound of Formula I or salt thereof is in deuterated
  • D represents a hydrogen position with substantially greater than natural deuterium incorporation (i.e., substantially greater than 0.0156%), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90% or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%, in free or pharmaceutically acceptable salt form, e.g., tosylate salt form;
  • the method provides enhanced neural growth in the brain of the subject (e.g., in the prefrontal cortex region of the brain);
  • the method provides enhanced neural connectivity, in the brain of the subject (e.g., in the prefrontal cortex region of the brain);
  • the method provides increased synaptic density, in the brain of the subject (e.g., in the prefrontal cortex region of the brain);
  • the method provides increased dendritic spine density, in
  • aneurysmal vascular disease e.g., thoracic aorta, abdominal aorta, intracranial, or peripheral arterial aneurysms
  • an oral antidepressant selected from duloxetine, escitalopram, sertraline, or ven
  • any foregoing method wherein the subject (e.g., patient) is not under concurrent treatment with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine; 3.61.
  • an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine; 3.61.
  • the subject e.g., patient
  • ketamine e.g., S-ketamine
  • the enhanced neuritogenesis and/or enhanced neurite outgrowth is associated with changes in synaptic neurotransmitter receptor or neurotransmitter transporter density (e.g., increases or decreases in such receptor or transporter density), such as serotonin receptor (e.g., 5-HT 2A , or 5-HT 2C ), dopamine receptor (e.g., D1 or D2), norepinephrine receptor, glutamate receptor (e.g., NMDA-type, AMPA-type, or mGluR-type), GABA receptor (e.g., GABAA or GABAB), serotonin transporter (SERT), dopamine transporter (DAT), norepinephrine transporter (NET), glutamate transporter (e.g., EAAT or VGLUT), and/or GABA transporter (e.g., GAT1, GAT3) density.
  • serotonin receptor e.g., 5-HT 2A , or 5-HT 2C
  • dopamine receptor
  • the present disclosure provides: 4.1. Method 4, wherein in the Compound of Formula II X is S, S(O), or S(O)2; 4.2. Method 4, wherein in the Compound of Formula II, X is O; 4.3. Method 4, wherein in the Compound of Formula II, X CH 2 , CHR b , or C(R b ) 2 ; 4.4. Method 4.3, wherein R b is independently C1-6alkyl (e.g., methyl); 4.5. Method 4, wherein in the Compound of Formula II, X is CH2; 4.6. Method 4, wherein in the Compound of Formula II, X is NH; 4.7.
  • Method 4 wherein in the Compound of Formula II, X is N(R a ); Method 4, wherein in the Compound of Formula II, X is N-C(O)-R a ; Method 4, wherein in the Compound of Formula II, X is N-C(O)-O-R a ; Method 4, wherein in the Compound of Formula II, X is N-C(O)-O-CH2-O-R a ; Method 4, wherein in the Compound of Formula II, X is N-CH 2 -O-C(O)-R a ; Method 4, or any of 4.4-4.11, wherein in the Compound of Formula II, R a is C1- 2alkylaryl (e.g., benzyl or phenethyl); Method 4, or any of 4.4-4.11, wherein in the Compound of Formula II, R a is C 1- 20alkyl (e.g., methyl or tert-butyl); Method 4, or any of 4.4-4.11,
  • Method 4 or any of 4.1-4.96, wherein in the Compound of Formula II, n is 1 and Z is -O- or -C(O)-; 4.103. Method 4, or any of 4.1-4.96, wherein in the Compound of Formula II, n is 1 and Z is a bond; 4.104. Method 4, or any of 4.1-4.103, wherein in the Compound of Formula II, A is H or C3-6cycloalkyl (e.g., cyclopropyl or cyclohexyl), Z is a bond or -C(O)-, and n is 1, 2, or 3; 4.105. Method 4, or any of 4.1-4.104, wherein the Compound of Formula II is selected from the group consisting of: acceptable salt or form; 4.106.
  • Method 2 or any of 2.1-2.105, wherein the Compound of Formula II is: wherein the variables are defined as provided in any of the following embodiments: X Y m n Z A ; Method 4, or any of 4.1-4.107, wherein the Compound of Formula II is in free form; Method 4, or any of 4.1-4.107, wherein the Compound of Formula II is in salt form, e.g., pharmaceutically acceptable salt form; Method 4, or any of 4.1-4.107, wherein the Compound of Formula II is in acid addition salt form, for example, hydrochloric or toluenesulfonic acid salt form; Method 4, or any of 4.1-4.110, wherein the Compound of Formula II is in substantially pure diastereomeric form (i.e., substantially free from other diastereomers); Method 4 or any of 4.1-4.110, wherein the Compound of Formula II has a diastereomeric excess of greater than 70%, preferably greater than 80%, more preferably greater than 90% and most preferably greater than 95%; Method 4 or any
  • Method 4 or any of 4.1-4.114 wherein the Compound of Formula II has 5-HT2A receptor binding affinity of at least 60% at 100 nM concentration, e.g., at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 98%, at 100 nM concentration; Method 4 or any of 4.1-4.115, wherein the Compound of Formula II has a 5-HT2A receptor dissociation constant (K d ) of less than 250 nM, or less than 100 nM, or less than 70 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM, or less than 10 nM; Method 4 or any of 4.1-4.116, wherein the Compound of Formula II is an agonist of beta-arrestin signaling via the 5-HT2A receptor, e.g., a partial agonist or a full agonist; Method 4.
  • any foregoing method wherein the subject (e.g., patient) is not under concurrent treatment with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine; 4.199.
  • an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine; 4.199.
  • the subject e.g., patient
  • ketamine e.g., S-ketamine
  • the enhanced neuritogenesis and/or enhanced neurite outgrowth is associated with changes in synaptic neurotransmitter receptor or neurotransmitter transporter density (e.g., increases or decreases in such receptor or transporter density), such as serotonin receptor (e.g., 5-HT 2A , or 5- HT 2C ), dopamine receptor (e.g., D1 or D2), norepinephrine receptor, glutamate receptor (e.g., NMDA-type, AMPA-type, or mGluR-type), GABA receptor (e.g., GABAA or GABAB), serotonin transporter (SERT), dopamine transporter (DAT), norepinephrine transporter (NET), glutamate transporter (e.g., EAAT or VGLUT), and/or GABA transporter (e.g., GAT1, GAT3) density.
  • serotonin receptor e.g., 5-HT 2A , or 5- HT 2C
  • the disclosure provides a Compound of Formula I or a deuterated analog thereof, as hereinbefore described, or a Compound of Formula II, as hereinbefore described, each in free or pharmaceutically acceptable salt form, for use in enhancing neuritogenesis and/or neurite outgrowth, in the brain of a subject in need thereof, e.g., in the prefrontal cortex region of the brain, e.g., for use in any of Methods 3 et seq. or 4, et seq.
  • the disclosure provides the use of a Compound of Formula I or a deuterated analog thereof, as hereinbefore described, or a Compound of Formula II, as hereinbefore described, each in free or pharmaceutically acceptable salt form, in the manufacture of a medicament for enhancing neuritogenesis and/or neurite outgrowth, in the brain of a subject in need thereof, e.g., in the medial prefrontal cortex region of the brain, e.g., for any of Methods 3, et seq. or 4 et seq.
  • the present disclosure provides a method (Method 5) for enhancing neural growth, enhancing neuritogenesis, enhancing neurite outgrowth, enhancing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and/or increasing excitatory neurotransmission, in a neural cell or neural tissue (e.g., a cell culture), in vitro or in vivo, the method comprising the step of contacting the neural cell or neural tissue with an effective amount of a Compound of Formula I or a deuterated analog thereof, or a Compound of Formula II, each in free or pharmaceutically acceptable salt form.
  • the present disclosure provides: 5.1.
  • Method 5 wherein the neural cell or neural tissue is contacted by an effective amount of a Compound of Formula I, or deuterated analog thereof, as described in any of Method 1 or 1.1-1.16 hereinabove; 5.2.
  • Method 5 wherein the neural cell or neural tissue is contacted by an effective amount of a Compound of Formula II, as described in any of Method 2 or 2.1-2.154 hereinabove; 5.3.
  • Any foregoing method, wherein the method provides enhanced neural growth in the neural cell or neural tissue; 5.4.
  • Any foregoing method wherein the method provides enhanced neural connectivity, in the neural cell or neural tissue; 5.5.
  • any foregoing method wherein the method provides increased dendritic spine density, in neural cell or neural tissue; 5.7. Any foregoing method, wherein the method provides increased dendritic spine size (e.g., increased width of spine heads and/or increased spine protrusion lengths), neural cell or neural tissue; 5.8. Any foregoing method, wherein the method provides increased excitatory neurotransmission (e.g., enhanced glutamatergic transmission or increased rate of mEPSCs), in the neural cell or neural tissue; 5.9.
  • the method provides increased dendritic spine density, in neural cell or neural tissue; 5.7. Any foregoing method, wherein the method provides increased dendritic spine size (e.g., increased width of spine heads and/or increased spine protrusion lengths), neural cell or neural tissue; 5.8. Any foregoing method, wherein the method provides increased excitatory neurotransmission (e.g., enhanced glutamatergic transmission or increased rate of mEPSCs), in the neural cell or neural tissue; 5.9.
  • Method 5 or any of 5.1-5.8, wherein the method provides the enhanced neural growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and/or increased excitatory neurotransmission, in the neural cell or neural tissue within less than 4 weeks of the initiation of administration of the Compound of Formula I, or deuterated analog thereof, or Compound of Formula II, e.g., less than 3 weeks, less than 2 weeks, less than 1 week, less than 6 days, less than 5 days, less than 4 days, less than 3 days, or less than 2 days, after the initiation of treatment with the Compound of Formula I, or deuterated analog thereof, or Compound of Formula II; Method 5, or any of 5.1-5.9, wherein the method maintains at least 50% of the peak enhanced neural growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and/or increased excitatory neurotransmission, in the brain of the subject (e.g., in the prefrontal cortex
  • Method 5.20 wherein the compound does not cause observations consistent with hallucinogenic side effects in the animal during administration of the compound; 5.22. Method 5, or any of 5.1-5.21, wherein the method is carried out to determine whether the compound is effective in enhancing neural growth, enhancing neuritogenesis, enhancing neurite outgrowth, enhancing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and/or increasing excitatory neurotransmission in vivo in an animal model, e.g. an animal model of a neuropsychiatric disorder; 5.23.
  • the disclosure provides a Compound of Formula I or a deuterated analog thereof, as hereinbefore described, or a Compound of Formula II, as hereinbefore described, each in free or pharmaceutically acceptable salt form, for use in a method for enhancing neural growth, enhancing neuritogenesis, enhancing neurite outgrowth, enhancing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and/or increasing excitatory neurotransmission, in a neural cell or neural tissue (e.g., a cell culture), in vitro or in vivo, e.g., any of Method 5 et seq.
  • a neural cell or neural tissue e.g., a cell culture
  • in vitro or in vivo e.g., any of Method 5 et seq.
  • the “Compounds of the Disclosure” refers to any compound described in any of Methods I or 1.1-1.16 or Methods 2 or 2.1-2.154, such as lumateperone, related analogs thereof, deuterated analogs thereof, and other octahydro-1H- pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalines, each in free or pharmaceutically acceptable salt form.
  • spiro-joined is meant to clarify that the stated C3- 6 cycloalkyl group or 3-6-membered heterocycloalkyl is present in a spiro-junction, meaning that one atom of said cyclic group is an atom of the ring to which the group is attached.
  • the follow are examples of compounds of Formula II having spiro-joined cyclic groups within the scope of the present disclosure: , , , .
  • the Compounds of Formula II are biased agonists of the serotonin 5-HT2A receptor.
  • biasing agonist as used herein, is used in reference to a compound having activity at the serotonin 5-HT2A receptor with either partial or full agonism for beta-arrestin signaling via the receptor, but with either antagonism or weak partial agonism for G-q mediated signaling.
  • a useful measure of bias is the “bias ratio”, which is calculated as the ratio of the intrinsic relative activity (RAi) for beta-arrestin signaling over the RAi for G-q signaling.
  • a non-biased agonist has a bias ratio of 1.0.
  • a biased agonist has a non-zero bias ratio.
  • compounds of the present disclosure are preferably biased towards beta-arrestin signaling, and thus have a bias ratio greater than 1.0.
  • the bias ratio towards beta-arrestin signaling is greater than 10, or greater than 100, or greater than 1000, or 10,000 or more.
  • partial agonist is understood to refer to a compound having agonism to any extent that is lesser than that of a reference standard full agonist.
  • the reference compound for 5-HT2A receptor agonism is alpha-methylserotonin.
  • a compound which has a maximum efficacy (Emax) that is less than 100% of the maximum efficacy for alpha-methylserotonin is a partial agonist.
  • hallucinogen refers to a compound which causes hallucinogenic symptoms, which are any one or more symptoms selected from visual hallucinations, auditory hallucinations, visual distortions (such as drifting, morphing, breathing or melting of objects and surfaces in the field of view), detachment from reality, dissociation, delirium, and undesired altered states of consciousness.
  • a compound of the present disclosure is considered “non- hallucinogenic” if at doses which are therapeutically effective for the treatment of neuropsychiatric disorders described herein (e.g., depression, anxiety, etc.) the compound does not cause hallucinogenic symptoms.
  • Alkyl as used herein is a saturated or unsaturated hydrocarbon moiety, e.g., one to twenty-one carbon atoms in length, unless indicated otherwise; any such alkyl may be linear or branched (e.g., n-butyl or tert-butyl), preferably linear, unless otherwise specified.
  • C1-21 alkyl denotes alkyl having 1 to 21 carbon atoms.
  • alkyl is optionally substituted with one or more hydroxy or C 1-22 alkoxy (e.g., ethoxy) groups.
  • alkyl contains 1 to 21 carbon atoms, preferably straight chain and optionally saturated or unsaturated, for example in some embodiments wherein R 1 is an alkyl chain containing 1 to 21 carbon atoms, preferably 6-15 carbon atoms, 16-21 carbon atoms, e.g., so that together with the -C(O)- to which it attaches, e.g., when cleaved from the compound of Formula II, forms the residue of a natural or unnatural, saturated or unsaturated fatty acid.
  • treatment and “treating” are to be understood accordingly as embracing prophylaxis and treatment or amelioration of symptoms of disease and/or treatment of the cause of the disease.
  • the words “treatment” and “treating” refer to prophylaxis or amelioration of symptoms of the disease.
  • the term “brain” or “brain region” may refer to any structural or functional region of the brain, including, but not limited to, the prefrontal cortex (e.g., medial prefrontal cortex, lateral prefrontal cortex, dorsomedial prefrontal cortex, dorsolateral prefrontal cortex, ventromedial prefrontal cortex, ventral prefrontal cortex), amygdala, hippocampus, frontal cortex, orbitofrontal cortex, insula cortex, fronto-insular cortex, anterior cingulate cortex, subcallosal cingulate cortex, ventral tegmental area, ventral palladium, nucleus accumbens, supramarginal gyrus, inferior temporal gyrus, and the subgenual cingulate area, Each of these brain regions has been associated with one or more of emotion, cognition, depression, psychos
  • the brain regions affected by the methods disclosed herein include subregions of the prefrontal cortex (e.g., the mPFC), the amygdala, and/or the hippocampus.
  • the prefrontal cortex is the anterior region of the frontal lobe of the cerebral cortex, and it is the primary region of the brain responsible for the orchestration of thoughts and actions.
  • the prefrontal cortex has several subregions. In humans, the PFC is generally divided into the ventromedial PFC (vmPFC, including the ventral prefrontal cortex, vPFC, and the medial prefrontal cortex, mPFC) and the lateral prefrontal cortex (LPFC, including the dorsolateral prefrontal cortex, dLPFC, and the ventrolateral prefrontal cortex, vLPFC).
  • vmPFC including the ventral prefrontal cortex, vPFC, and the medial prefrontal cortex, mPFC
  • LPFC lateral prefrontal cortex
  • the mPFC includes the anterior cingulate cortex, which is important for many higher-level functions.
  • the dlPFC is thought to be particularly important in the pathogenesis of depression.
  • the methods are directed to providing structural remodeling in any of the regions of the PFC, including for example, the mPFC or the dLPFC.
  • the term “patient” may include a human or non-human patient.
  • DSM-5 The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (“DSM-5”), defines “major depressive disorder” (MDD) as having five or more of a set of symptoms during the same two-week period of time, which symptoms represent a change from the patient’s previous functioning.
  • the five symptoms are selected from depressed mood, markedly diminished interest or pleasure in almost all activities, significant weight changes, insomnia or hyposomnia, psychomotor agitation or retardation, fatigue, feelings of worthlessness or excessive guilt, diminished ability to think or indecisiveness, and recurrent thoughts of death or suicidal ideation, wherein each of such symptoms is present nearly every day.
  • MDD diagnosis requires at least depressed mood or loss of interest or pleasure as one of the five symptoms.
  • MDD may consist of one or more “major depressive episodes” which can be spaced many weeks or months apart (more than 2 weeks apart to qualify as separate episodes).
  • the DSM-5 notes that there is a risk of suicidal behavior at all time during a major depressive episode.
  • MDD is an acute disorder in so far as the DSM-5 distinguishes it from “persistent depressive disorder”, in which a patient has many of the same symptoms as for MDD, but which persists for at least a 2-year period.
  • the DSM-5 also defines a “short-duration depressive episode” as having a depressed affect and at least four of the other symptoms which define MDD for at least 4 days, but less than 14 days.
  • the DSM further defines “recurrent brief depression” as the concurrent presence of depressed mood and at least four other symptoms of depression for 2 to 13 days at least once per month, and persisting for at least 12 consecutive months.
  • recurrent brief depression similarly consists of brief episodes of depression which recur regularly.
  • the DSM-5 also includes major depressive episodes as one of the diagnostic criteria for a patient suffering from bipolar disorder.
  • a patient presenting a major depressive episode may be suffering from either major depressive disorder or bipolar disorder.
  • SSRI anti-depressive agents take up to 2-4 weeks for beneficial effects to appear. The same is true for treatment of short duration depressive episodes as well as individual episodes of recurrent brief depression.
  • the DSM-5 categorizes what has traditionally been termed “post-partum depression” or “peri-partum depression” as a merely a sub-type of the DSM’s recognized depressive disorders, rather than as an independent depressive disorder. Thus, both major depressive disorder and acute depressive disorders can be diagnosed as being “with peripartum onset” (DSM-5 also does not distinguish peri- versus post-partum). Thus, as used herein, any of the depression indications may be considered to include such depression indication with peri-partum or post-partum onset, and thus, these indications embrace post-partum and peri-partum depression as well.
  • the DSM-5 defines a variety of anxiety disorders, including generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobias. Like the depressive disorders discussed above, anxiety disorders can be marked by recurrent episodes of short duration, such as panic attacks, which may persist over the course of a chronic disorder.
  • generalized anxiety disorder is defined by the DSM-5 to require excessive anxiety and worry occurring more days that not for at least 6 months, about a number of events or activities.
  • a panic attack is defined as an abrupt surge of intense fear or intense discomfort that reaches a peak within minutes, but it can repeatedly recur in response to either expected stimuli or unexpected stimuli.
  • Negative symptoms of schizophrenia can be divided into two categories: emotional experience (e.g., emotional withdrawal, passive social withdrawal, active social avoidance) and emotional expression (e.g., blunted effect, poor rapport, lack of spontaneity, and motor retardation).
  • emotional experience e.g., emotional withdrawal, passive social withdrawal, active social avoidance
  • emotional expression e.g., blunted effect, poor rapport, lack of spontaneity, and motor retardation.
  • administration of lumateperone once daily (60 mg P.O.) for up to 28 days, resulted in a significant and unexpected improvement in symptoms of emotional experience compared to placebo.
  • Compounds of the Disclosure may be highly effective in treating the emotional experience symptoms of other psychiatric disorders, such as social anxiety disorders, or any other psychiatric disorders in which social withdrawal and social avoidance are symptoms.
  • the following terms herein have the following meanings:
  • the Compounds of the Disclosure, as described herein may be in free or pharmaceutically acceptable salt form.
  • Pharmaceutically acceptable salts include, for example, the tosylate salts in the case of Compounds of Formula I or II.
  • dosages or amounts of a salt are given by weight, e.g., milligrams per day or milligrams per unit dose, the dosage amount of the salt is given as the weight of the corresponding free base, unless otherwise indicated.
  • the term “concurrently” when referring to a therapeutic use means administration of two or more active ingredients to a patient as part of a regimen for the treatment of a disease or disorder, whether the two or more active agents are given at the same or different times or whether given by the same or different routes of administrations. Concurrent administration of the two or more active ingredients may be at different times on the same day, or on different dates or at different frequencies.
  • the term “simultaneously” when referring to a therapeutic use means administration of two or more active ingredients at or about the same time by the same route of administration. [0068] The term “separately” when referring to a therapeutic use means administration of two or more active ingredients at or about the same time by different route of administration. [0069] With respect to concurrent treatment using Compounds of the Disclosure and an NMDA receptor antagonist (e.g., ketamine), without being bound by theory, it is believed that the combination of these agents would permit lower doses of both agents to be provide the desired effects according to the methods described herein, such that the dissociative effects produced by the NMDA receptor antagonist would be minimized while the synergistic effects would be maximized.
  • an NMDA receptor antagonist e.g., ketamine
  • an amount of an active compound for administration refers to or is based on the amount of the compound in free form (i.e., the calculation of the amount is based on the amount of active moiety in free form, not taking into account the weight of the counter ion in the case of a salt).
  • the Compounds of the Disclosure may be administered by any suitable route, including oral, parenteral, transdermal, or transmucosal, for example in the form of a tablet, a capsule, a subcutaneous injection, or an oral, rapidly disintegrating tablet or film for sublingual or buccal administration.
  • any disclosure of a numerical range, e.g., “up to X” amount is intended to include the upper numerical limit X. Therefore, a disclosure of “up to 60 mg” is intended to include 60 mg.
  • Pharmaceutical compositions comprising compounds of the Disclosure may be prepared using conventional diluents or excipients and techniques known in the galenic art.
  • oral dosage forms may include tablets, capsules, solutions, suspensions and the like.
  • Compounds of the Disclosure may be included as a depot formulation, e.g., by dispersing, dissolving, suspending, or encapsulating the Compounds of the Disclosure in a polymeric matrix as described in herein, such that the Compound is continually released as the polymer degrades over time.
  • the release of the Compounds of the Disclosure from the polymeric matrix provides for the controlled- and/or delayed- and/or sustained-release of the Compounds, e.g., from the pharmaceutical depot composition, into a subject, for example a warm-blooded animal such as man, to which the pharmaceutical depot is administered.
  • the pharmaceutical depot delivers the Compounds of the Disclosure to the subject at concentrations effective for treatment of the particular disease or medical condition over a sustained period of time, e.g., 1 week to 3 months.
  • Polymers useful for the polymeric matrix in the Composition of the Disclosure may include a polyester of a hydroxyfatty acid and derivatives thereof or other agents such as polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, poly-beta.-hydroxybutyric acid, epsilon.-capro-lactone ring opening polymer, lactic acid-glycolic acid copolymer, 2-hydroxybutyric acid-glycolic acid copolymer, polylactic acid-polyethyleneglycol copolymer or polyglycolic acid-polyethyleneglycol copolymer), a polymer of an alkyl alpha-cyanoacrylate (for example poly(butyl 2-cyanoacrylate)), a polyalky
  • the polymers are copolymers, they may be any of random, block and/or graft copolymers.
  • any one of D-isomers, L- isomers and/or DL-isomers may be used.
  • alpha-hydroxycarboxylic acid polymer preferably lactic acid-glycolic acid polymer
  • its ester preferably lactic acid-glycolic acid polymer
  • poly-alpha-cyanoacrylic acid esters etc.
  • lactic acid-glycolic acid copolymer also referred to as poly(lactide-alpha- glycolide) or poly(lactic-co-glycolic acid), and hereinafter referred to as PLGA
  • PLGA lactic acid-glycolic acid copolymer
  • the polymer useful for the polymeric matrix is PLGA.
  • the term PLGA includes polymers of lactic acid (also referred to as polylactide, poly(lactic acid), or PLA).
  • the polymer is the biodegradable poly(d,l-lactide-co-glycolide) polymer, such as PLGA 50:50, PLGA 85:15 and PLGA 90:10.
  • the polymeric matrix is a biocompatible and biodegradable polymeric material.
  • biocompatible is defined as a polymeric material that is not toxic, is not carcinogenic, and does not significantly induce inflammation in body tissues.
  • the matrix material should be biodegradable wherein the polymeric material should degrade by bodily processes to products readily disposable by the body and should not accumulate in the body.
  • the products of the biodegradation should also be biocompatible with the body in that the polymeric matrix is biocompatible with the body.
  • polymeric matrix materials include poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid, copolymers of the foregoing, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxanone, poly(ortho carbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and natural polymers including albumin, casein, and waxes, such as, glycerol mono- and distearate, and the like.
  • the preferred polymer for use in the practice of this invention is dl(polylactide-co-glycolide).
  • Useful PLGA polymers may have a weight-average molecular weight of from about 5,000 to 500,000 Daltons, preferably about 150,000 Daltons. Dependent on the rate of degradation to be achieved, different molecular weight of polymers may be used. For a diffusional mechanism of drug release, the polymer should remain intact until all of the drug is released from the polymeric matrix and then degrade. The drug can also be released from the polymeric matrix as the polymeric excipient bioerodes.
  • the PLGA may be prepared by any conventional method, or may be commercially available.
  • PLGA can be produced by ring-opening polymerization with a suitable catalyst from cyclic lactide, glycolide, etc. (see EP-0058481B2; Effects of polymerization variables on PLGA properties: molecular weight, composition and chain structure).
  • a suitable catalyst from cyclic lactide, glycolide, etc.
  • EP-0058481B2 Effects of polymerization variables on PLGA properties: molecular weight, composition and chain structure.
  • Both lactic acid and glycolic acid are water-soluble, non-toxic products of normal metabolism, which may further biodegrade to form carbon dioxide and water.
  • PLGA is believed to degrade by means of hydrolysis of its ester groups in the presence of water, for example in the body of a warm-blooded animal such as man, to produce lactic acid and glycolic acid and create the acidic microclimate.
  • Lactic and glycolic acid are by-products of various metabolic pathways in the body of a warm-blooded animal such as man under normal physiological conditions and therefore are well tolerated and produce minimal systemic toxicity.
  • the resulting mixture is heated to 95 °C and stirred for 6.5 hours. After cooling to room temperature, the solvent is removed, and the residue is suspended in ethyl acetate (50 mL) and water (50 mL). The aqueous phase is separated and extracted twice with ethyl acetate (30 mL). The combined organic phase is dried over MgSO4 and concentrated. The residue is purified by silica gel column chromatography using a gradient of 0 – 20% mixed solvents [ethyl acetate/methanol/7N NH3 in methanol (10 : 1 : 0.1 v/v)] in ethyl acetate to obtain the title product as a brown solid (0.8 g, yield 16%).
  • Example 2 Evaluation of a Compound of Formula I and/or Compound of Formula II for Effects on Dendritic Spine Turnover in Mice
  • One or more Compounds of Formula I or II are evaluated using procedures as more fully described in Shao et al., Neuron, 109(16):2535-2544 (2021), such as the Compound of Example 1.
  • the purpose of the study is to evaluate dendritic spine turnover (formation of new spines and loss of spines) in mice as a function of treatment with the Compound(s).
  • the study analyzes the effects of acute and chronic Compound administration on longitudinal spine analyses in the mPFC using two-photon imaging technique (see below) in anesthetized mice.
  • mice Male and female transgenic mice Thy1 GFP (line M) mice are obtained from Jackson Laboratory and are 4 to 8-weeks old at receipt in order to be used for imaging about 2 weeks later. Mice are group housed (2 – 5 mice per cage) under controlled temperature in a 12- hour light–dark cycle with free access to food and water. [0087] The Compound(s) are formulated about 30 minutes before use in a vehicle composed of 5% DMSO, 5% Tween-20, 15% PEG-400 and 75% water for the acute injection.
  • mice are divided into at least four groups: (1) no stress, vehicle treatment; (2) stress, vehicle treatment; (3) stress, Compound treatment (10 mg/kg, i.p. or s.c.); (4) stress, psilocybin (1 mg/kg, i.p.) treatment. There are 4-6 animals per group. If more than one Compound is tested, then additional groups (3) may be employed.
  • either one of more of the Compounds and the psilocybin may be evaluated both after acute treatment (single injection) or chronic treatment (daily injection for a period of days or a single long-acting injection), and thus, additional groups may be employed.
  • Drug injections (vehicle, Compound(s), or psilocybin) are given once daily beginning on either day -15, day -7, or day 0.
  • a single drug injection is given once on either day -15, day -7, or day 0. Imaging is conducted through day 22, for example, at days -15, -3, -1, 1, 8, 15, and 22 (+/- 1 day).
  • Restraint stress is a model of chronic stress-induced depression that has been described to lead to robust morphological and neurochemical brain alterations, as well as behavioral and cognitive deficits Stress is applied as chronic restraint stress from day -21 to day -1 or day 0, according to standard procedures (e.g., Buynitsky et al. 2009, PMID: 19463853; Chiba et al. 2012, PMID: 22664354; Jaggi et al. 2011, PMID: 21927881; O'Mahony et al., 2011, PMID: 21110995; Ju et al. 2022, PMID: 35291971; Codeluppi et al., 2021. PMID: 34346493).
  • standard procedures e.g., Buynitsky et al. 2009, PMID: 19463853; Chiba et al. 2012, PMID: 22664354; Jaggi et al. 2011, PMID: 21927881; O'Mahony e
  • restraint stress is performed using either one of two methods.
  • mice are individually placed head-first into a well-ventilated 50 ml Falcon polypropylene conical tube with a small hole at each extremity of the tube (bottom and cap). The nose of the mouse is the closest to the bottom hole, hence assuring proper ventilation. Mice are not able to move forward or backward in this device and are maintained in the restraint tube placed on a secure surface at room temperature under the hood of the Biological Safety Cabinet.
  • restraint stress maybe performed in a mouse restrainer device (e.g., Stoelting Ref# 51338 Cylindrical Restrainer or a tapered plastic DecapiCone).
  • mice are returned to their home cages in the animal facility and allowed free access to food and water until the next restraint cycle.
  • Spine density is assessed from baseline before stress on day -21 to day 22. Spine formation and elimination rates are assessed during stress on day -3 and day -1, and after treatment on day 1.
  • carprofen 5 mg/kg, s.c.
  • dexamethasone 3 mg/kg, i.m.
  • each mouse is anesthetized with isoflurane (3 – 4% for induction and 1 – 1.5% for the remainder of surgery) and fixed in a stereotaxic apparatus (David Kopf Instruments).
  • the body of the mouse rests on a water-circulating heating pad set to 38 °C.
  • the hair on the head is shaved, and the scalp is then wiped and disinfected with ethanol pad and betadine.
  • An incision is made to remove the skin and the connective tissue above the skull is removed.
  • a dental drill is used to make an about 3-mm-diameter circular craniotomy above the right medial frontal cortex (center position: +1.5 mm anterior-posterior, AP; +0.4 mm medial-lateral, ML; relative to bregma).
  • Artificial cerebrospinal fluid (ACSF, containing (in mM): 135 NaCl, 5 HEPES, 5 KCl, 1.8 CaCl2, 1 MgCl2; pH 7.3) is used to irrigate the exposed dura above brain.
  • a two-layer glass window is made from two round 3-mm-diameter, #1 thickness glass coverslip, bonded by UV-curing optical adhesive.
  • the glass window is carefully placed over the craniotomy and, while maintaining a slight pressure, adhesive (Henkel Loctite 454) is used to secure the glass window to the surrounding skull.
  • a stainless steel headplate is affixed on the skull with C&B Metabond (Parkell) centered on the glass window.
  • Carprofen (5 mg/kg, s.c.) is given to the mouse immediately after surgery and on each of the following 3 days. The mouse recovers for at least 20 days after the surgery and before the start of imaging experiments.
  • a two-photon microscope (Movable Objective Microscope, Sutter Instrument) is controlled by ScanImage 2020 software21.
  • the laser excitation is provided by a tunable Ti:Sapphire femtosecond laser (Chameleon Ultra II, Coherent) and focused onto the mouse brain with a water-immersion 20X objective (XLUMPLFLN, 20x/0.95 N.A., Olympus).
  • the laser power measured at the objective is less than or equal to 40 mW.
  • the mouse is head fixed and anesthetized with 1-1.5% isoflurane.
  • Body temperature is controlled using a heating pad and a DC Temperature Controller with rectal thermistor probe feedback.
  • Each imaging session does not exceed 2 hours.
  • Apical tuft dendrites are imaged at 0-200 ⁇ m below the dura. Multiple fields of view are imaged in the same mouse.
  • the head width of a dendritic spine is measured as the width at the widest part of the head of the spine.
  • the protrusion length of a dendritic spine refers to the distance from its root at the shaft to the tip of the head.
  • the line segment tool in ImageJ will be used to measure the distances. Changes in spine density, spine head width, and spine protrusion length, across imaging sessions are shown as fold-change from the value measured on the first imaging session (day -3) for each dendritic segment.
  • the spine formation rate is calculated as the number of dendritic spines newly formed between two consecutive imaging sessions divided by the total number of dendritic spines observed in the first imaging session.
  • the spine elimination rate is calculated as the number of dendritic spines lost between two consecutive imaging sessions divided by the total number of dendritic spines observed in the first imaging session. To quantify the persistence of newly formed spines, the number of dendritic spines newly formed on day 1 that are still be present on day 15 and 22 is calculated, and divided by the total number of newly formed dendritic spines on day 1. [0096] These results of the study will show that the test Compounds, and psilocybin, both promote the formation of new dendritic spines, and otherwise promote dendritic growth and neuritogenesis.
  • Example 3 Evaluation of a Compound of Formula I and/or Compound of Formula II for Effects on mTOR signaling in the brain pre-frontal cortex (PFC)
  • Male adult mice are injected SC with either test compound (1 mg/kg and/or 3 mg/kg and/or 10 mg/kg) or vehicle.
  • samples from the brain e.g., the pre- frontal cortex (PFC) region or the amygdala
  • a synaptoneurosome-enriched fraction is collected and prepared for Western blotting.
  • Quantitative analysis of phospho (p) protein immunoblots are determined relative to total levels of each protein.
  • Changes in the amount of phosphorylated ERK, Akt, mTOR, and P70S6K proteins, in the tested brain regions are determined relative to vehicle-treated mice, as previously described (Dutheil, et al., J. Neuroscience, 43(5):863-77, 2023). [0098]
  • the test compounds are found to stimulate mTOR signaling in a dose-dependent fashion in the mouse medial PFC, as demonstrated by increases in one or more of p-ERK, p- mTOR, and p-P70s6k in the tested brain regions.
  • the mTOR signaling pathway has been shown to contribute to neuroplasticity and enhanced cognitive function and it is altered in brain regions associated with major depressive disorder.
  • Rapid-acting antidepressants have been reported to stimulate this pathway in the prefrontal cortex. Similar results are obtained using samples from the amygdala. Further studies are performed using hippocampus brain samples. [0099] These results will support that the compound of the present disclosure, through their effects on the mTOR signaling pathway, are expected to provide enhanced neural growth, enhanced neuritogenesis, enhanced neurite outgrowth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and/or increasing excitatory neurotransmission, and other effects described herein, in the brain of a human or animal or in neural cell or neural tissue, in vivo or in vitro.
  • the compounds of the present disclosure may be studied using in vivo or in vitro examination of the synaptic intensity of fluorescent-tagged neurotransmitter receptors or transporters, for example GFP (green fluorescent protein)- or SEP (super-ecliptic pHluorin)-tagged receptors or transporters, such as AMPA-type glutamate receptors.
  • fluorescent-tagged neurotransmitter receptors or transporters for example GFP (green fluorescent protein)- or SEP (super-ecliptic pHluorin)-tagged receptors or transporters, such as AMPA-type glutamate receptors.
  • Various methods of fluorescence microscopy can be utilized, optionally with machine-learning-enhanced analytical methods, such as those described in Xu et al., “Cross-modality supervised image restoration enables nanoscale tracking of synaptic plasticity in living mice,” Nature Methods 20:935-944 (June 2023; published online May 2023).
  • Such methods may be applied to the analysis of the function, activity, and distribution of numerous synaptic receptors and transporters, such as serotonin receptor (e.g., 5-HT 2A , or 5-HT 2C ), dopamine receptor (e.g., D1 or D2), norepinephrine receptor, glutamate receptor (e.g., NMDA-type, AMPA-type, or mGluR- type), GABA receptor (e.g., GABAA or GABAB), serotonin transporter (SERT), dopamine transporter (DAT), norepinephrine transporter (NET), glutamate transporter (e.g., EAAT or VGLUT), and/or GABA transporter (e.g., GAT1, GAT3) density in the synapses.
  • serotonin receptor e.g., 5-HT 2A , or 5-HT 2C
  • dopamine receptor e.g., D1 or D2
  • norepinephrine receptor e

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Abstract

La présente invention concerne l'utilisation de composés de formule (I), de composés de formule (II) et d'analogues associés pour améliorer la neuritogenèse, améliorer l'excroissance des neurites, améliorer la croissance neuronale, la connectivité neuronale, la densité synaptique, la densité des épines dendritiques, la taille des épines dendritiques et la neurotransmission excitatrice, dans le cerveau (p. ex. dans le cortex préfrontal médial), et d'autres procédés et utilisations associées.
EP24715032.9A 2023-02-17 2024-02-16 Lumatépérone et ses dérivés pour moduler le système nerveux Pending EP4665344A1 (fr)

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