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WO2024227149A2 - Sels d'amines quaternaires d'alcoxy et de carbamoyle utilisés comme promédicaments de trpytamines - Google Patents

Sels d'amines quaternaires d'alcoxy et de carbamoyle utilisés comme promédicaments de trpytamines Download PDF

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Publication number
WO2024227149A2
WO2024227149A2 PCT/US2024/026797 US2024026797W WO2024227149A2 WO 2024227149 A2 WO2024227149 A2 WO 2024227149A2 US 2024026797 W US2024026797 W US 2024026797W WO 2024227149 A2 WO2024227149 A2 WO 2024227149A2
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compound
disorder
minutes
cycloalkyl
life
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PCT/US2024/026797
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WO2024227149A3 (fr
Inventor
Alan Gibbs
Tanweer Khan
Bob PERNI
Glenn Short
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Atai Therapeutics Inc
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Atai Therapeutics Inc
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Publication of WO2024227149A2 publication Critical patent/WO2024227149A2/fr
Publication of WO2024227149A3 publication Critical patent/WO2024227149A3/fr
Anticipated expiration legal-status Critical
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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
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to novel compounds with potential for treating mental health disorders which overcome solubility and oral bioavailability issues to act as (partial) agonists of the CNS serotonin receptor, 5-HT2A. Specifically, these compounds persist through first pass metabolism and cross the blood brain barrier, resulting in therapeutically effective concentrations at the site of action.
  • G protein-coupled receptors, or GPCRs are a major class of membrane proteins.
  • GPCRs are encoded by the human genome and when expressed are located in the plasma membrane to act as the ‘eyes and ears’ of the cell (Gurevich and Gurevich, GPCR Signaling Regulation: the Role of GRKs and Arrestins, Front Pharmacol 10:125 (2019)). Structurally they are composed of seven transmembrane alpha helices connected by intra- and inter-cellular loops of various lengths. These helices and loops play important roles in binding effectors, and/or other proteins, which often results in a signaling or communication event. Signaling of GPCRs produce cellular responses crucial for the health and benefit of the cell and organism.
  • GPCRs are expressed in the central nervous system (CNS), one example is the serotonin family of receptors.
  • the serotonin family is divided into subfamilies, 5-HT1 to 5- HT7 (note: 5-HT3 is a non-GPCR subfamily) and further into subtypes, eg.: the 5-HT2 subfamily is composed of 5-HT2A, 5-HT2B and 5-HT2C (Pandy-Szekeres, G. et. al., The G protein database, GprotieinDb. Nucleic acids research, 50:D518-D525 (2022)). 12 serotonin GPCR subtypes have been identified.
  • Serotonin receptors bind serotonin (or 5-hydroxytryptamine) triggering signal transduction, the downstream effects of which modulate a variety of processes such as: memory, sleep, mood and vision among others (Sizemore, T.R., et. al., Serotonergic modulation across sensory modalities, J Neurophysiol, 123, 2406 (2020)).
  • serotonin receptors are known to bind other endogenous neurotransmitters as well as exogenous small molecules. Indeed, many small molecule drugs have been developed that either activate or deactivate serotonin receptors leading to positive outcomes for a variety of neuropsychiatric disorders (Terry, A.V., Drugs that target serotonergic receptors.
  • a strong first pass effect oxidizes 100% of DMT after oral administration and therefore DMT must be administered with a MOA-A inhibitor to be orally active (Riba, J., et. al., Metabolism and urinary disposition of N, N -dimethyltryptamine after oral and smoked administration: a comparative study. Drug Test Anal, 7(5), 401 (2015)).
  • classic psychedelic tryptamine solubility and duration of target engagement may not be ideal for many therapeutic purposes. [0005] Therefore, a significant need exists for readily administrable medications which overcome solubility and oral bioavailability issues to act as (partial) agonists of the CNS serotonin receptor, 5-HT2A, to treat neurological diseases and conditions.
  • the present disclosure provides, in one respect, compounds which act as (partial) agonists of the central nervous system (CNS) serotine receptor, 5-HT2A. These compounds overcome solubility and oral bioavailability issues and persist through first pass metabolism and cross the blood brain barrier.
  • the compounds identified herein maintain overall selectivity profiles similar to that of DMT, 5-MeO-DMT and 4-hydroxy-DMT but with potentially improved PK properties and half-life.
  • the compounds are a compound of Formula I: ATTORNEY DOCKET NO.: 100014_00074 wherein L is a counter ion; X, Y, and Z are independently hydrogen, deuterium, OR 1 , CO 2 R 1 , or NR 1 R 2 ; W is NR 1 , OR 1 , or CR 1 R 2 ; M is a CR 5 R 6 R 7 , OR 5 , or NR 5 R 6 ; and R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 , are independently hydrogen, deuterium, alkyl, cycloalkyl, heteroatom substituted and halogen substituted alkyl or cycloalkyl, aromatic, or heteroaromatic.
  • L is a counter ion
  • X, Y, and Z are independently hydrogen, deuterium, OR 1 , CO 2 R 1 , or NR 1 R 2
  • W is NR 1 , OR 1 , or CR 1 R 2
  • M
  • L is a Cl-, Br-, I-, CH 2 FCOO-, CF 3 COO-, C 1 -C 6 aliphatic carboxylic acid anion, or C 1 -C 6 aliphatic sulfonic acid anion.
  • R 1 and R 2 and/or R 5 and R 6 are combined in a 3-7 membered saturated ring.
  • the compound has a solubility greater than 200 ⁇ M.
  • the compound has a half-life greater than 1,500 minutes in simulated gastric fluid.
  • the compound has a half-life greater than 1,500 minutes in simulated gastric fluid with pepsin. [0013] In some embodiments, the compound has a half-life greater than 1,500 minutes in PBS (pH 6.5). [0014] In some embodiments, the compound further comprises a pharmaceutical carrier. [0015] In some embodiments, the compound is administered to a patient orally. [0016] In some embodiments, the compound is used to treat a neurological disease or condition.
  • the compound is synthesized by: reacting the tryptamine solution with Formula II: ATTORNEY DOCKET NO.: 100014_00074 wherein R 5 and R 6 is independently alkyl, cycloalkyl, heteroatom substituted or halogen substituted alkyl or cycloalkyl, aromatic or heteroaromatic.
  • the compound is synthesized by: reacting a tryptamine solution with Formula III: wherein R 5 , R 6 , and R 7 is independently hydrogen, deuterium, alkyl, cycloalkyl, heteroatom substituted or halogen substituted alkyl or cycloalkyl, aromatic or heteroaromatic.
  • the soft-drugs described herein are (partial) agonists in present form but are subsequently metabolized in vivo to known inactive metabolites, in an appropriate time interval. Also, these prodrugs hydrolyzed hydroxy methyl may act (partial) agonists for the serotonin receptors.
  • the present invention contains, but is not limited to, the compounds of Formula I: ATTORNEY DOCKET NO.: 100014_00074 wherein L is a counter ion; X, Y, and Z are independently hydrogen, deuterium, OR 1 , CO 2 R 1 , or NR 1 R 2 ; W is NR 1 , OR 1 , or CR 1 R 2 ; M is a CR 5 R 6 R 7 , OR 5 , or NR 5 R 6 ; and R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are independently hydrogen, deuterium, alkyl, cycloalkyl, heteroatom substituted and halogen substituted alkyl or cycloalkyl, aromatic, or heteroaromatic.
  • L is a counter ion
  • X, Y, and Z are independently hydrogen, deuterium, OR 1 , CO 2 R 1 , or NR 1 R 2
  • W is NR 1 , OR 1 , or CR 1
  • L is a Cl-, Br-, I-, CH 2 FCOO-, CF 3 COO-, C 1 -C 6 aliphatic carboxylic acid anion, or C 1 -C 6 aliphatic sulfonic acid anion.
  • R 1 and R 2 and/or R 5 and R 6 are combined in a 3-7 membered saturated ring.
  • Table 1 contains specific compounds of Formula I, Compounds 1-12, that overcome solubility and oral bioavailability issues with potential for treating mental health disorders.
  • Scheme 2 illustrates the general method of which all alkoxy quaternary amin salts in Table 1 can be synthesized by (Compounds 2 and 7-9).
  • EXAMPLE 1 [0026] Compound 1 was synthesized by following the method shown in Scheme 3: [0027] To a stirred mixture of chloromethyl chloroformate 3.1 (1.0 g, 7.7 mmol, 1.0 equiv.) in THF was added TEA (3.9 g, 38.7 mmol, 5.0 equiv.) and dimethylamine 3.2 (0.70 g, 15.5 mmol, 2.0 equiv.) dropwise at -20°C under an argon atmosphere.
  • the product (53mg) was further purified by reverse phase Preparative-HPLC; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 55% B in 8 min, to afford 12 mg of Compound 1, N-(((dimethylcarbamoyl)oxy) methyl)-2-(1H-indol-3-yl)- N,N-dimethylethan-1-aminium.
  • the resulting solution was diluted with 20 mL of saturated sodium bicarbonate and extracted with ethyl acetate (3 ⁇ 20 mL). The combined organic layers were washed with brine (2 ⁇ 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum.
  • the term "device,” as used herein, refers to an apparatus or system capable of delivering a drug to a patient in need thereof.
  • the term "in need of treatment” and the term “in need thereof” when referring to treatment are used interchangeably and refer to a judgment made by a caregiver (e.g. physician, nurse, nurse practitioner) that a patient will benefit from treatment.
  • the terms “treat” and “treatment” refer herein to therapeutic treatment, including prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change associated with a disease or condition.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of the extent of a disease or condition, stabilization of a disease or condition (i.e., where the disease or condition does not worsen), delay or slowing of the progression of a disease or condition, amelioration or palliation of the disease or condition, and remission (whether partial or total) of the disease or condition.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the disease or condition as well as those prone to having the disease or condition or those in which the disease or condition is to be prevented.
  • Treatment can, when concerning depression, also include reducing at least one sign or symptom of depression.
  • Examples of a sign or symptom of depression include depressed mood, diminished interest in activities, weight loss or gain, decrease or increase in appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, diminished ability to concentrate or indecisiveness, or suicidal ideation or behavior.
  • pharmaceutically acceptable refers to a component of a pharmaceutical composition that is compatible with the other ingredients of the formulation and not overly deleterious to the recipient thereof.
  • carrier' refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered and includes, but is not limited to, such liquids and powders that are hydrophilic substances, hydrophobic substances and substances that possess both hydrophilic and hydrophobic properties such as emulsifiers.
  • effective amount or “therapeutically effective amount” as used herein, refers to the amount of active agent that elicits the biological or medicinal response in a tissue, system, or individual that is being sought by a researcher, healthcare provider or individual.
  • neuropsychiatric disorder such as depression (including severe depression such as treatment-resistant depression, major depressive disorder and persistent depressive disorder), catatonic depression, a depressive disorder due to a medical condition, postpartum depression, premenstrual dysphoric disorder, or seasonal affective disorder, anxiety, anxiety disorder, social anxiety disorder, general anxiety disorder (GAD), avolition disorder, bipolar disorder (including bipolar I disorder and bipolar II disorder), post-traumatic stress disorder, body dysmorphic disorder, abnormalities of mood or emotion, including the above conditions, dysthymia, schizoaffective disorder, schizophrenia and other psychotic disorders, panic disorder, traumatic stress disorders, phobic disorders, and personality disorders with abnormal mood, such as borderline personality disorder, schizoid and schizotypal disorders and suicide ideation, or rumination/unproductive repetitive thoughts negatively impacting one's behavior/mood/ability to focus, obses
  • a neuropsychiatric disorder such as depression (including severe depression such as treatment-resistant depression, major depressive disorder and persistent
  • TRD treatment-resistant depression
  • MOD major depressive disorder

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des composés pharmaceutiques montrant un potentiel pour le traitement de troubles de la santé mentale, lesquels composés surmontent les problèmes de solubilité et de biodisponibilité orale pour jouer le rôle d'agonistes (partiels) du récepteur de la sérotonine du SNC, 5-HT2A.
PCT/US2024/026797 2023-04-27 2024-04-29 Sels d'amines quaternaires d'alcoxy et de carbamoyle utilisés comme promédicaments de trpytamines Pending WO2024227149A2 (fr)

Applications Claiming Priority (2)

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US202363576462P 2023-04-27 2023-04-27
US63/576,462 2023-04-27

Publications (2)

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WO2024227149A2 true WO2024227149A2 (fr) 2024-10-31
WO2024227149A3 WO2024227149A3 (fr) 2025-02-06

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12378194B2 (en) 2021-05-25 2025-08-05 Atai Therapeutics, Inc. N, n-dimethyltryptamine salts and crystalline salt forms
US12396982B2 (en) 2020-05-08 2025-08-26 Atai Therapeutics, Inc. Compositions of matter and pharmaceutical compositions

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20220137083A (ko) * 2020-02-04 2022-10-11 마인드셋 파마 인크. Cns 장애의 치료를 위한 세로토닌성 사이키델릭 작용제로서의 실로신 유도체
KR20230119028A (ko) * 2021-01-11 2023-08-14 캄테크, 인크. 4차 트립타민 및 이의 치료적 용도
JP2024522174A (ja) * 2021-06-09 2024-06-11 アタイ セラピューティクス， インコーポレイテッド ジメチルトリプタミンの新規プロドラッグおよびコンジュゲート
EP4137131A1 (fr) * 2021-08-17 2023-02-22 Centre National de la Recherche Scientifique (CNRS) Nouveaux analogues de sérotonine et leurs utilisations pour le traitement des troubles associés au fer
WO2024118767A2 (fr) * 2022-11-29 2024-06-06 Caamtech, Inc. Dérivés de tryptamine

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12396982B2 (en) 2020-05-08 2025-08-26 Atai Therapeutics, Inc. Compositions of matter and pharmaceutical compositions
US12472163B2 (en) 2020-05-08 2025-11-18 Atai Therapeutics, Inc. Compositions of matter and pharmaceutical compositions
US12378194B2 (en) 2021-05-25 2025-08-05 Atai Therapeutics, Inc. N, n-dimethyltryptamine salts and crystalline salt forms

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WO2024227149A3 (fr) 2025-02-06

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